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Sample records for a-induced oxidative liver

  1. Oxidative Stress and Liver Morphology in Experimental Cyclosporine A-Induced Hepatotoxicity.

    PubMed

    Korolczuk, Agnieszka; Caban, Kinga; Amarowicz, Magdalena; Czechowska, Grażyna; Irla-Miduch, Joanna

    2016-01-01

    Cyclosporine A is an immunosuppressive drug used after organ's transplantation. The adverse effects on such organs as kidney or liver may limit its use. Oxidative stress is proposed as one of the mechanisms of organs injury. The study was designed to elucidate CsA-induced changes in liver function, morphology, oxidative stress parameters, and mitochondria in rat's hepatocytes. Male Wistar rats were used: group A (control) receiving physiological saline, group B cyclosporine A in a dose of 15 mg/kg/day subcutaneously, and group C the CsA-vehicle (olive oil). On the 28th day rats were anesthetized. The following biochemical changes were observed in CsA-treated animals: increased levels of ALT, AST, and bilirubin in the serum, statistically significant changes in oxidative stress parameters, and lipid peroxidation products in the liver supernatants: MDA+4HAE, GSH, GSSG, caspase 3 activity, and ADP/ATP, NAD(+)/NADH, and NADP(+)/NADPH ratios. Microscopy of the liver revealed congestion, sinusoidal dilatation, and focal hepatocytes necrosis with mononuclear cell infiltration. Electron microscope revealed marked mitochondrial damage. Biochemical studies indicated that CsA treatment impairs liver function and triggers oxidative stress and redox imbalance in rats hepatocytes. Changes of oxidative stress markers parallel with mitochondrial damage suggest that these mechanisms play a crucial role in the course of CsA hepatotoxicity.

  2. Oxidative Stress and Liver Morphology in Experimental Cyclosporine A-Induced Hepatotoxicity

    PubMed Central

    Czechowska, Grażyna; Irla-Miduch, Joanna

    2016-01-01

    Cyclosporine A is an immunosuppressive drug used after organ's transplantation. The adverse effects on such organs as kidney or liver may limit its use. Oxidative stress is proposed as one of the mechanisms of organs injury. The study was designed to elucidate CsA-induced changes in liver function, morphology, oxidative stress parameters, and mitochondria in rat's hepatocytes. Male Wistar rats were used: group A (control) receiving physiological saline, group B cyclosporine A in a dose of 15 mg/kg/day subcutaneously, and group C the CsA-vehicle (olive oil). On the 28th day rats were anesthetized. The following biochemical changes were observed in CsA-treated animals: increased levels of ALT, AST, and bilirubin in the serum, statistically significant changes in oxidative stress parameters, and lipid peroxidation products in the liver supernatants: MDA+4HAE, GSH, GSSG, caspase 3 activity, and ADP/ATP, NAD+/NADH, and NADP+/NADPH ratios. Microscopy of the liver revealed congestion, sinusoidal dilatation, and focal hepatocytes necrosis with mononuclear cell infiltration. Electron microscope revealed marked mitochondrial damage. Biochemical studies indicated that CsA treatment impairs liver function and triggers oxidative stress and redox imbalance in rats hepatocytes. Changes of oxidative stress markers parallel with mitochondrial damage suggest that these mechanisms play a crucial role in the course of CsA hepatotoxicity. PMID:27298826

  3. Inflammation, oxidative stress and apoptosis cascade implications in bisphenol A-induced liver fibrosis in male rats.

    PubMed

    Elswefy, Sahar El-Sayed; Abdallah, Fatma Rizk; Atteia, Hebatallah Husseini; Wahba, Alaa Samir; Hasan, Rehab Abdallah

    2016-10-01

    Bisphenol A (BPA) is a key monomer in the production of plastics. It has been shown to be hepatotoxic. Inflammation and oxidative stress are closely linked with liver fibrosis, the major contributing factor to hepatic failure. Therefore, the aim of this study was to evaluate the impact of chronic exposure to BPA on the development of hepatic fibrosis in male rats and to determine the cross-talk between the hepatic cytokine network, oxidative stress and apoptosis. For this purpose, 30 male Wistar albino rats were divided into three equal groups as follows: the first group was given no treatment (normal control group); the second group was given corn oil once daily by oral gavage for 8 weeks (vehicle control group); and the third group received BPA (50 mg/kg body weight/day, p.o.) for 8 weeks. BPA administration induced liver fibrosis as reflected in an increase in serum hepatic enzymes activities, hepatic hydroxyproline content and histopathological changes particularly increased collagen fibre deposition around the portal tract. In addition, there was inflammation (as reflected in increase in interleukin-1beta 'IL-1β', decrease in interleukin-10 'IL-10' serum levels and increase in IL-1β/IL-10 ratio), oxidative stress (as reflected in increase in malondialdehyde (MDA) level, reduction in reduced glutathione (GSH) content and inhibition of catalase (CAT) activity) and apoptosis [as reflected in an increase in caspase-3 level and a decrease in numbers of B-cell lymphoma 2 (BCL2)-immunopositive hepatocytes]. Interestingly, BPA had an upregulating effect on an extracellular matrix turnover gene [as reflected in matrix metalloproteinase-9 (MMP-9)] and a downregulating effect on its inhibitor gene [as reflected in tissue inhibitor of matrix metalloproteinase-2 (TIMP-2)] expression. Thus, the mechanism by which BPA induced liver fibrosis seems to be related to stimulation of the inflammatory response, along with oxidative stress, the apoptotic pathway and activation

  4. Stellate Cells Orchestrate Concanavalin A-Induced Acute Liver Damage.

    PubMed

    Rani, Richa; Tandon, Ashish; Wang, Jiang; Kumar, Sudhir; Gandhi, Chandrashekhar R

    2017-09-01

    Concanavalin A (ConA) causes immune cell-mediated liver damage, but the contribution of resident nonparenchymal cells (NPCs) is also evident. Hepatic stellate cells (HSCs) induce hepatic inflammation and immunological reactions; we therefore investigated their role in ConA-induced liver injury. ConA was administered i.v. to control or HSC-depleted mice; hepatic histopathology and cytokines/chemokines were determined after 6 hours. In vitro, effects of ConA-conditioned HSC medium on hepatocytes were determined. ConA induced inflammation, sinusoidal congestion, and extensive midzonal hepatocyte death in control mice, which were strongly minimized in HSC-depleted mice. CD4 and natural killer T cells and neutrophils were markedly reduced in ConA-treated HSC-depleted mice compared with control mice. The increase in cytokines/chemokines of hepatic injury was much higher in ConA-treated control mice than in HSC-depleted mice. ConA-treated HSCs showed increased expression of interferon-β, tumor necrosis factor-α, and CXCL1, induced oxidative stress in hepatocytes, and caused hepatocyte apoptosis. ConA induced nuclear translocation of interferon-regulatory factor-1 (IRF1) in hepatocytes in vivo, and ConA/HSC induced a similar effect in cultured hepatocytes. IRF1-knockout mice were resistant to ConA-induced liver damage, and anti-interferon β antibody mitigated ConA/HSC-induced injury. In HSC-NPC co-culture, ConA-induced expression of inflammatory cytokines/chemokines was significantly augmented compared with NPCs alone. HSCs play an essential role in ConA-induced liver injury directly via the interferon-β/IRF1 axis, and by modulating properties of NPCs. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  5. Hepatoprotective effect of apple polyphenols against concanavalin A-induced immunological liver injury in mice.

    PubMed

    Wang, Fang; Xue, Yang; Yang, Jingyu; Lin, Fang; Sun, Ying; Li, Ting; Wu, Chunfu

    2016-10-25

    Apple polyphenols (AP), a polyphenol extracted from the unripe apple, has been reported to improve acute hepatotoxicity induced by CCl4 in mice due to its significant antioxidant activity. In this study, the hepatoprotective effect of AP against concanavalin A (Con A)-induced immunological liver injury in mice was investigated. Mice were treated with AP daily for seven days prior to a single intravenous administration of Con A. The serum levels of AST, ALT, TP, Alb and histopathological changes were determined and the A/G ratio was calculated. Potential mechanisms were further explored by measuring TNF-α and IFN-γ levels, NO content as well as changes in the levels of endogenous oxidants and antioxidants. AP significantly improved the abnormal levels of ALT, AST, TP and Alb, and the A/G ratio. AP was also associated with improvement of liver histopathological changes after Con A-induced liver injury. Moreover, AP reduced serum levels of TNF-α and IFN-γ, decreased serum NO content, inhibited oxidative DNA single-strand breaks, and improved the abnormalities of MDA content, SOD activity and GSH level. These results suggest that AP exerts a protective effect against Con A-induced immunological liver injury through suppressing pro-inflammatory cytokines and activating the antioxidant system.

  6. The Role of Oxidative Stress and Antioxidants in Liver Diseases.

    PubMed

    Li, Sha; Tan, Hor-Yue; Wang, Ning; Zhang, Zhang-Jin; Lao, Lixing; Wong, Chi-Woon; Feng, Yibin

    2015-11-02

    A complex antioxidant system has been developed in mammals to relieve oxidative stress. However, excessive reactive species derived from oxygen and nitrogen may still lead to oxidative damage to tissue and organs. Oxidative stress has been considered as a conjoint pathological mechanism, and it contributes to initiation and progression of liver injury. A lot of risk factors, including alcohol, drugs, environmental pollutants and irradiation, may induce oxidative stress in liver, which in turn results in severe liver diseases, such as alcoholic liver disease and non-alcoholic steatohepatitis. Application of antioxidants signifies a rational curative strategy to prevent and cure liver diseases involving oxidative stress. Although conclusions drawn from clinical studies remain uncertain, animal studies have revealed the promising in vivo therapeutic effect of antioxidants on liver diseases. Natural antioxidants contained in edible or medicinal plants often possess strong antioxidant and free radical scavenging abilities as well as anti-inflammatory action, which are also supposed to be the basis of other bioactivities and health benefits. In this review, PubMed was extensively searched for literature research. The keywords for searching oxidative stress were free radicals, reactive oxygen, nitrogen species, anti-oxidative therapy, Chinese medicines, natural products, antioxidants and liver diseases. The literature, including ours, with studies on oxidative stress and anti-oxidative therapy in liver diseases were the focus. Various factors that cause oxidative stress in liver and effects of antioxidants in the prevention and treatment of liver diseases were summarized, questioned, and discussed.

  7. The Role of Oxidative Stress and Antioxidants in Liver Diseases

    PubMed Central

    Li, Sha; Tan, Hor-Yue; Wang, Ning; Zhang, Zhang-Jin; Lao, Lixing; Wong, Chi-Woon; Feng, Yibin

    2015-01-01

    A complex antioxidant system has been developed in mammals to relieve oxidative stress. However, excessive reactive species derived from oxygen and nitrogen may still lead to oxidative damage to tissue and organs. Oxidative stress has been considered as a conjoint pathological mechanism, and it contributes to initiation and progression of liver injury. A lot of risk factors, including alcohol, drugs, environmental pollutants and irradiation, may induce oxidative stress in liver, which in turn results in severe liver diseases, such as alcoholic liver disease and non-alcoholic steatohepatitis. Application of antioxidants signifies a rational curative strategy to prevent and cure liver diseases involving oxidative stress. Although conclusions drawn from clinical studies remain uncertain, animal studies have revealed the promising in vivo therapeutic effect of antioxidants on liver diseases. Natural antioxidants contained in edible or medicinal plants often possess strong antioxidant and free radical scavenging abilities as well as anti-inflammatory action, which are also supposed to be the basis of other bioactivities and health benefits. In this review, PubMed was extensively searched for literature research. The keywords for searching oxidative stress were free radicals, reactive oxygen, nitrogen species, anti-oxidative therapy, Chinese medicines, natural products, antioxidants and liver diseases. The literature, including ours, with studies on oxidative stress and anti-oxidative therapy in liver diseases were the focus. Various factors that cause oxidative stress in liver and effects of antioxidants in the prevention and treatment of liver diseases were summarized, questioned, and discussed. PMID:26540040

  8. Nitric oxide in liver inflammation and regeneration.

    PubMed

    Martin-Sanz, Paloma; Hortelano, Sonsoles; Callejas, Nuria A; Goren, Nora; Casado, Marta; Zeini, Miriam; Boscá, Lisardo

    2002-12-01

    Hepatocytes express and release inflammatory mediators after challenge with bacterial cell wall molecules and proinflammatory cytokines. Nitric oxide synthase-2 (NOS-2) is expressed under these conditions and the high-output NO synthesis that follows contributes to the inflammatory response in this tissue and participates in the onset of several hepatopathies. However, in the course of liver regeneration, for example, after partial hepatectomy, NOS-2 is expressed at moderate levels and contributes to inhibit apoptosis and to favor progression in the cell cycle until the organ size and function are restored. The mechanisms involved in the regulation of NOS-2 expression under these conditions are revised.

  9. Influence of nutrition on liver oxidative metabolism.

    PubMed

    Jorquera, F; Culebras, J M; González-Gallego, J

    1996-06-01

    The liver plays a major role in the disposition of the majority of drugs. This is due to the presence of several drug-metabolizing enzyme systems, including a group of membrane-bound mixed-function oxidative enzymes, mainly the cytochrome P450 system. Hepatic oxidative capacity can be assessed by changes in antipyrine metabolism. Different drugs and other factors may induce or inhibit the cytochrome P450-dependent system. This effect is important in terms of the efficacy or toxicity of drugs that are substrates for the system. Microsomal oxidation in animals fed with protein-deficient diets is depressed. The mixed-function oxidase activity recovers after a hyperproteic diet or the addition of lipids. Similar findings have been reported in patients with protein-calorie malnutrition, although results in the elderly are conflicting. Different studies have revealed that microsomal oxidation is impaired by total parenteral nutrition and that this effect is absent when changing the caloric source from carbohydrates to a conventional amino acid solution or after lipid addition, especially when administered as medium-chain/long-chain triglyceride mixtures. Peripheral parenteral nutrition appears to increase antipyrine clearance.

  10. Bisphenol A Induces Hepatotoxicity through Oxidative Stress in Rat Model

    PubMed Central

    Hassan, Zeinab K.; Elobeid, Mai A.; Virk, Promy; Omer, Sawsan A.; ElAmin, Maha; Daghestani, Maha H.; AlOlayan, Ebtisam M.

    2012-01-01

    Reactive oxygen species (ROS) are cytotoxic agents that lead to significant oxidative damage. Bisphenol A (BPA) is a contaminant with increasing exposure to it and exerts both toxic and estrogenic effects on mammalian cells. Due to limited information concerning the effect of BPA on liver, this study investigates whether BPA causes hepatotoxicity by induction of oxidative stress in liver. Rats were divided into five groups: The first four groups, BPA (0.1, 1, 10, 50 mg/kg/day) were administrated orally to rats for four weeks. The fifth group was taken water with vehicle. The final body weights in the 0.1 mg group showed a significant decrease compared to control group. Significant decreased levels of reduced glutathione, superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and catalase activity were found in the 50 mg BPA group compared to control groups. High dose of BPA (50 mg/kg) significantly increased the biochemical levels of ALT, ALP and total bilirubin. BPA effect on the activity of antioxidant genes was confirmed by real time PCR in which the expression levels of these genes in liver tissue were significantly decrease compared to control. Data from this study demonstrate that BPA generate ROS and reduce the antioxidant gene expression that causes hepatotoxicity. PMID:22888396

  11. Preventive Effect of Halofuginone on Concanavalin A-Induced Liver Fibrosis

    PubMed Central

    Liang, Jie; Zhang, Bei; Shen, Ruo-wu; Liu, Jia-Bao; Gao, Mei-hua; Li, Ying; Li, Yuan-Yuan; Zhang, Wen

    2013-01-01

    Halofuginone (HF) is an active component of extracts derived from the plant alkaloid febrifugine and has shown therapeutic promise in animal models of fibrotic disease. Our main objectives were to clarify the suppressive effect of HF on concanavalin A (ConA)-induced liver fibrosis. ConA injection into the tail vein caused a great increase in the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, while orally administration of HF significantly decreased the levels of the transaminases. In addition, the levels of hyaluronic acid (HA), procollagen III (PCIII) and TGF-β1 in the serum and collagen I, α-SMA, tissue inhibitors of metalloproteinase 2 (TIMP2) and Smad3 in the liver tissue were significantly lowered with the treatment of HF. Histological examination also demonstrated that HF significantly reduced the severity of liver fibrosis. Since ConA-induced liver fibrosis is caused by the repeated activation of T cells, immunomodulatory substances might be responsible for the suppressive effect of HF. We found that the production of nuclear factor (NF)-kB in the serum was increased in ConA-treated group, while decreased significantly with the treatment of HF. The changes of inflammatory cytokines tumor necrosis factor (TNF-α), IL-6 and IL-1β in the serum followed the same rhythm. All together, our findings indicate that orally administration HF (10ppm) would attenuate the liver fibrosis by suppressing the synthesis of collagen I and inflammation-mediated liver injury. PMID:24358159

  12. Interleukin-22 contributes to liver regeneration in mice with concanavalin A-induced hepatitis after hepatectomy.

    PubMed

    Zhang, Ya-Min; Liu, Zi-Rong; Cui, Zi-Lin; Yang, Chao; Yang, Long; Li, Yang; Shen, Zhong-Yang

    2016-02-14

    To investigate the therapeutic effects and mechanisms of interleukin (IL)-22 in liver regeneration in mice with concanavalin A (ConA)-induced liver injury following 70% hepatectomy. Mice were injected intravenously with ConA at 10 μg/g body weight 4 d before 70% hepatectomy to create a hepatitis model, and recombinant IL-22 was injected at 0.125 μg/g body weight 30 min prior to 70% hepatectomy to create a therapy model. Control animals received an intravenous injection of an identical volume of normal saline. IL-22 treatment prior to 70% hepatectomy performed under general anesthesia resulted in reductions in the biochemical and histological evidence of liver injury, earlier proliferating cell nuclear antigen expression and accelerated recovery of liver mass. IL-22 pretreatment also significantly induced signal transducer and activator of transcription factor 3 (STAT3) activation and increased the expression of a variety of mitogenic proteins, such as Cyclin D1. Furthermore, alpha fetal protein mRNA expression was significantly elevated after IL-22 treatment. In this study, we demonstrated that IL-22 is a survival factor for hepatocytes and prevents and repairs liver injury by enhancing pro-growth pathways via STAT3 activation. Treatment with IL-22 protein may represent a novel therapeutic strategy for preventing liver injury in patients with liver disease who have undergone hepatectomy.

  13. Interleukin-22 contributes to liver regeneration in mice with concanavalin A-induced hepatitis after hepatectomy

    PubMed Central

    Zhang, Ya-Min; Liu, Zi-Rong; Cui, Zi-Lin; Yang, Chao; Yang, Long; Li, Yang; Shen, Zhong-Yang

    2016-01-01

    AIM: To investigate the therapeutic effects and mechanisms of interleukin (IL)-22 in liver regeneration in mice with concanavalin A (ConA)-induced liver injury following 70% hepatectomy. METHODS: Mice were injected intravenously with ConA at 10 μg/g body weight 4 d before 70% hepatectomy to create a hepatitis model, and recombinant IL-22 was injected at 0.125 μg/g body weight 30 min prior to 70% hepatectomy to create a therapy model. Control animals received an intravenous injection of an identical volume of normal saline. RESULTS: IL-22 treatment prior to 70% hepatectomy performed under general anesthesia resulted in reductions in the biochemical and histological evidence of liver injury, earlier proliferating cell nuclear antigen expression and accelerated recovery of liver mass. IL-22 pretreatment also significantly induced signal transducer and activator of transcription factor 3 (STAT3) activation and increased the expression of a variety of mitogenic proteins, such as Cyclin D1. Furthermore, alpha fetal protein mRNA expression was significantly elevated after IL-22 treatment. CONCLUSION: In this study, we demonstrated that IL-22 is a survival factor for hepatocytes and prevents and repairs liver injury by enhancing pro-growth pathways via STAT3 activation. Treatment with IL-22 protein may represent a novel therapeutic strategy for preventing liver injury in patients with liver disease who have undergone hepatectomy. PMID:26877612

  14. Oxidative stress as a crucial factor in liver diseases

    PubMed Central

    Cichoż-Lach, Halina; Michalak, Agata

    2014-01-01

    Redox state constitutes an important background of numerous liver disorders. The redox state participates in the course of inflammatory, metabolic and proliferative liver diseases. Reactive oxygen species (ROS) are primarily produced in the mitochondria and in the endoplasmic reticulum of hepatocytes via the cytochrome P450 enzymes. Under the proper conditions, cells are equipped with special molecular strategies that control the level of oxidative stress and maintain a balance between oxidant and antioxidant particles. Oxidative stress represents an imbalance between oxidant and antioxidant agents. Hepatocytic proteins, lipids and DNA are among the cellular structures that are primarily affected by ROS and reactive nitrogen species. The process results in structural and functional abnormalities in the liver. Thus, the phenomenon of oxidative stress should be investigated for several reasons. First, it may explain the pathogenesis of various liver disorders. Moreover, monitoring oxidative markers among hepatocytes offers the potential to diagnose the degree of liver damage and ultimately to observe the response to pharmacological therapies. The present report focuses on the role of oxidative stress in selected liver diseases. PMID:25009380

  15. Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver

    PubMed Central

    Satapati, Santhosh; Kucejova, Blanka; Duarte, Joao A.G.; Fletcher, Justin A.; Reynolds, Lacy; Sunny, Nishanth E.; He, Tianteng; Nair, L. Arya; Livingston, Kenneth; Fu, Xiaorong; Merritt, Matthew E.; Sherry, A. Dean; Malloy, Craig R.; Shelton, John M.; Lambert, Jennifer; Parks, Elizabeth J.; Corbin, Ian; Magnuson, Mark A.; Browning, Jeffrey D.; Burgess, Shawn C.

    2015-01-01

    Mitochondria are critical for respiration in all tissues; however, in liver, these organelles also accommodate high-capacity anaplerotic/cataplerotic pathways that are essential to gluconeogenesis and other biosynthetic activities. During nonalcoholic fatty liver disease (NAFLD), mitochondria also produce ROS that damage hepatocytes, trigger inflammation, and contribute to insulin resistance. Here, we provide several lines of evidence indicating that induction of biosynthesis through hepatic anaplerotic/cataplerotic pathways is energetically backed by elevated oxidative metabolism and hence contributes to oxidative stress and inflammation during NAFLD. First, in murine livers, elevation of fatty acid delivery not only induced oxidative metabolism, but also amplified anaplerosis/cataplerosis and caused a proportional rise in oxidative stress and inflammation. Second, loss of anaplerosis/cataplerosis via genetic knockdown of phosphoenolpyruvate carboxykinase 1 (Pck1) prevented fatty acid–induced rise in oxidative flux, oxidative stress, and inflammation. Flux appeared to be regulated by redox state, energy charge, and metabolite concentration, which may also amplify antioxidant pathways. Third, preventing elevated oxidative metabolism with metformin also normalized hepatic anaplerosis/cataplerosis and reduced markers of inflammation. Finally, independent histological grades in human NAFLD biopsies were proportional to oxidative flux. Thus, hepatic oxidative stress and inflammation are associated with elevated oxidative metabolism during an obesogenic diet, and this link may be provoked by increased work through anabolic pathways. PMID:26571396

  16. Effects of fasting on oxidative stress in rat liver mitochondria.

    PubMed

    Sorensen, M; Sanz, A; Gómez, J; Pamplona, R; Portero-Otín, M; Gredilla, R; Barja, G

    2006-04-01

    While moderate caloric restriction has beneficial effects on animal health state, fasting may be harmful. The present investigation was designed to test how fasting affects oxidative stress, and to find out whether the effects are opposite to those previously found in caloric restriction studies. We have focused on one of the main determinants of aging rate: the rate of mitochondrial free radical generation. Different parameters related to lipid and protein oxidative damage were also analyzed. Liver mitochondria from rats subjected to 72 h of fasting leaked more electrons per unit of O(2) consumed at complex III, than mitochondria from ad libitum fed rats. This increased leak led to a higher free radical generation under state 3 respiration using succinate as substrate. Regarding lipids, fasting altered fatty acid composition of hepatic membranes, increasing the double bond and the peroxidizability indexes. In accordance with this, we observed that hepatic membranes from the fasted animals were more sensitive to lipid peroxidation. Hepatic protein oxidative damage was also increased in fasted rats. Thus, the levels of oxidative modifications, produced either indirectly by reactive carbonyl compounds (N(epsilon)-malondialdehyde-lysine), or directly through amino acid oxidation (glutamic and aminoadipic semialdehydes) were elevated due to the fasting treatment in both liver tissue and liver mitochondria. The current study shows that severe food deprivation increases oxidative stress in rat liver, at least in part, by increasing mitochondrial free radical generation during state 3 respiration and by increasing the sensitivity of hepatic membranes to oxidative damage, suggesting that fasting and caloric restriction have different effects on liver mitochondrial oxidative stress.

  17. Melatonin protects rat liver against irradiation-induced oxidative injury.

    PubMed

    Koc, Mehmet; Taysi, Seyithan; Buyukokuroglu, Mehmet Emin; Bakan, Nuri

    2003-09-01

    The aim of this study was to investigate the antioxidant roles of different doses of melatonin (5 and 10 mg x kg (-1) ) against gamma-irradiation-caused oxidative damage in liver tissue after total body irradiation (TBI) with a single dose of 6.0 Gy. Fifty adult rats were divided into 5 equal groups, 10 rats each. Groups I and II were injected with 5 and 10 mg x kg (-1) of melatonin, and group III was injected with an isotonic NaCl solution. Group IV was injected with only 5 mg x kg (-1) of melatonin. Group V was reserved as a sham control. Following a 30-min-period, 6.0 Gy TBI was given to groups 1, 2 and 3 in a single fraction. The liver malondialdehyde (MDA) levels, super oxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were measured in all groups. TBI resulted in a significant increase in the liver tissue MDA levels and a decrease of SOD and GSH-Px activities. The results demonstrated that the liver tissue MDA levels in irradiated rats that were pretreated with melatonin (5 or 10 mg x kg (-1) ) were significantly decreased, while the SOD and GSH-Px activities were significantly increased. Decreasing the MDA levels by melatonin was dose dependent, but the liver tissue SOD and GSH activities were not. The data obtained in this study suggest that melatonin administration prior to irradiation may prevent liver damage by irradiation.

  18. OXIDATIVE PHOSPHORYLATION IN MITOCHONDRIA FROM LIVERS SHOWING CLOUDY SWELLING

    PubMed Central

    Fonnesu, Alberto; Severi, Clara

    1956-01-01

    Using succinate and α-ketoglutarate as substrates, oxidative phosphorylation has been measured in mitochondria isolated from livers showing cloudy swelling. This cellular change was obtained by injecting rats with S. typhi murium toxin and guinea pigs with diphtheria toxin. It has been found that phosphorylation associated with the oxidation of either of these substrates was partially inhibited in mitochondria from livers showing cloudy swelling, while the oxygen consumption was unchanged. Thus, the P:O ratios for both succinate and α-ketoglutarate were lower in mitochondria from treated animals than they were in normal mitochondria. Dephosphorylation of ATP was not significantly modified in mitochondria from livers showing cloudy swelling as compared with normal controls. No dephosphorylation of AMP and G-6-P was observed either in normal mitochondria or in mitochondria from treated animals. PMID:13331961

  19. Stimuli-responsive electrodes detect oxidative stress and liver injury.

    PubMed

    Aran, Kiana; Parades, Jacobo; Rafi, Mohammad; Yau, Jennifer F; Acharya, Abhinav P; Zibinsky, Mikhail; Liepmann, Dorian; Murthy, Niren

    2015-02-25

    A digital point-of-care biosensor for measuring reactive oxygen species is presented based on novel reactive oxygen species responsive polymer-based electrodes. The biosensor is able to detect a drug-induced liver injury by monitoring the oxidative stress in the blood.

  20. Polyaspartic acid coated manganese oxide nanoparticles for efficient liver MRI.

    PubMed

    Xing, Ruijun; Zhang, Fan; Xie, Jin; Aronova, Maria; Zhang, Guofeng; Guo, Ning; Huang, Xinglu; Sun, Xiaolian; Liu, Gang; Bryant, L Henry; Bhirde, Ashwinkumar; Liang, Amy; Hou, Yanglong; Leapman, Richard D; Sun, Shouheng; Chen, Xiaoyuan

    2011-12-01

    We report in this communication a simple, facile surface modification strategy to transfer hydrophobic manganese oxide nanoparticles (MONPs) into water by using polyaspartic acid (PASP). We systematically investigated the effect of the size of PASP-MONPs on MRI of normal liver and found that the particles with a core size of 10 nm exhibited greater enhancement than those with larger core sizes.

  1. Enzymatic oxidation of phthalazine with guinea pig liver aldehyde oxidase and liver slices: inhibition by isovanillin.

    PubMed

    Panoutsopoulos, Georgios I; Beedham, Christine

    2004-01-01

    The enzymes aldehyde oxidase and xanthine oxidase catalyze the oxidation of a wide range of N-heterocycles and aldehydes. These enzymes are widely known for their role in the metabolism of N-heterocyclic xenobiotics where they provide a protective barrier by aiding in the detoxification of ingested nitrogen-containing heterocycles. Isovanillin has been shown to inhibit the metabolism of aromatic aldehydes by aldehyde oxidase, but its inhibition towards the heterocyclic compounds has not been studied. The present investigation examines the oxidation of phthalazine in the absence and in the presence of the inhibitor isovanillin by partially purified aldehyde oxidase from guinea pig liver. In addition, the interaction of phthalazine with freshly prepared guinea pig liver slices, both in the absence and presence of specific inhibitors of several liver oxidizing enzymes, was investigated. ldehyde oxidase rapidly converted phthalazine into 1-phthalazinone, which was completely inhibited in the presence of isovanillin (a specific inhibitor of aldehyde oxidase). In freshly prepared liver slices, phthalazine was also rapidly converted to 1-phthalazinone. The formation of 1-phthalazinone was completely inhibited by isovanillin, whereas disulfiram (a specific inhibitor of aldehyde dehydrogenase) only inhibited 1-phthalazinone formation by 24% and allopurinol (a specific inhibitor of xanthine oxidase) had little effect. Therefore, isovanillin has been proved as an inhibitor of the metabolism of heterocyclic substrates, such as phthalazine, by guinea pig liver aldehyde oxidase, since it had not been tested before. Thus it would appear from the inhibitor results that aldehyde oxidase is the predominant enzyme in the oxidation of phthalazine to 1-phthalazinone in freshly prepared guinea pig liver slices, whereas xanthine oxidase only contributes to a small extent and aldehyde dehydrogenase does not take any part.

  2. Oxidation of hydrogen sulfide by human liver mitochondria.

    PubMed

    Helmy, Nada; Prip-Buus, Carina; Vons, Corinne; Lenoir, Véronique; Abou-Hamdan, Abbas; Guedouari-Bounihi, Hala; Lombès, Anne; Bouillaud, Frédéric

    2014-09-15

    Hydrogen sulfide (H2S) is the third gasotransmitter discovered. Sulfide shares with the two others (NO and CO) the same inhibiting properties towards mitochondrial respiration. However, in contrast with NO or CO, sulfide at concentrations lower than the toxic (μM) level is an hydrogen donor and a substrate for mitochondrial respiration. This is due to the activity of a sulfide quinone reductase found in a large majority of mitochondria. An ongoing study of the metabolic state of liver in obese patients allowed us to evaluate the sulfide oxidation capacity with twelve preparations of human liver mitochondria. The results indicate relatively high rates of sulfide oxidation with a large variability between individuals. These observations made with isolated mitochondria appear in agreement with the main characteristics of sulfide oxidation as established before with the help of cellular models.

  3. Hepatic NK cell-mediated hypersensitivity to ConA-induced liver injury in mouse liver expressing hepatitis C virus polyprotein.

    PubMed

    Fu, Qiuxia; Yan, Shaoduo; Wang, Licui; Duan, Xiangguo; Wang, Lei; Wang, Yue; Wu, Tao; Wang, Xiaohui; An, Jie; Zhang, Yulong; Zhou, Qianqian; Zhan, Linsheng

    2016-08-04

    The role of hepatic NK cells in the pathogenesis of HCV-associated hepatic failure is incompletely understood. In this study, we investigated the effect of HCV on ConA-induced immunological hepatic injury and the influence of HCV on hepatic NK cell activation in the liver after ConA administration. An immunocompetent HCV mouse model that encodes the entire viral polyprotein in a liver-specific manner based on hydrodynamic injection and φC31o integrase was used to study the role of hepatic NK cells. Interestingly, the frequency of hepatic NK cells was reduced in HCV mice, whereas the levels of other intrahepatic lymphocytes remained unaltered. Next, we investigated whether the reduction in NK cells within HCV mouse livers might elicit an effect on immune-mediated liver injury. HCV mice were subjected to acute liver injury models upon ConA administration. We observed that HCV mice developed more severe ConA-induced immune-mediated hepatitis, which was dependent on the accumulated intrahepatic NK cells. Our results indicated that after the administration of ConA, NK cells not only mediated liver injury through the production of immunoregulatory cytokines (IFN-γ, TNF-α and perforin) with direct antiviral activity, but they also killed target cells directly through the TRAIL/DR5 and NKG2D/NKG2D ligand signaling pathway in HCV mice. Our findings suggest a critical role for NK cells in oversensitive liver injury during chronic HCV infection.

  4. Coronin 1 is dispensable for leukocyte recruitment and liver injury in concanavalin A-induced hepatitis.

    PubMed

    Siegmund, Kerstin; Lee, Woo-Yong; Tchang, Vincent S; Stiess, Michael; Terracciano, Luigi; Kubes, Paul; Pieters, Jean

    2013-06-01

    Coronin 1, a member of the evolutionary conserved coronin protein family, is highly expressed in all leukocytes. In mice and human, genetic inactivation of coronin 1 results in immuno-deficiencies that are linked to a strong reduction of naïve T cell numbers in peripheral organs, while memory/effector T cells, B cells, monocytes and neutrophils are less or not at all affected. Whether or not coronin 1 is important for leukocyte functions such as migration and phagocytosis has been a matter of debate. The current work addresses coronin 1-dependent leukocyte function by analyzing the response of coronin 1-deficient mice in a model of concanavalin A (Con A)-induced liver injury. Histological evaluation and determination of serum liver enzyme levels showed that coronin 1-deficient mice develop signs of acute hepatitis similar to Con A-treated wild type mice despite a reduced activation of T cells in the absence of coronin 1. Furthermore, analysis by intravital microscopy following Con A stimulation revealed that Gr-1+ neutrophils and CD4+ T cell adhesion in the post-sinusoidal venules increased in wild type as well as in coronin 1-deficient mice. These results suggest that coronin 1, while important for naïve T cell survival, is dispensable for other leukocyte function under inflammatory conditions in vivo. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. Hepatoprotective Effects of Nicotiflorin from Nymphaea candida against Concanavalin A-Induced and d-Galactosamine-Induced Liver Injury in Mice

    PubMed Central

    Zhao, Jun; Zhang, Shilei; You, Shuping; Liu, Tao; Xu, Fang; Ji, Tengfei; Gu, Zhengyi

    2017-01-01

    Nymphaea candida was used to treat hepatitis in Ugyhur medicine, and nicotiflorin (kaempferol 3-O-β-rutinoside) is the main characteristic component in this plant. In this study, The the hepatoprotective activities of nicotiflorin from N. candida were investigated by Concanavalin A (Con A, 20 mg/kg bw)- and d-Galactosamine (d-GalN, 800 mg/kg bw)-induced acute liver injury in mice. Pretreatment with nicotiflorin (25, 50, 100 mg/kg bw/day, p.o.) for ten days significantly reduced the impact of Con A toxicity (20 mg/kg bw) on the serum markers of liver injury, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). The hepatic anti-oxidant parameters (malondialdehyde, MDA; superoxide dismutase, SOD; glutathione, GSH; and nitric oxide, NO) in mice with nicotiflorin treatment were significantly antagonized for the pro-oxidant effects of Con A. Moreover, pretreatment with nicotiflorin (100 mg/kg bw) significantly decreased Con A-induced elevation in the serum levels of pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) (p < 0.05). A protective effect was reconfirmed against d-GalN-induced chemical liver injury, elevated serum enzymatic and cytokines levels were significantly decreased by nicotiflorin, and liver homogenate antioxidant indicators were significantly restored toward normal levels. Both histopathological studies also supported the protective effects of nicotiflorin. Therefore, the presented results suggest that nicotiflorin is the potent hepatoprotective agent that could protect the liver against acute immunological and chemical injury; this ability might be attributed to its antioxidant and immunoregulation potential. PMID:28282879

  6. CONTROL OF GLUTAMATE OXIDATION IN BRAIN AND LIVER MITOCHONDRIAL SYSTEMS.

    PubMed

    BALAZS, R

    1965-05-01

    1. Glutamate oxidation in brain and liver mitochondrial systems proceeds mainly through transamination with oxaloacetate followed by oxidation of the alpha-oxoglutarate formed. Both in the presence and absence of dinitrophenol in liver mitochondria this pathway accounted for almost 80% of the uptake of glutamate. In brain preparations the transamination pathway accounted for about 90% of the glutamate uptake. 2. The oxidation of [1-(14)C]- and [5-(14)C]-glutamate in brain preparations is compatible with utilization through the tricarboxylic acid cycle, either after the formation of alpha-oxoglutarate or after decarboxylation to form gamma-aminobutyrate. There is no indication of gamma-decarboxylation of glutamate. 3. The high respiratory control ratio obtained with glutamate as substrate in brain mitochondrial preparations is due to the low respiration rate in the absence of ADP: this results from the low rate of formation of oxaloacetate under these conditions. When oxaloacetate is made available by the addition of malate or of NAD(+), the respiration rate is increased to the level obtained with other substrates. 4. When the transamination pathway of glutamate oxidation was blocked with malonate, the uptake of glutamate was inhibited in the presence of ADP or ADP plus dinitrophenol by about 70 and 80% respectively in brain mitochondrial systems, whereas the inhibition was only about 50% in dinitrophenol-stimulated liver preparations. In unstimulated liver mitochondria in the presence of malonate there was a sixfold increase in the oxidation of glutamate by the glutamate-dehydrogenase pathway. Thus the operating activity of glutamate dehydrogenase is much less than the ;free' (non-latent) activity. 5. The following explanation is put forward for the control of glutamate metabolism in liver and brain mitochondrial preparations. The oxidation of glutamate by either pathway yields alpha-oxoglutarate, which is further metabolized. Since aspartate aminotransferase is

  7. Polyaspartic acid coated manganese oxide nanoparticles for efficient liver MRI

    NASA Astrophysics Data System (ADS)

    Xing, Ruijun; Zhang, Fan; Xie, Jin; Aronova, Maria; Zhang, Guofeng; Guo, Ning; Huang, Xinglu; Sun, Xiaolian; Liu, Gang; Bryant, L. Henry; Bhirde, Ashwinkumar; Liang, Amy; Hou, Yanglong; Leapman, Richard D.; Sun, Shouheng; Chen, Xiaoyuan

    2011-12-01

    We report in this communication a simple, facile surface modification strategy to transfer hydrophobic manganese oxide nanoparticles (MONPs) into water by using polyaspartic acid (PASP). We systematically investigated the effect of the size of PASP-MONPs on MRI of normal liver and found that the particles with a core size of 10 nm exhibited greater enhancement than those with larger core sizes.We report in this communication a simple, facile surface modification strategy to transfer hydrophobic manganese oxide nanoparticles (MONPs) into water by using polyaspartic acid (PASP). We systematically investigated the effect of the size of PASP-MONPs on MRI of normal liver and found that the particles with a core size of 10 nm exhibited greater enhancement than those with larger core sizes. Electronic supplementary information (ESI) available. See DOI: 10.1039/c1nr11242b

  8. Oxidative Stress and Liver Cancer: Etiology and Therapeutic Targets

    PubMed Central

    Wang, Zhanpeng; Li, Zhuonan; Ye, Yanshuo; Xie, Lijuan

    2016-01-01

    Accumulating evidence has indicated that oxidative stress (OS) is associated with the development of hepatocellular carcinoma (HCC). However, the mechanisms remain largely unknown. Normally, OS occurs when the body receives any danger signal—from either an internal or external source—and further induces DNA oxidative damage and abnormal protein expression, placing the body into a state of vulnerability to the development of various diseases such as cancer. There are many factors involved in liver carcinogenesis, including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, alcohol abuse, and nonalcoholic fatty liver disease (NAFLD). The relationship between OS and HCC has recently been attracting increasing attention. Therefore, elucidation of the impact of OS on the development of liver carcinogenesis is very important for the prevention and treatment of liver cancer. This review focuses mainly on the relationship between OS and the development of HCC from the perspective of cellular and molecular mechanisms and the etiology and therapeutic targets of HCC. PMID:27957239

  9. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

    PubMed Central

    Gentric, Géraldine; Maillet, Vanessa; Paradis, Valérie; Couton, Dominique; L’Hermitte, Antoine; Panasyuk, Ganna; Fromenty, Bernard; Celton-Morizur, Séverine; Desdouets, Chantal

    2015-01-01

    Polyploidization is one of the most dramatic changes that can occur in the genome. In the liver, physiological polyploidization events occur during both liver development and throughout adult life. Here, we determined that a pathological polyploidization takes place in nonalcoholic fatty liver disease (NAFLD), a widespread hepatic metabolic disorder that is believed to be a risk factor for hepatocellular carcinoma (HCC). In murine models of NAFLD, the parenchyma of fatty livers displayed alterations of the polyploidization process, including the presence of a large proportion of highly polyploid mononuclear cells, which are rarely observed in normal hepatic parenchyma. Biopsies from patients with nonalcoholic steatohepatitis (NASH) revealed the presence of alterations in hepatocyte ploidy compared with tissue from control individuals. Hepatocytes from NAFLD mice revealed that progression through the S/G2 phases of the cell cycle was inefficient. This alteration was associated with activation of a G2/M DNA damage checkpoint, which prevented activation of the cyclin B1/CDK1 complex. Furthermore, we determined that oxidative stress promotes the appearance of highly polyploid cells, and antioxidant-treated NAFLD hepatocytes resumed normal cell division and returned to a physiological state of polyploidy. Collectively, these findings indicate that oxidative stress promotes pathological polyploidization and suggest that this is an early event in NAFLD that may contribute to HCC development. PMID:25621497

  10. Creatine supplementation and oxidative stress in rat liver

    PubMed Central

    2013-01-01

    Background The objective of this study was to determine the effects of creatine supplementation on liver biomarkers of oxidative stress in exercise-trained rats. Methods Forty 90-day-old adult male Wistar rats were assigned to four groups for the eight-week experiment. Control group (C) rats received a balanced control diet; creatine control group (CCr) rats received a balanced diet supplemented with 2% creatine; trained group (T) rats received a balanced diet and intense exercise training equivalent to the maximal lactate steady state phase; and supplemented-trained (TCr) rats were given a balanced diet supplemented with 2% creatine and subjected to intense exercise training equivalent to the maximal lactate steady state phase. At the end of the experimental period, concentrations of creatine, hydrogen peroxide (H2O2) and thiobarbituric acid reactive substances (TBARS) were measured as well as the enzyme activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-GPx) and catalase (CAT). Liver tissue levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and the GSH/GSSG ratio were also determined. Results Hepatic creatine levels were highest in the CCr and TCr groups with increased concentration of H2O2 observed in the T and TCr animal groups. SOD activity was decreased in the TCr group. GSH-GPx activity was increased in the T and TCr groups while CAT was elevated in the CCr and TCr groups. GSH, GGS and the GSH/GSSG ratio did not differ between all animal subsets. Conclusions Our results demonstrate that creatine supplementation acts in an additive manner to physical training to raise antioxidant enzymes in rat liver. However, because markers of liver oxidative stress were unchanged, this finding may also indicate that training-induced oxidative stress cannot be ameliorated by creatine supplementation. PMID:24325803

  11. Polyaspartic acid coated manganese oxide nanoparticles for efficient liver MRI†

    PubMed Central

    Xing, Ruijun; Zhang, Fan; Xie, Jin; Aronova, Maria; Zhang, Guofeng; Guo, Ning; Huang, Xinglu; Sun, Xiaolian; Liu, Gang; Bryant, L. Henry; Bhirde, Ashwinkumar; Liang, Amy; Hou, Yanglong; Leapman, Richard D.; Sun, Shouheng; Chen, Xiaoyuan

    2013-01-01

    We report in this communication a simple, facile surface modification strategy to transfer hydrophobic manganese oxide nanoparticles (MONPs) into water by using polyaspartic acid (PASP). We systematically investigated the effect of the size of PASP-MONPs on MRI of normal liver and found that the particles with a core size of 10 nm exhibited greater enhancement than those with larger core sizes. PMID:22064945

  12. Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in the liver[S

    PubMed Central

    Moffat, Cynthia; Bhatia, Lavesh; Nguyen, Teresa; Lynch, Peter; Wang, Miao; Wang, Dongning; Ilkayeva, Olga R.; Han, Xianlin; Hirschey, Matthew D.; Claypool, Steven M.; Seifert, Erin L.

    2014-01-01

    Acyl-CoA thioesterase (Acot)2 localizes to the mitochondrial matrix and hydrolyses long-chain fatty acyl-CoA into free FA and CoASH. Acot2 is expressed in highly oxi­dative tissues and is poised to modulate mitochondrial FA oxidation (FAO), yet its biological role is unknown. Using a model of adenoviral Acot2 overexpression in mouse liver (Ad-Acot2), we show that Acot2 increases the utilization of FA substrate during the daytime in ad libitum-fed mice, but the nighttime switch to carbohydrate oxidation is similar to control mice. In further support of elevated FAO in Acot2 liver, daytime serum ketones were higher in Ad-Acot2 mice, and overnight fasting led to minimal hepatic steatosis as compared with control mice. In liver mitochondria from Ad-Acot2 mice, phosphorylating O2 consumption was higher with lipid substrate, but not with nonlipid substrate. This increase depended on whether FA could be activated on the outer mitochondrial membrane, suggesting that the FA released by Acot2 could be effluxed from mitochondria then taken back up again for oxidation. This circuit would prevent the build-up of inhibitory long-chain fatty acyl-CoA esters. Altogether, our findings indicate that Acot2 can enhance FAO, possibly by mitigating the accumulation of FAO intermediates within the mitochondrial matrix. PMID:25114170

  13. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

    PubMed Central

    Ceni, Elisabetta; Mello, Tommaso; Galli, Andrea

    2014-01-01

    Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell

  14. Transport and oxidation of choline by liver mitochondria

    PubMed Central

    Tyler, D. D.

    1977-01-01

    1. Rapid choline oxidation and the onset of Pi-induced swelling by liver mitochondria, incubated in a sucrose medium at or above pH7.0, required the addition of both Pi and an uncoupling agent. Below pH7.0, Pi alone was required for rapid choline oxidation and swelling. 2. Choline oxidation was inhibited by each of several reagents that also inhibited Pi-induced swelling under similar conditions of incubation, including EGTA, mersalyl, Mg2+, the Ca2+-ionophore A23187, rotenone and nupercaine. None of these reagents had any significant effect on the rate of choline oxidation by sonicated mitochondria. There was therefore a close correlation between the conditions required for rapid choline oxidation and for Pi-induced swelling to occur, suggesting that in the absence of mitochondrial swelling the rate of choline oxidation is regulated by the rate of choline transport across the mitochondrial membrane. 3. Respiratory-chain inhibitors, uncoupling agents (at pH6.5) and ionophore A23187 caused a loss of endogenous Ca2+ from mitochondria, whereas nupercaine and Mg2+ had no significant effect on the Ca2+ content. Inhibition of choline oxidation and mitochondrial swelling by ionophore A23187 was reversed by adding Ca2+, but not by Mg2+. It is concluded that added Pi promotes the Ca2+-dependent activation of mitochondrial membrane phospholipase activity in respiring mitochondria, causing an increase in the permeability of the mitochondrial inner membrane to choline and therefore enabling rapid choline oxidation to occur. Nupercaine and Mg2+ appear to block choline oxidation and swelling by inhibiting phospholipase activity. 4. Choline was oxidized slowly by tightly coupled mitochondria largely depleted of their endogenous adenine nucleotides, suggesting that these compounds are not directly concerned in the regulation of choline oxidation. 5. The results are discussed in relation to the possible mechanism of choline transport across the mitochondrial membrane in vivo and

  15. Oxidative metabolism of cinnarizine in rat liver microsomes.

    PubMed

    Kariya, S; Isozaki, S; Narimatsu, S; Suzuki, T

    1992-10-06

    The oxidative metabolism of cinnarizine (CZ) [1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)-piperazine] to 1-(diphenylmethyl)piperazine (M-1), 1-(diphenylmethyl)-4-[3-(4'-hydroxyphenyl)-2-propenyl]piperazine (M-2), benzophenone (M-3) and 1-[4'-hydroxyphenyl)-phenylmethyl]-4-(3- phenyl-2-propenyl)piperazine (M-4) has been studied in rat liver microsomes. In Wistar rats, kinetic analysis revealed sex differences (male > female) in the Km values for formation of all the metabolites and the Vmax values for the formation of M-1, M-3 and M-4. The reactions required NADPH, and were inhibited by carbon monoxide and SKF 525-A. Only M-2 formation was suppressed by sparteine or metoprolol, and was significantly lower in female Dark Agouti rats than in Wistar rats of both sexes. The results suggest that CZ is oxidized by cytochrome P450, and M-2 formation is related to debrisoquine/sparteine-type polymorphic drug oxidation.

  16. Pathogenesis of liver fibrosis: role of oxidative stress.

    PubMed

    Poli, G

    2000-06-01

    In the liver, the progressive accumulation of connective tissue, a complex and dynamic process termed fibrosis, represents a very frequent event following a repeated or chronic insult of sufficient intensity to trigger a "wound healing"-like reaction. The fibrotic process recognises the involvement of various cells and different factors in bringing about an excessive fibrogenesis with disruption of intercellular contacts and interactions and of extracellular matrix composition. However, Kupffer cells, together with recruited mononuclear cells, and hepatic stellate cells are by far the key-players in liver fibrosis. Their cross-talk is triggered and favoured by a series of chemical mediators, with a prominent role played by the transforming growth factor beta. Both expression and synthesis of this inflammatory and pro-fibrogenic cytokine are mainly modulated through redox-sensitive reactions. Further, involvement of reactive oxygen species and lipid peroxidation products can be clearly demonstrated in other fundamental events of hepatic fibrogenesis, like activation and effects of stellate cells, expression of metalloproteinases and of their specific inhibitors. The important outcome of such findings as regards the pathogenesis of liver fibrosis derives from the observation of a consistent and marked oxidative stress condition in many if not all chronic disease processes affecting hepatic tissue. Hence, reactive oxidant species likely contribute to both onset and progression of fibrosis as induced by alcohol, viruses, iron or copper overload, cholestasis, hepatic blood congestion.

  17. Behavior of Oxidative Stress Markers in Alcoholic Liver Cirrhosis Patients

    PubMed Central

    Galicia-Moreno, Marina; Rosique-Oramas, Dorothy; Medina-Avila, Zaira; Álvarez-Torres, Tania; Falcón, Dalia; Higuera-de la tijera, Fátima; Béjar, Yadira L.; Cordero-Pérez, Paula; Muñoz-Espinosa, Linda; Pérez-Hernández, José Luis; Kershenobich, David

    2016-01-01

    Alcohol is the most socially accepted addictive substance worldwide, and its metabolism is related with oxidative stress generation. The aim of this work was to evaluate the role of oxidative stress in alcoholic liver cirrhosis (ALC). This study included 187 patients divided into two groups: ALC, classified according to Child-Pugh score, and a control group. We determined the levels of reduced and oxidized glutathione (GSH and GSSG) and the GSH/GSSG ratio by an enzymatic method in blood. Also, protein carbonyl and malondialdehyde (MDA) content were estimated in serum. MDA levels increased in proportion to the severity of damage, whereas the GSH and GSSG levels decreased and increased, respectively, at different stages of cirrhosis. There were no differences in the GSH/GSSG ratio and carbonylated protein content between groups. We also evaluated whether the active consumption of or abstinence from alcoholic beverages affected the behavior of these oxidative markers and only found differences in the MDA, GSH, and GSSG determination and the GSH/GSSG ratio. Our results suggest that alcoholic cirrhotic subjects have an increase in oxidative stress in the early stages of disease severity and that abstinence from alcohol consumption favors the major antioxidant endogen: GSH in patients with advanced disease severity. PMID:28074118

  18. Behavior of Oxidative Stress Markers in Alcoholic Liver Cirrhosis Patients.

    PubMed

    Galicia-Moreno, Marina; Rosique-Oramas, Dorothy; Medina-Avila, Zaira; Álvarez-Torres, Tania; Falcón, Dalia; Higuera-de la Tijera, Fátima; Béjar, Yadira L; Cordero-Pérez, Paula; Muñoz-Espinosa, Linda; Pérez-Hernández, José Luis; Kershenobich, David; Gutierrez-Reyes, Gabriela

    2016-01-01

    Alcohol is the most socially accepted addictive substance worldwide, and its metabolism is related with oxidative stress generation. The aim of this work was to evaluate the role of oxidative stress in alcoholic liver cirrhosis (ALC). This study included 187 patients divided into two groups: ALC, classified according to Child-Pugh score, and a control group. We determined the levels of reduced and oxidized glutathione (GSH and GSSG) and the GSH/GSSG ratio by an enzymatic method in blood. Also, protein carbonyl and malondialdehyde (MDA) content were estimated in serum. MDA levels increased in proportion to the severity of damage, whereas the GSH and GSSG levels decreased and increased, respectively, at different stages of cirrhosis. There were no differences in the GSH/GSSG ratio and carbonylated protein content between groups. We also evaluated whether the active consumption of or abstinence from alcoholic beverages affected the behavior of these oxidative markers and only found differences in the MDA, GSH, and GSSG determination and the GSH/GSSG ratio. Our results suggest that alcoholic cirrhotic subjects have an increase in oxidative stress in the early stages of disease severity and that abstinence from alcohol consumption favors the major antioxidant endogen: GSH in patients with advanced disease severity.

  19. Ochratoxin A induces rat renal carcinogenicity with limited induction of oxidative stress responses

    SciTech Connect

    Qi, Xiaozhe; Yu, Tao; Zhu, Liye; Gao, Jing; He, Xiaoyun; Huang, Kunlun; Luo, Yunbo; Xu, Wentao

    2014-11-01

    Ochratoxin A (OTA) has displayed nephrotoxicity and renal carcinogenicity in mammals, however, no clear mechanisms have been identified detailing the relationship between oxidative stress and these toxicities. This study was performed to clarify the relationship between oxidative stress and the renal carcinogenicity induced by OTA. Rats were treated with 70 or 210 μg/kg b.w. OTA for 4 or 13 weeks. In the rats administrated with OTA for 13 weeks, the kidney was damaged seriously. Cytoplasmic vacuolization was observed in the outer stripe of the outer medulla. Karyomegaly was prominent in the tubular epithelium. Kidney injury molecule-1 (Kim-1) was detected in the outer stripe of the outer medulla in both low- and high-dose groups. OTA increased the mRNA levels of clusterin in rat kidneys. Interestingly, OTA did not significantly alter the oxidative stress level in rat liver and kidney. Yet, some indications related to proliferation and carcinogenicity were observed. A dose-related increase in proliferating cell nuclear antigen (PCNA) was observed at 4 weeks in both liver and kidney, but at 13 weeks, only in the kidney. OTA down-regulated reactive oxygen species (ROS) and up-regulated vimentin and lipocalin 2 in rat kidney at 13 weeks. The p53 gene was decreased in both liver and kidney at 13 weeks. These results suggest that OTA caused apparent kidney damage within 13 weeks but exerted limited effect on oxidative stress parameters. It implies that cell proliferation is the proposed mode of action for OTA-induced renal carcinogenicity. - Highlights: • We studied OTA toxicities in both the rat liver and kidney for 13 weeks. • OTA exerts limited effects on oxidative stress in the rat liver and kidney. • OTA induced renal carcinogenicity resulting from cell proliferation.

  20. The acute toxicity of iron and copper: biomolecule oxidation and oxidative damage in rat liver.

    PubMed

    Boveris, Alberto; Musacco-Sebio, Rosario; Ferrarotti, Nidia; Saporito-Magriñá, Christian; Torti, Horacio; Massot, Francisco; Repetto, Marisa G

    2012-11-01

    The transition metals iron (Fe) and copper (Cu) are needed at low levels for normal health and at higher levels they become toxic for humans and animals. The acute liver toxicity of Fe and Cu was studied in Sprague Dawley male rats (200 g) that received ip 0-60 mg/kg FeCl(2) or 0-30 mg/kg CuSO(4). Dose and time-responses were determined for spontaneous in situ liver chemiluminescence, phospholipid lipoperoxidation, protein oxidation and lipid soluble antioxidants. The doses linearly defined the tissue content of both metals. Liver chemiluminescence increased 4 times and 2 times after Fe and Cu overloads, with half maximal responses at contents (C(50%)) of 110 μgFe/g and 42 μgCu/g liver, and with half maximal time responses (t(1/2)) of 4h for both metals. Phospholipid peroxidation increased 4 and 1.8 times with C(50%) of 118 μg Fe/g and 45 μg Cu/g and with t(1/2) of 7h and 8h. Protein oxidation increased 1.6 times for Fe with C(50%) at 113 μg Fe/g and 1.2 times for Cu with 50 μg Cu/g and t(1/2) of 4h and 5h respectively. The accumulation of Fe and Cu in liver enhanced the rate of free radical reactions and produced oxidative damage. A similar free radical-mediated process, through the formation HO(•) and RO(•) by a Fenton-like homolytic scission of H(2)O(2) and ROOH, seems to operate as the chemical mechanism for the liver toxicity of both metals.

  1. Nonylphenol induces liver toxicity and oxidative stress in rat.

    PubMed

    Kazemi, Sohrab; Mousavi Kani, Seydeh Narges; Ghasemi-Kasman, Maryam; Aghapour, Fahimeh; Khorasani, Hamidreza; Moghadamnia, Ali Akbar

    2016-10-07

    Nonylphenol (NP) is one of the most widely used synthetic xenoestrogens in detergents, plastic products, paints and the most important environmental degradation factor. In this study, the effects NP was investigated on hepatic oxidative stress-related gene expression in rats. Wistar male rats weighing 150-200 g were divided into control and NP receiving groups. NP was given in three doses (5, 25, and 125 μg/kg). All doses were given by gavage and the experiment continued for a consecutive 35 days. AST, ALT and ALP determined by the colorimetric method. The RNA was extracted from the rats liver tissue and RT- PCR was used to investigate the changes in gene expression. For this purpose, primers and specific probes of HO1 and Gadd45b genes as well as B-actin as control were prepared and the expression of each gene was separately assessed with ABI-7300. Hematoxylin and eosin staining was performed for evaluating of cell death. The data from our study indicated nonylphenol increased alkaline phosphatase level but not changed aspartate aminotransferase and alanine aminotransferase in serum. That various doses of NP result in a dose-dependent increase in the expression of HO-1 gene. The intensified expression of HO-1 was statistically significant just at the doses of 25 and 125 μg/kg compared to control group (p < 0.05). In addition, it was shown that different doses of nonylphenol raised the expression of Gadd45b gene and this increase was significantly evident at 5 μg/kg (p < 0.05). Histological evaluation also indicated that NP increased hepatocytes cell death. We conclude that NP increased serum alkaline phosphatase, lead to liver damage and can increase the expression of HO1 and Gadd45b genes and may modify the toxic effects on liver through induction of oxidative stress. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Catalase takes part in rat liver mitochondria oxidative stress defense.

    PubMed

    Salvi, Mauro; Battaglia, Valentina; Brunati, Anna Maria; La Rocca, Nicoletta; Tibaldi, Elena; Pietrangeli, Paola; Marcocci, Lucia; Mondovì, Bruno; Rossi, Carlo A; Toninello, Antonio

    2007-08-17

    Highly purified rat liver mitochondria (RLM) when exposed to tert-butylhydroperoxide undergo matrix swelling, membrane potential collapse, and oxidation of glutathione and pyridine nucleotides, all events attributable to the induction of mitochondrial permeability transition. Instead, RLM, if treated with the same or higher amounts of H2O2 or tyramine, are insensitive or only partially sensitive, respectively, to mitochondrial permeability transition. In addition, the block of respiration by antimycin A added to RLM respiring in state 4 conditions, or the addition of H2O2, results in O2 generation, which is blocked by the catalase inhibitors aminotriazole or KCN. In this regard, H2O2 decomposition yields molecular oxygen in a 2:1 stoichiometry, consistent with a catalytic mechanism with a rate constant of 0.0346 s(-1). The rate of H2O2 consumption is not influenced by respiratory substrates, succinate or glutamate-malate, nor by N-ethylmaleimide, suggesting that cytochrome c oxidase and the glutathione-glutathione peroxidase system are not significantly involved in this process. Instead, H2O2 consumption is considerably inhibited by KCN or aminotriazole, indicating activity by a hemoprotein. All these observations are compatible with the presence of endogenous heme-containing catalase with an activity of 825 +/- 15 units, which contributes to mitochondrial protection against endogenous or exogenous H2O2. Mitochondrial catalase in liver most probably represents regulatory control of bioenergetic metabolism, but it may also be proposed for new therapeutic strategies against liver diseases. The constitutive presence of catalase inside mitochondria is demonstrated by several methodological approaches as follows: biochemical fractionating, proteinase K sensitivity, and immunogold electron microscopy on isolated RLM and whole rat liver tissue.

  3. Aspects of the regulation of long-chain fatty acid oxidation in bovine liver

    SciTech Connect

    Jesse, B.W.; Emery, R.S.; Thomas, J.W.

    1986-09-01

    Factors involved in regulation of bovine hepatic fatty acid oxidation were examined using liver slices. Fatty acid oxidation was measured as the conversion of l-(/sup 14/C) palmitate to /sup 14/CO/sub 2/ and total (/sup 14/C) acid-soluble metabolites. Extended (5 to 7 d) fasting of Holstein cows had relatively little effect on palmitate oxidation to acid-soluble metabolites by liver slices, although oxidation to CO/sup 2/ was decreased. Feeding a restricted roughage, high concentrate ration to lactating cows resulted in inhibition of palmitate oxidation. Insulin, glucose, and acetate inhibited palmitate oxidation by bovine liver slices. The authors suggest the regulation of bovine hepatic fatty acid oxidation may be less dependent on hormonally induced alterations in enzyme activity as observed in rat liver and more dependent upon action of rumen fermentation products or their metabolites on enzyme systems involved in fatty acid oxidation.

  4. Oxidative phosphorylation accompanying oxidation of short-chain fatty acids by rat-liver mitochondria

    PubMed Central

    Hird, F. J. R.; Weidemann, M. J.

    1966-01-01

    1. The factors concerned in the estimation of P/O ratios when fatty acids are oxidized by rat-liver mitochondria have been assessed. 2. The oxidation of butyrate, hexanoate and octanoate is accompanied by ATP synthesis. At low concentrations of the fatty acids, P/O ratios approximately 2·5 are obtained. 3. Oxidative phosphorylation is uncoupled, respiratory control ratios are lowered and respiration is inhibited when the concentration of the fatty acid in the incubating medium is raised (to 5–10mm); octanoate is a more potent uncoupler than either hexanoate or butyrate. 4. Serum albumin and carnitine, either singly or in combination, protect the mitochondria from the effect exerted by the fatty acids. 5. The rate of oxidation of short-chain fatty acids in the presence of ADP is increased in the presence of carnitine. PMID:4223170

  5. Alcohol-Induced Oxidative Stress in the Liver

    PubMed Central

    Arteel, Gavin E.

    2008-01-01

    Summary Oxidative stress is increasingly suspected to contribute to the initiation and progression of many disease, including those caused by alcohol exposure. Two major products of reactive oxygen and nitrogen species formation are 4OH-nonenal and 3-nitrotyrosine protein adducts, both of which can be detected by immunohistochemistry. In the past, immunohistochemical techniques have served largely as qualitative measures of changes. However, coupled with digital capture and analysis of photomicrographs, one can now quantitate treatment-related changes with immunohistochemistry. This chapter summarizes techniques for immunohistochemical detection of these products of reactive oxygen and nitrogen species and subsequent image-analysis. Although the methods described herein are based on liver, these techniques have been employed successfully in most tissue types with minor modifications and are therefore broadly applicable. PMID:18369920

  6. [Sodium butyrate inhibits HMGB1 expression and release and attenuates concanavalin A-induced acute liver injury in mice].

    PubMed

    Gong, Quan; Chen, Mao-Jian; Wang, Chao; Nie, Hao; Zhang, Yan-Xiang; Shu, Ke-Gang; Li, Gang

    2014-10-25

    The purpose of the present study is to explore the protective effects of sodium butyrate (SB) pretreatment on concanavalin A (Con A)-induced acute liver injury in mice. The model animals were first administered intraperitoneally with SB. Half an hour later, acute liver injury mouse model was established by caudal vein injection with Con A (15 mg/kg). Then, levels of serous alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured using standard clinical method by an automated chemistry analyzer, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) were measured by ELISA, and pathological changes in hepatic tissue were observed by using HE staining and light microscopy. The expression and release of high-mobility group box 1 (HMGB1) were assessed by using reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry and ELISA. The results showed that the pretreatment of SB significantly protected Con A-treated mice from liver injury as evidenced by the decrease of serum ALT, AST (P < 0.01) and reduction of hepatic tissues necrosis. SB also decreased levels of serous TNF-α and IFN-γ (P < 0.01). Furthermore, the expression and release of HMGB1 were markedly inhibited by SB pretreatment (P < 0.05 or P < 0.01). These results suggest that the attenuating effect of SB on Con A-induced acute liver injury may be due to its role of reducing the TNF-α and IFN-γ production, and inhibiting HMGB1 expression and release.

  7. Is Liver Enzyme Release Really Associated with Cell Necrosis Induced by Oxidant Stress?

    PubMed

    Contreras-Zentella, Martha Lucinda; Hernández-Muñoz, Rolando

    2016-01-01

    Hepatic diseases are a major concern worldwide. Increased specific plasma enzyme activities are considered diagnostic features for liver diseases, since enzymes are released into the blood compartment following the deterioration of the organ. Release of liver mitochondrial enzymes is considered strong evidence for hepatic necrosis, which is associated with an increased production of ROS, often leading to greater hepatic lipid peroxidation. Lipotoxic mediators and intracellular signals activated Kupffer cells, which provides evidence strongly suggesting the participation of oxidant stress in acute liver damage, inducing the progression of liver injury to chronic liver damage. Elevated transaminase activities are considered as an index marker of hepatotoxicity, linked to oxidant stress. However, a drastic increase of serum activities of liver enzyme markers ought not necessarily to reflect liver cell death. In fact, increased serum levels of cytoplasmic enzymes have readily been observed after partial hepatectomy (PH) in the regenerating liver of rats. In this regard, we are now showing that in vitro modifications of the oxidant status affect differentially the release of liver enzymes, indicating that this release is a strictly controlled event and not directly related to the onset of oxidant stress of the liver.

  8. Is Liver Enzyme Release Really Associated with Cell Necrosis Induced by Oxidant Stress?

    PubMed Central

    Contreras-Zentella, Martha Lucinda; Hernández-Muñoz, Rolando

    2016-01-01

    Hepatic diseases are a major concern worldwide. Increased specific plasma enzyme activities are considered diagnostic features for liver diseases, since enzymes are released into the blood compartment following the deterioration of the organ. Release of liver mitochondrial enzymes is considered strong evidence for hepatic necrosis, which is associated with an increased production of ROS, often leading to greater hepatic lipid peroxidation. Lipotoxic mediators and intracellular signals activated Kupffer cells, which provides evidence strongly suggesting the participation of oxidant stress in acute liver damage, inducing the progression of liver injury to chronic liver damage. Elevated transaminase activities are considered as an index marker of hepatotoxicity, linked to oxidant stress. However, a drastic increase of serum activities of liver enzyme markers ought not necessarily to reflect liver cell death. In fact, increased serum levels of cytoplasmic enzymes have readily been observed after partial hepatectomy (PH) in the regenerating liver of rats. In this regard, we are now showing that in vitro modifications of the oxidant status affect differentially the release of liver enzymes, indicating that this release is a strictly controlled event and not directly related to the onset of oxidant stress of the liver. PMID:26798419

  9. Ochratoxin A induces rat renal carcinogenicity with limited induction of oxidative stress responses.

    PubMed

    Qi, Xiaozhe; Yu, Tao; Zhu, Liye; Gao, Jing; He, Xiaoyun; Huang, Kunlun; Luo, Yunbo; Xu, Wentao

    2014-11-01

    Ochratoxin A (OTA) has displayed nephrotoxicity and renal carcinogenicity in mammals, however, no clear mechanisms have been identified detailing the relationship between oxidative stress and these toxicities. This study was performed to clarify the relationship between oxidative stress and the renal carcinogenicity induced by OTA. Rats were treated with 70 or 210 μg/kg b.w. OTA for 4 or 13 weeks. In the rats administrated with OTA for 13 weeks, the kidney was damaged seriously. Cytoplasmic vacuolization was observed in the outer stripe of the outer medulla. Karyomegaly was prominent in the tubular epithelium. Kidney injury molecule-1 (Kim-1) was detected in the outer stripe of the outer medulla in both low- and high-dose groups. OTA increased the mRNA levels of clusterin in rat kidneys. Interestingly, OTA did not significantly alter the oxidative stress level in rat liver and kidney. Yet, some indications related to proliferation and carcinogenicity were observed. A dose-related increase in proliferating cell nuclear antigen (PCNA) was observed at 4 weeks in both liver and kidney, but at 13 weeks, only in the kidney. OTA down-regulated reactive oxygen species (ROS) and up-regulated vimentin and lipocalin 2 in rat kidney at 13 weeks. The p53 gene was decreased in both liver and kidney at 13 weeks. These results suggest that OTA caused apparent kidney damage within 13 weeks but exerted limited effect on oxidative stress parameters. It implies that cell proliferation is the proposed mode of action for OTA-induced renal carcinogenicity.

  10. Protection by nitric oxide against liver inflammatory injury in animals carrying a nitric oxide synthase-2 transgene.

    PubMed

    Mojena, M; Hortelano, S; Castrillo, A; Diaz-Guerra, M J; Garcia-Barchino, M J; Saez, G T; Bosca, L

    2001-03-01

    The effect of pre-existent hepatic NO synthesis on liver injury induced by lipopolysaccharide was studied in animals carrying a nitric oxide synthase-2 (NOS-2) transgene under the control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter. These animals expressed NOS-2 in liver cells under fasting conditions. Lipopolysaccharide-induced liver injury in D-galactosamine-conditioned mice, which enhanced notably the effect of the endotoxin on the liver, was impaired in animals expressing NOS-2. This protection against inflammatory liver damage was dependent on NO synthesis and was caused by an inhibition of nuclear factor kB (NF-kB) activity and an impairment of the synthesis of the proinflammatory cytokines tumor necrosis factor a and interleukin 1b. These data indicate that intrahepatic synthesis of NO protects liver by inhibiting the release of cascades of proinflammatory mediators and suggest a beneficial role for local delivery of NO in the control of liver injury.

  11. Dietary phosphatidylinositol protects C57BL/6 mice from concanavalin A-induced liver injury by modulating immune cell functions.

    PubMed

    Inafuku, Masashi; Nagao, Koji; Inafuku, Ayako; Yanagita, Teruyoshi; Taira, Naoyuki; Toda, Takayoshi; Oku, Hirosuke

    2013-09-01

    Several recent studies have demonstrated that phospholipids (PLs) supplementation can modulate the function of cultured-immune cells. Furthermore, dietary PLs have been shown to ameliorate inflammatory processes and immune responses in arthritic and diabetic murine models, respectively. Thus, the aim of this study was to examine the immune-modulating activities of dietary soybean PLs in mice, with particular emphasis on the immune cell functions. Mice were fed semisynthetic diets for 6 weeks, which contained either 7% soybean oil or 5% soybean oil plus 2% of either PL: phosphatidylcholine (PC), phosphatidylinositol (PI), or phosphatidylserine (PS). Production of concanavalin A (Con A)-induced proinflammatory cytokines was significantly decreased in the splenocytes isolated from mice fed PI compared to other lipids. Supplementation of the diet with PI, but not with the other lipids, significantly suppressed the proinflammatory cytokine serum levels and the development of Con A-induced liver damages. These observations suggest that dietary PI influenced immune functions, resulting in the prevention of pathogenesis and development of the liver injury in mice. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Susceptibility of L-FABP−/− mice to oxidative stress in early-stage alcoholic liver[S

    PubMed Central

    Smathers, Rebecca L.; Galligan, James J.; Shearn, Colin T.; Fritz, Kristofer S.; Mercer, Kelly; Ronis, Martin; Orlicky, David J.; Davidson, Nicholas O.; Petersen, Dennis R.

    2013-01-01

    Chronic ethanol consumption is a prominent cause of liver disease worldwide. Dysregulation of an important lipid uptake and trafficking gene, liver-fatty acid binding protein (L-FABP), may contribute to alterations in lipid homeostasis during early-stage alcoholic liver. We have reported the detrimental effects of ethanol on the expression of L-FABP and hypothesize this may deleteriously impact metabolic networks regulating fatty acids. Male wild-type (WT) and L-FABP−/− mice were fed a modified Lieber-DeCarli liquid diet for six weeks. To assess the response to chronic ethanol ingestion, standard biochemical indicators for alcoholic liver disease (ALD) and oxidative stress were measured. Ethanol ingestion resulted in attenuation of hepatic triglyceride accumulation and elevation of cholesterol in L-FABP−/− mice. Lipidomics analysis validated multiple alterations in hepatic lipids resulting from ethanol treatment. Increased immunohistochemical staining for the reactive aldehydes 4-hydroxynonenal and malondialdehyde were observed in WT mice ingesting ethanol; however, L-FABP−/− mice displayed prominent protein adducts in liver sections evaluated from pair-fed and ethanol-fed mice. Likewise, alterations in glutathione, thiobarbituric acid reactive substances (TBARS), 8-isoprostanes, and protein carbonyl content all indicated L-FABP−/− mice exhibit high sustained oxidative stress in the liver. These data establish that L-FABP is an indirect antioxidant protein essential for sequestering FFA and that its impairment could contribute to in the pathogenesis of ALD. PMID:23359610

  13. Peroxisomal L-pipecolic acid oxidation is deficient in liver from Zellweger syndrome patients.

    PubMed

    Mihalik, S J; Moser, H W; Watkins, P A; Danks, D M; Poulos, A; Rhead, W J

    1989-05-01

    L-Pipecolic acid, a cyclic imino acid produced during the degradation of lysine, accumulates in body fluids of infants with the generalized peroxisomal disorders, including Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease. Peroxisome-enriched fractions from normal human liver oxidized L-[3H]pipecolic acid to alpha-[3H]aminoadipic acid (AAA). When human liver organelles were separated on a Percoll gradient, L-[3H]pipecolic acid oxidation activity (as measured by [3H]AAA formation) most closely segregated with the peroxisomal marker, catalase, and was not associated with the mitochondria. L-Pipecolic acid oxidation was not inhibited by antimycin A and rotenone and produced H2O2, consistent with its involving a peroxisomal oxidase. We measured L-pipecolic acid oxidation in liver specimens from patients with peroxisomal disorders. While liver homogenates from adult (n = 5) and infant (n = 10) controls formed 47.1 +/- 6.6 and 48.3 +/- 10.0 pmol AAA/mg protein/h, respectively, Zellweger syndrome livers (n = 8) formed only 1.7 +/- 0.3 pmol AAA/mg protein/h. L-pipecolic acid oxidation in normal infant livers was low at birth and increased with age, but Zellweger syndrome livers showed little activity at any age. Thus, the high circulating levels of L-pipecolic acid in Zellweger syndrome probably result from defective peroxisomal oxidation of L-pipecolic acid to AAA.

  14. Salidroside alleviates oxidative stress in the liver with non- alcoholic steatohepatitis in rats.

    PubMed

    Yang, Ze-ran; Wang, Hui-fang; Zuo, Tie-cheng; Guan, Li-li; Dai, Ning

    2016-04-14

    Nonalcoholic steatohepatitis (NASH) is characterized by fat accumulation in the hepatocyte, inflammation, liver cell injury, and varying degrees of fibrosis, and can lead to oxidative stress in liver. Here, we investigated whether Salidroside, a natural phenolic antioxidant product, can protect rat from liver injury during NASH. NASH model was established by feeding the male SD rats with high-fat and high-cholesterol diet for 14 weeks. Four groups of male SD rats including, normal diet control group, NASH model group, and Salidroside treatment group with150mg/kg and 300 mg/kg respectively, were studied. Salidroside was given by oral administration to NASH in rats from 9 weeks to 14 weeks. At the end of 14 weeks, liver and serum were harvested, and the liver injury, oxidative stress and histological features were evaluated. NASH rats exhibited significant increases in the following parameters as compared to normal diet control rats: fat droplets with foci of inflammatory cell infiltration in the liver. ALT, AST in serum and TG, TC in hepatocyte elevated. Oxidative responsive genes including CYP2E1 and Nox2 increased. Additionally, NASH model decreased antioxidant enzymes SOD, GSH, GPX, and CAT in the liver due to their rapid depletion after battling against oxidative stress. Compared to NASH model group, treatment rats with Salidroside effectively reduced lipid accumulation, inhibited liver injury in a does-dependent manner. Salidroside treatment restored antioxidant enzyme levels, inhibited expression of CYP2E1 and Nox2 mRNA in liver, which prevented the initial step of generating free radicals from NASH. The data presented here show that oral administration of Salidroside prevented liver injury in the NASH model, likely through exerting antioxidant actions to suppress oxidative stress and the free radical-generating CYP2E1 enzyme, Nox2 in liver.

  15. Methane-rich saline protects against concanavalin A-induced autoimmune hepatitis in mice through anti-inflammatory and anti-oxidative pathways.

    PubMed

    He, Rong; Wang, Liping; Zhu, Jiali; Fei, Miaomiao; Bao, Suhong; Meng, Yan; Wang, Yuanyuan; Li, Jinbao; Deng, Xiaoming

    2016-01-29

    Methane is a common gas which has been reported to play a protective role in organ injury and presents an anti-inflammatory property. However, its effects on Concanavalin A (Con A)-induced autoimmune hepatitis (AIH) remain unknown. Thus, the aim of this study was to investigate the effects of methane on Con A-induced autoimmune hepatitis in mice and its underlying mechanism. Autoimmune hepatitis was induced by Con A (15 mg/kg) in healthy C57BL/6 mice and methane-rich saline (MS) (20 ml/kg) was intraperitoneally injected 30 min after the challenge with Con A. We found that methane treatment significantly reduced the elevated serum aminotransferase levels and ameliorated liver pathological damage. Furthermore, methane treatment obviously suppressed the secretion of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-6 (IL-6) and interleukin-1β (IL-1β) and increased anti-inflammatory cytokine interleukin-10 (IL-10). Moreover, we found that the levels of malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were highly increased while the activities of superoxide dismutase (SOD) and catalase (CAT) were decreased in liver with the injection of Con A, which was reversed by methane. Also, the data demonstrated that the phosphorylated IκB, NF-κB and P38 MAPK in liver were significantly down-regulated by methane. These results suggested that methane protected liver against Con A-induced injury through anti-inflammatory and anti-oxidative pathways.

  16. [Oxidative phosphorylation in liver mitochondria in toxic form of experimental form of influenza].

    PubMed

    Bykova, N O; Gorbunov, N V; Bolgarev, A A; Savina, M V; Ivanova, T I; Egoiants, M A; Vanin, V F; Prozorovskaia, M P

    1991-12-01

    The effect of free radical processes on the oxidation-phosphorylation activity in the liver of CBA-mice has been studied, using a model of toxic form viral infection. The EPR-spectroscopic and electrochemical methods applied in the study of animals infected with pathogenic form of the influenza virus made it possible to reveal a decrease in the activity of the respiratory chain in mitochondria. This seems likely to be due to accumulation of endogenic nitric oxide in the liver tissue.

  17. Effects of Bauhinia forficata Tea on Oxidative Stress and Liver Damage in Diabetic Mice

    PubMed Central

    Salgueiro, Andréia Caroline Fernandes; da Silva, Marianne Pires; Mendez, Andreas Sebastian Loureiro; Zemolin, Ana Paula Pegoraro; Posser, Thaís; Puntel, Robson Luiz; Puntel, Gustavo Orione

    2016-01-01

    This study was designed to evaluate the effects of Bauhinia forficata Link subsp. pruinosa (BF) tea on oxidative stress and liver damage in streptozotocin (STZ)-induced diabetic mice. Diabetic male mice have remained 30 days without any treatment. BF treatment started on day 31 and continued for 21 days as a drinking-water substitute. We evaluated (1) BF chemical composition; (2) glucose levels; (3) liver/body weight ratio and liver transaminases; (4) reactive oxygen species (ROS), lipid peroxidation, and protein carbonylation in liver; (5) superoxide dismutase (SOD) and catalase (CAT) activities in liver; (6) δ-aminolevulinate dehydratase (δ-ALA-D) and nonprotein thiols (NPSH) in liver; (7) Nrf2, NQO-1, and HSP70 levels in liver and pancreas. Phytochemical analyses identified four phenols compounds. Diabetic mice present high levels of NQO-1 in pancreas, increased levels of ROS and lipid peroxidation in liver, and decrease in CAT activity. BF treatment normalized all these parameters. BF did not normalize hyperglycemia, liver/body weight ratio, aspartate aminotransferase, protein carbonyl, NPSH levels, and δ-ALA-D activity. The raised oxidative stress seems to be a potential mechanism involved in liver damage in hyperglycemic conditions. Our results indicated that BF protective effect could be attributed to its antioxidant capacity, more than a hypoglycemic potential. PMID:26839634

  18. Effects of Bauhinia forficata Tea on Oxidative Stress and Liver Damage in Diabetic Mice.

    PubMed

    Salgueiro, Andréia Caroline Fernandes; Folmer, Vanderlei; da Silva, Marianne Pires; Mendez, Andreas Sebastian Loureiro; Zemolin, Ana Paula Pegoraro; Posser, Thaís; Franco, Jeferson Luis; Puntel, Robson Luiz; Puntel, Gustavo Orione

    2016-01-01

    This study was designed to evaluate the effects of Bauhinia forficata Link subsp. pruinosa (BF) tea on oxidative stress and liver damage in streptozotocin (STZ)-induced diabetic mice. Diabetic male mice have remained 30 days without any treatment. BF treatment started on day 31 and continued for 21 days as a drinking-water substitute. We evaluated (1) BF chemical composition; (2) glucose levels; (3) liver/body weight ratio and liver transaminases; (4) reactive oxygen species (ROS), lipid peroxidation, and protein carbonylation in liver; (5) superoxide dismutase (SOD) and catalase (CAT) activities in liver; (6) δ-aminolevulinate dehydratase (δ-ALA-D) and nonprotein thiols (NPSH) in liver; (7) Nrf2, NQO-1, and HSP70 levels in liver and pancreas. Phytochemical analyses identified four phenols compounds. Diabetic mice present high levels of NQO-1 in pancreas, increased levels of ROS and lipid peroxidation in liver, and decrease in CAT activity. BF treatment normalized all these parameters. BF did not normalize hyperglycemia, liver/body weight ratio, aspartate aminotransferase, protein carbonyl, NPSH levels, and δ-ALA-D activity. The raised oxidative stress seems to be a potential mechanism involved in liver damage in hyperglycemic conditions. Our results indicated that BF protective effect could be attributed to its antioxidant capacity, more than a hypoglycemic potential.

  19. Hydration of arene and alkene oxides by epoxide hydrase in human liver microsomes.

    PubMed

    Kapitulnik, J; Levin, W; Morecki, R; Dansette, P M; Jerina, D M; Conney, A H

    1977-02-01

    The comparative hydration of styrene 7,8-oxide, octene 1,2-oxide, naphthalene 1,2-oxide, phenanthrene 9,10-oxide, benzo[a]anthracene 5,6-oxide, 3-methylcholanthrene 11,12-oxide, dibenzo[a,h]anthracene 5,6-oxide, and benzo[a, 7,8-, 9,10-, and 11,12-oxides to their respective dihydrodiols was investigated in microsomes from nine human autopsy livers. The substrate specificity of the epoxide hydrase in human liver microsomes was very similar to that of the epoxide hydrase in rat liver microsomes. Phenanthrene 9,10-oxide was the best substrate for the human and rat epoxide hydrases and dibenzo[a,h]anthracene 5,6-oxide and benzo[a-a)pyrene 11, 12-oxide were the poorest substrates. Plotting epoxide hydrase activity obtained with one substrate against epoxide hydrase activity for another substrate for each of the nine human livers revealed excellent correlations for all combinations of the 11 substrates studied (r = 0.87 to 0.99). The data suggest the presence in human liver of a single epoxide hydrase with broad substrate specificity. However, the results do not exclude the possible presence in human liver of several epoxide hydrases that are under similar regulatory control. These results suggest the need for further investigation to determine whether there is a safe epoxide of a drug whose in vivo metabolism is predictive of the capacity of different individuals to metabolize a wide variety of epoxides of drugs and environmental chemicals.

  20. Tamarind seed extract mitigates the liver oxidative stress in arthritic rats.

    PubMed

    Sundaram, Mahalingam Shanmuga; Hemshekhar, Mahadevappa; Thushara, Ram M; Santhosh, Martin Sebastin; Kumar, Somanathapura K Naveen; Paul, Manoj; Devaraja, Sannaningaiah; Kemparaju, Kempaiah; Rangappa, Kanchugarakoppal S; Girish, Kesturu S

    2014-03-01

    Although arthritis is primarily a joint disorder that mainly targets the articular cartilage and subchondral bone, several recent investigations have reported oxidative burst and vital organ damage that are being considered as secondary complications of arthritis. The continuous generation of free radicals like reactive oxygen and nitrogen species is considered as a key culprit in the initiation and propagation of oxidative damage. In addition, activation of T and B cells, macrophages, inflammatory mediators such as TNF-α, IL-1β and IL-6 aggravates the oxidative damage of the vital organs, particularly the liver. The current piece of work demonstrates oxidative stress in the liver of arthritic rats and its amelioration by the procyanidin-rich tamarind seed extract (TSE). The arthritic liver homogenate, mitochondrial and cytosolic fractions were found with increased levels of oxidative stress markers including free radicals. As a consequence, depletion in the levels of glutathione, total thiols, glutathione peroxidase and reductase was evident. Furthermore, the activities of endogenous antioxidant enzymes like superoxide dismutase, catalase and glutathione-S-transferase were found to be significantly altered. The increased and decreased activity of transaminases respectively in serum and liver, along with histological observations, further confirms the liver damage. Unfortunately, the commonly used drugs like NSAIDs and DMARDs have failed to prevent oxidative damage, rather they were found to be the inducers themselves. Interestingly, TSE supplementation was found to significantly inhibit oxidative burst in the liver and maintain homeostasis. Thus, the study clearly demonstrates the protective efficacy of TSE against arthritis-associated oxidative liver damage, including mitochondrial oxidative burst and its associated secondary complications.

  1. Anti-oxidative effects of curcumin on immobilization-induced oxidative stress in rat brain, liver and kidney.

    PubMed

    Samarghandian, Saeed; Azimi-Nezhad, Mohsen; Farkhondeh, Tahereh; Samini, Fariborz

    2017-03-01

    Restraint stress has been indicated to induce oxidative damage in tissues. Several investigations have reported that curcumin (CUR) may have a protective effect against oxidative stress. The present study was designed to investigate the protective effects of CUR on restraint stress induced oxidative stress damage in the brain, liver and kidneys. For chronic restraint stress, rats were kept in the restrainers for 1h every day, for 21 consecutive days. The animals received systemic administrations of CUR daily for 21days. In order to evaluate the changes of the oxidative stress parameters following restraint stress, the levels of malondialdehyde (MDA), reduced glutathione (GSH), as well as antioxidant enzyme activities superoxide dismutase (SOD) glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CAT) were measured in the brain, liver and kidney of rats after the end of restraint stress. The restraint stress significantly increased MDA level, but decreased the level of GSH and activists of SOD, GPx, GR, and CAT the brain, liver and kidney of rats in comparison to the normal rats (P<0.001). Intraperitoneal administration of CUR significantly attenuated oxidative stress and lipid peroxidation, prevented apoptosis, and increased antioxidant defense mechanism activity in the tissues versus the control group (P<0.05). This study shows that CUR can prevent restraint stress-induced oxidative damage in the brain, liver and kidney of rats and propose that CUR may be useful agents against oxidative stress in the tissues. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  2. Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases

    PubMed Central

    Li, Sha; Hong, Ming

    2016-01-01

    The crucial roles of oxidative stress and inflammation in the development of hepatic diseases have been unraveled and emphasized for decades. From steatosis to fibrosis, cirrhosis and liver cancer, hepatic oxidative stress, and inflammation are sustained and participated in this pathological progressive process. Notably, increasing evidences showed that oxidative stress and inflammation are tightly related, which are regarded as essential partners that present simultaneously and interact with each other in various pathological conditions, creating a vicious cycle to aggravate the hepatic diseases. Clarifying the interaction of oxidative stress and inflammation is of great importance to provide new directions and targets for developing therapeutic intervention. Herein, this review is concerned with the regulation and interdependence of oxidative stress and inflammation in a variety of liver diseases. In addition to classical mediators and signaling, particular emphasis is placed upon immune suppression, a potential linkage of oxidative stress and inflammation, to provide new inspiration for the treatment of liver diseases. Furthermore, since antioxidation and anti-inflammation have been extensively attempted as the strategies for treatment of liver diseases, the application of herbal medicines and their derived compounds that protect liver from injury via regulating oxidative stress and inflammation collectively were reviewed and discussed. PMID:28070230

  3. Dietary moderately oxidized oil activates the Nrf2 signaling pathway in the liver of pigs

    PubMed Central

    2012-01-01

    Background Previous studies have shown that administration of oxidized oils increases gene expression and activities of various enzymes involved in xenobiotic metabolism and stress response in the liver of rats and guinea pigs. As these genes are controlled by nuclear factor erythroid-derived 2-like 2 (Nrf2), we investigated the hypothesis that feeding of oxidized fats causes an activation of that transcription factor in the liver which in turn activates the expression of antioxidant, cytoprotective and detoxifying genes. Methods Twenty four crossbred pigs were allocated to two groups of 12 pigs each and fed nutritionally adequate diets with either fresh rapeseed oil (fresh fat group) or oxidized rapeseed oil prepared by heating at a temperature of 175°C for 72 h (oxidized fat group). Results After 29 days of feeding, pigs of the oxidized fat group had a markedly increased nuclear concentration of the transcription factor Nrf2 and a higher activity of cellular superoxide dismutase and T4-UDP glucuronosyltransferase in liver than the fresh fat group (P < 0.05). In addition, transcript levels of antioxidant and phase II genes in liver, like superoxide dismutase 1, heme oxygenase 1, glutathione peroxidase 1, thioredoxin reductase 1, microsomal glutathione-S-transferase 1, UDP glucuronosyltransferase 1A1 and NAD(P)H:quinone oxidoreductase 1 in the liver were higher in the oxidized fat group than in the fresh fat group (P < 0.05). Moreover, pigs of the oxidized fat group had an increased hepatic nuclear concentration of the transcription factor NF-κB which is also an important transcription factor mediating cellular stress response. Conclusion The present study shows for the first time that administration of an oxidized fat activates the Nrf2 in the liver of pigs which likely reflects an adaptive mechanism to prevent cellular oxidative damage. Activation of the NF-κB pathway might also contribute to this effect of oxidized fat. PMID:22364167

  4. Oxidative stress: New insights on the association of non-alcoholic fatty liver disease and atherosclerosis.

    PubMed

    Polimeni, Licia; Del Ben, Maria; Baratta, Francesco; Perri, Ludovica; Albanese, Fabiana; Pastori, Daniele; Violi, Francesco; Angelico, Francesco

    2015-06-08

    Non-alcoholic fatty liver disease (NAFLD) represents the most common and emerging chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and more severe liver complications such as cirrhosis, hepatocellular carcinoma and liver mortality. NAFLD is strongly associated with obesity, insulin resistance, hypertension, and dyslipidaemia, and is now regarded as the liver manifestation of the metabolic syndrome. The increased mortality of patients with NAFLD is primarily a result of cardiovascular disease and, to a lesser extent, to liver related diseases. Increased oxidative stress has been reported in both patients with NAFLD and patient with cardiovascular risk factors. Thus, oxidative stress represents a shared pathophysiological disorder between the two conditions. Several therapeutic strategies targeting oxidative stress reduction in patients with NAFLD have been proposed, with conflicting results. In particular, vitamin E supplementation has been suggested for the treatment of non-diabetic, non-cirrhotic adults with active NASH, although this recommendation is based only on the results of a single randomized controlled trial. Other antioxidant treatments suggested are resveratrol, silybin, L-carnitine and pentoxiphylline. No trial so far, has evaluated the cardiovascular effects of antioxidant treatment in patients with NAFLD. New, large-scale studies including as end-point also the assessment of the atherosclerosis markers are needed.

  5. Oxidative stress: New insights on the association of non-alcoholic fatty liver disease and atherosclerosis

    PubMed Central

    Polimeni, Licia; Del Ben, Maria; Baratta, Francesco; Perri, Ludovica; Albanese, Fabiana; Pastori, Daniele; Violi, Francesco; Angelico, Francesco

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) represents the most common and emerging chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and more severe liver complications such as cirrhosis, hepatocellular carcinoma and liver mortality. NAFLD is strongly associated with obesity, insulin resistance, hypertension, and dyslipidaemia, and is now regarded as the liver manifestation of the metabolic syndrome. The increased mortality of patients with NAFLD is primarily a result of cardiovascular disease and, to a lesser extent, to liver related diseases. Increased oxidative stress has been reported in both patients with NAFLD and patient with cardiovascular risk factors. Thus, oxidative stress represents a shared pathophysiological disorder between the two conditions. Several therapeutic strategies targeting oxidative stress reduction in patients with NAFLD have been proposed, with conflicting results. In particular, vitamin E supplementation has been suggested for the treatment of non-diabetic, non-cirrhotic adults with active NASH, although this recommendation is based only on the results of a single randomized controlled trial. Other antioxidant treatments suggested are resveratrol, silybin, L-carnitine and pentoxiphylline. No trial so far, has evaluated the cardiovascular effects of antioxidant treatment in patients with NAFLD. New, large-scale studies including as end-point also the assessment of the atherosclerosis markers are needed. PMID:26052378

  6. Pregnenolone 16α-carbonitrile ameliorates concanavalin A-induced liver injury in mice independent of the nuclear receptor PXR activation.

    PubMed

    Kodama, Susumu; Shimura, Takuto; Kuribayashi, Hideaki; Abe, Taiki; Yoshinari, Kouichi

    2017-04-05

    The pregnane X receptor (PXR) is well-known as a key regulator of drug/xenobiotic clearance. Upon activation by ligand, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and drug transporters. Recent studies have revealed that PXR also plays a role in regulating immune/inflammatory responses. Specific PXR activators, including synthetic ligands and phytochemicals, have been shown to ameliorate chemically induced colitis in mice. In this study, we investigated an anti-inflammatory effect of pregnenolone 16α-carbonitrile (PCN), a prototypical activator for rodent PXR, in concanavalin A (Con A)-induced liver injury, a model of immune-mediated liver injury, using wild-type and Pxr(-/-) mice. Unexpectedly, pretreatment with PCN significantly ameliorated Con A-induced liver injury in not only wild-type but Pxr(-/-) mice as well, accompanied with lowered plasma ALT levels and histological improvements. Pretreatment with PCN was found to significantly repress the induction of Cxcl2 and Ccl2 mRNA expression and neutrophil infiltration into the liver of both wild-type and Pxr(-/-) mice at the early time point of Con A-induced liver injury. Our results indicate that PCN has unexpected immunosuppressive activity independent of PXR activation to protect mice from immune-mediated liver injury induced by Con A.

  7. Rat liver microsomal lipid peroxidation produced during the oxidative metabolism of ethacrynic acid.

    PubMed

    Yamamoto, K; Masubuchi, Y; Narimatsu, S; Kobayashi, S; Horie, T

    2001-04-01

    Thiobarbituric acid reactive substances (TBARS) were produced in rat liver microsomal suspension incubated with ethacrynic acid (loop diuretic drug) and NADPH. Two oxidative metabolites of ethacrynic acid with dicarboxylic acid and hydroxylated ethyl group, respectively, were formed in the reaction mixture. The oxidative metabolism of ethacrynic acid was inhibited by cytochrome P450 inhibitors. The formation of TBARS was remarkably depressed by inhibitors like diethyldithiocarbamate and disulfiram. These results indicate that lipid peroxidation occurred in rat liver microsomes through the oxidative metabolism of ethacrynic acid.

  8. Obstructive jaundice leads to accumulation of oxidized low density lipoprotein in human liver tissue.

    PubMed

    Comert, Mustafa; Ustundag, Yucel; Tekin, Ishak Ozel; Gun, Banu Dogan; Barut, Figen

    2006-08-21

    Oxidized low density lipoprotein (ox-LDL) molecule is one of the most important modified lipoproteins produced during the oxidative stress. Modified lipoproteins have been defined as being part of the immune inflammatory mechanisms in association with oxidant stress. We have reported the accumulation of ox-LDL in Balb/c mice liver after bile duct ligation previously. Here, we investigated this finding in human beings with obstructive jaundice. Our study demonstrates that obstructive jaundice results in tremendous accumulation of ox-LDL in the liver tissue of patients.

  9. Oxidative stress and altered lipid homeostasis in the programming of offspring fatty liver by maternal obesity.

    PubMed

    Alfaradhi, Maria Z; Fernandez-Twinn, Denise S; Martin-Gronert, Malgorzata S; Musial, Barbara; Fowden, Abigail; Ozanne, Susan E

    2014-07-01

    Changes in the maternal nutritional environment during fetal development can influence offspring's metabolic risk in later life. Animal models have demonstrated that offspring of diet-induced obese dams develop metabolic complications, including nonalcoholic fatty liver disease. In this study we investigated the mechanisms in young offspring that lead to the development of nonalcoholic fatty liver disease (NAFLD). Female offspring of C57BL/6J dams fed either a control or obesogenic diet were studied at 8 wk of age. We investigated the roles of oxidative stress and lipid metabolism in contributing to fatty liver in offspring. There were no differences in body weight or adiposity at 8 wk of age; however, offspring of obese dams were hyperinsulinemic. Oxidative damage markers were significantly increased in their livers, with reduced levels of the antioxidant enzyme glutathione peroxidase-1. Mitochondrial complex I and II activities were elevated, while levels of mitochondrial cytochrome c were significantly reduced and glutamate dehydrogenase was significantly increased, suggesting mitochondrial dysfunction. Offspring of obese dams also had significantly greater hepatic lipid content, associated with increased levels of PPARγ and reduced triglyceride lipase. Liver glycogen and protein content were concomitantly reduced in offspring of obese dams. In conclusion, offspring of diet-induced obese dams have disrupted liver metabolism and develop NAFLD prior to any differences in body weight or body composition. Oxidative stress may play a mechanistic role in the progression of fatty liver in these offspring.

  10. Taurine supplementation reduces oxidative stress and protects the liver in an iron-overload murine model.

    PubMed

    Zhang, Zeyu; Liu, Dan; Yi, Bo; Liao, Zhangping; Tang, Lei; Yin, Dong; He, Ming

    2014-11-01

    We previously demonstrated that iron overload induces liver damage by causing the formation of reactive oxygen species (ROS). Taurine is a potent free radical scavenger that attenuates the damage caused by excessive oxygen free radicals. Therefore, the aim of the present study was to investigate whether taurine could reduce the hepatotoxicity of iron overload with regard to ROS production. Mice were intraperitoneally injected with iron 5 days/week for 13 weeks to achieve iron overload. It was found that iron overload resulted in liver dysfunction, increased apoptosis and elevated oxidative stress. Taurine supplementation increased liver taurine levels by 40% and led to improved liver function, as well as a reduction in apoptosis, ROS formation and mitochondrial swelling and an attenuation in the loss of the mitochondrial membrane potential. Treatment with taurine mediated a reduction in oxidative stress in iron‑overloaded mice, attenuated liver lipid peroxidation, elevated antioxidant enzyme activities and maintained reduced glutathione levels. These results indicate that taurine reduces iron‑induced hepatic oxidative stress, preserves liver function and inhibits hepatocyte apoptosis. Therefore, taurine may be a potential therapeutic drug to reduce liver damage caused by iron overload.

  11. Taurine supplementation reduces oxidative stress and protects the liver in an iron-overload murine model

    PubMed Central

    ZHANG, ZEYU; LIU, DAN; YI, BO; LIAO, ZHANGPING; TANG, LEI; YIN, DONG; HE, MING

    2014-01-01

    We previously demonstrated that iron overload induces liver damage by causing the formation of reactive oxygen species (ROS). Taurine is a potent free radical scavenger that attenuates the damage caused by excessive oxygen free radicals. Therefore, the aim of the present study was to investigate whether taurine could reduce the hepatotoxicity of iron overload with regard to ROS production. Mice were intraperitoneally injected with iron 5 days/week for 13 weeks to achieve iron overload. It was found that iron overload resulted in liver dysfunction, increased apoptosis and elevated oxidative stress. Taurine supplementation increased liver taurine levels by 40% and led to improved liver function, as well as a reduction in apoptosis, ROS formation and mitochondrial swelling and an attenuation in the loss of the mitochondrial membrane potential. Treatment with taurine mediated a reduction in oxidative stress in iron-overloaded mice, attenuated liver lipid peroxidation, elevated antioxidant enzyme activities and maintained reduced glutathione levels. These results indicate that taurine reduces iron-induced hepatic oxidative stress, preserves liver function and inhibits hepatocyte apoptosis. Therefore, taurine may be a potential therapeutic drug to reduce liver damage caused by iron overload. PMID:25201602

  12. Maternal nicotine exposure leads to higher liver oxidative stress and steatosis in adult rat offspring.

    PubMed

    Conceição, E P; Peixoto-Silva, N; Pinheiro, C R; Oliveira, E; Moura, E G; Lisboa, P C

    2015-04-01

    Early nicotine exposure causes future obesity and insulin resistance. We evaluated the long-term effect of the maternal nicotine exposure during lactation in liver oxidative status, insulin sensitivity and morphology in adult offspring. Two days after birth, osmotic minipumps were implanted in the dams: nicotine (N), 6 mg/kg/day for 14 days or saline (C). Offspring were killed at 180 days. Protein content of superoxide dismutase, glutathione peroxidase, catalase, nitrotyrosine, 4HNE, IRS1, Akt1 and PPARs were measured. MDA, bound protein carbonyl content, SOD, GPx and catalase activities were determined in liver and plasma. Hepatic morphology and triglycerides content were evaluated. Albumin and bilirubin were determined. In plasma, N offspring had higher catalase activity, and SOD/GPx ratio, albumin and bilirubin levels but lower MDA content. In liver, they presented higher MDA and 4HNE levels, bound protein carbonyl content, SOD activity but lower GPx activity. N offspring presented an increase of lipid droplet, higher triglyceride content and a trend to lower PPARα in liver despite unchanged insulin signaling pathway. Early nicotine exposure causes oxidative stress in liver at adulthood, while protect against oxidative stress at plasma level. In addition, N offspring develop liver microsteatosis, which is related to oxidative stress but not to insulin resistance. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Salecan protected against concanavalin A-induced acute liver injury by modulating T cell immune responses and NMR-based metabolic profiles.

    PubMed

    Sun, Qi; Xu, Xi; Yang, Xiao; Weng, Dan; Wang, Junsong; Zhang, Jianfa

    2017-02-15

    Salecan, a water-soluble extracellular β-glucan produced by Agrobacterium sp. ZX09, has been reported to exhibit a wide range of biological effects. The aims of the present study were to investigate the protective effect of salecan against Concanavalin A (ConA)-induced hepatitis, a well-established animal model of immune-mediated liver injury, and to search for possible mechanisms. C57BL/6 mice were pretreated with salecan followed by ConA injection. Salecan treatment significantly reduced ConA-induced acute liver injury, and suppressed the expression and secretion of inflammatory cytokines including interferon (IFN)-γ, interleukin (IL)-6 and IL-1β in ConA-induced liver injury model. The high expression levels of chemokines and adhesion molecules such as MIP-1α, MIP-1β, ICAM-1, MCP-1 and RANTES in the liver induced by ConA were also down-regulated after salecan treatment. Salecan inhibited the infiltration and activation of inflammatory cells, especially T cells, in the liver induced by ConA. Moreover, salecan reversed the metabolic profiles of ConA-treated mice towards the control group by partly recovering the metabolic perturbations induced by ConA. Our results suggest the preventive and therapeutic potential of salecan in immune-mediated hepatitis.

  14. [Inhibiting effects of three components of Astragalus membranaceus on oxidative stress in Chang Liver cells].

    PubMed

    Li, Jian; Han, Lin; Ma, Yu-fang; Huang, Yi-fan

    2015-01-01

    The main objective of this research is to investigate the effects of astragaloside IV, calycosin separately glucoside, formononetin on oxidative stress in Chang Liver cells induced by H2O2. In the experiments, Chang Liver cells (a kind of normal human hepatocytes) were used as the research object, bifendate which has a clear hepatoprotective effect was used as the positive control drug, then the oxidative damage model of Chang Liver cells were established by H2O2. Cells were divided into six groups: blank control group, oxidative stress group, astragaloside IV group, calycosin separately glucoside group, formononetin group and positive control group. Then endogenous antioxidant system related indexes were detected by micro plate and colorimetric method; intracellular reactive oxygen species (ROS) were detected by DCFH-DA fluorescent probe; and the expressions of CYP2E1 were evaluated by liver microsomes, mRNA, and protein, respectively with spectrophotometry, Real-time PCR method, and Western blot technique. Results showed that H2O2 decreased antioxidant activity, and increased ROS level and expression of CYP2E1. The above oxidative stress status had been changed with protections of the three components of Astragalus membranaceus (compared with oxidative stress group, P < 0.05, P < 0.01), which taken as a whole had equivalent effects as the drug of positive control group( bifendate). Taken together, three Astragalus membranaceus ingredients all had significant or extremely significant inhibiting effects on oxidative damaged Chang Liver cells which were induced by H2O2, and the oxidative damage of Chang Liver cells had been relieved.

  15. Pretreatment with Fucoidan from Fucus vesiculosus Protected against ConA-Induced Acute Liver Injury by Inhibiting Both Intrinsic and Extrinsic Apoptosis.

    PubMed

    Li, Jingjing; Chen, Kan; Li, Sainan; Liu, Tong; Wang, Fan; Xia, Yujing; Lu, Jie; Zhou, Yingqun; Guo, Chuanyong

    2016-01-01

    This study aimed to explore the effects of fucoidan from Fucus vesiculosus on concanavalin A (ConA)-induced acute liver injury in mice. Pretreatment with fucoidan protected liver function indicated by ALT, AST and histopathological changes by suppressing inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). In addition, intrinsic and extrinsic apoptosis mediated by Bax, Bid, Bcl-2, Bcl-xL and Caspase 3, 8, and 9 were inhibited by fucoidan and the action was associated with the TRADD/TRAF2 and JAK2/STAT1 signal pathways. Our results demonstrated that fucoidan from Fucus vesiculosus alleviated ConA-induced acute liver injury via the inhibition of intrinsic and extrinsic apoptosis mediated by the TRADD/TRAF2 and JAK2/STAT1 pathways which were activated by TNF-α and IFN-γ. These findings could provide a potential powerful therapy for T cell-related hepatitis.

  16. Proteomic profile of carbonylated proteins in rat liver: exercise attenuated oxidative stress may be involved in fatty liver improvement.

    PubMed

    Hu, Xiaofei; Duan, Zhigui; Hu, Hui; Li, Guolin; Yan, Siyu; Wu, Jinfeng; Wang, Jun; Yin, Dazhong; Xie, Qingji

    2013-05-01

    To screen target proteins of oxidative stress which mediate the effects of exercise on preventing nonalcoholic fatty liver disease (NAFLD), the methods for selecting carbonylated proteins were modified, and carbonylated proteins were profiled. The results showed that treadmill training reduced oxidative stress and the levels of intrahepatic triglyceride (IHTG). The changes in IHTG showed a significant positive correlation with oxidative stress as indicated by malondialdehyde level. Further results from proteomics illustrated that 17 functional proteins were susceptible to oxidative modification, and exercise protected three proteins from carbonylation. The latter three proteins may serve as both direct target proteins of oxidative stress and mediators contributing to the beneficial effects of exercise. In particular, a long-chain specific acyl-CoA dehydrogenase (ACADL) which was a key enzyme in lipid metabolism was not carbonylated and with higher activities in exercise group. These findings indicate that this modified technique is practical and powerful in selecting carbonylated proteins. Long-term treadmill training is effective in ameliorating oxidative stress and preventing the accumulation of IHTG. Among the 17 target proteins of oxidative modification, three proteins contribute to the beneficial effects of exercise. Preventing ACADL from carbonylation may be involved in the physiological mechanism of exercise-induced NAFLD improvement.

  17. Alterations in soluble guanylate cyclase content and modulation by nitric oxide in liver disease.

    PubMed

    Rodrigo, Regina; Montoliu, Carmina; Chatauret, Nicolas; Butterworth, Roger; Behrends, Soenke; Del Olmo, Juan A; Serra, Miguel A; Rodrigo, José M; Erceg, Slaven; Felipo, Vicente

    2004-11-01

    Hyperammonemia is the main responsible for the neurological alterations in hepatic encephalopathy in patients with liver failure. We studied the function of the glutamate-nitric oxide (NO)-cGMP pathway in brain in animal models of hyperammonemia and liver failure and in patients died with liver cirrhosis. Activation of glutamate receptors increases intracellular calcium that binds to calmodulin and activates neuronal nitric oxide synthase, increasing nitric oxide, which activates soluble guanylate cyclase (sGC), increasing cGMP. This glutamate-NO-cGMP pathway modulates cerebral processes such as circadian rhythms, the sleep-waking cycle, and some forms of learning and memory. These processes are impaired in patients with hepatic encephalopathy. Activation of sGC by NO is significantly increased in cerebral cortex and significantly reduced in cerebellum from cirrhotic patients died in hepatic coma. Portacaval anastomosis in rats, an animal model of liver failure, reproduces the effects of liver failure on modulation of sGC by NO both in cerebral cortex and cerebellum. In vivo brain microdialisis studies showed that sGC activation by NO is also reduced in vivo in cerebellum in hyperammonemic rats with or without liver failure. The content of alpha but not beta subunits of sGC are increased both in frontal cortex and cerebellum from patients died due to liver disease and from rats with portacaval anastomosis. We assessed whether determination of activation of sGC by NO-generating agent SNAP in lymphocytes could serve as a peripheral marker for the impairment of sGC activation by NO in brain. Chronic hyperammonemia and liver failure also alter sGC activation by NO in lymphocytes from rats or patients. These findings show that the content and modulation by NO of sGC are strongly altered in brain of patients with liver disease. These alterations could be responsible for some of the neurological alterations in hepatic encephalopathy such as sleep disturbances and

  18. Expression and activity of inducible nitric oxide synthase and endothelial nitric oxide synthase correlate with ethanol-induced liver injury

    PubMed Central

    Yuan, Guang-Jin; Zhou, Xiao-Rong; Gong, Zuo-Jiong; Zhang, Pin; Sun, Xiao-Mei; Zheng, Shi-Hua

    2006-01-01

    AIM: To study the expression and activity of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in rats with ethanol-induced liver injury and their relation with liver damage, activation of nuclear factor-κB (NF-κB) and tumor necrosis factor-α (TNF-α) expression in the liver. METHODS: Female Sprague-Dawley rats were given fish oil (0.5 mL) along with ethanol or isocaloric dextrose daily via gastrogavage for 4 or 6 wk. Liver injury was assessed using serum alanine aminotransferase (ALT) activity and pathological analysis. Liver malondialdehyde (MDA), nitric oxide contents, iNOS and eNOS activity were determined. NF-κB p65,iNOS, eNOS and TNF-α protein or mRNA expression in the liver were detected by immunohistochemistry or reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Chronic ethanol gavage for 4 wk caused steatosis, inflammation and necrosis in the liver, and elevated serum ALT activity. Prolonged ethanol administration (6 wk) enhanced the liver damage. These responses were accompanied with increased lipid peroxidation, NO contents, iNOS activity and reduced eNOS activity. NF-κB p65, iNOS and TNF-α protein or mRNA expression were markedly induced after chronic ethanol gavage, whereas eNOS mRNA expression remained unchanged. The enhanced iNOS activity and expression were positively correlated with the liver damage, especially the necro-inflammation, activation of NF-κB, and TNF-α mRNA expression. CONCLUSION: iNOS expression and activity are induced in the liver after chronic ethanol exposure in rats, which are correlated with the liver damage, especially the necro-inflammation, activation of NF-κB and TNF-α expression. eNOS activity is reduced, but its mRNA expression is not affected. PMID:16688828

  19. Mechanism of aldehyde oxidation catalyzed by horse liver alcohol dehydrogenase.

    PubMed

    Olson, L P; Luo, J; Almarsson, O; Bruice, T C

    1996-07-30

    The mechanism of oxidation of benzaldehyde to benzoic acid catalyzed by horse liver alcohol dehydrogenase (HLADH) has been investigated using the HLADH structure at 2.1 A resolution with NAD+ and pentafluorobenzyl alcohol in the active site [Ramaswamy et al. (1994) Biochemistry 33,5230-5237]. Constructs for molecular dynamics (MD) investigations with HLADH were obtained by a best-fit superimposition of benzaldehyde or its hydrate on the pentafluorobenzyl alcohol bound to the active site Zn(II)ion. Equilibrium bond lengths, angles, and dihedral parameters for Zn(II) bonding residues His67, Cys46, and Cys174 were obtained from small-molecule X-ray crystal structures and an ab initio-derived parameterization of zinc in HLADH [Ryde, U. (1995) Proteins: Struct., Funct., Genet. 21,40-56]. Dynamic simulations in CHARMM were carried out on the following three constructs to 100 ps: (MD1) enzyme with NAD+, benzaldehyde, and zinc-ligated HO-in the active site; (MD2) enzyme with NAD+ and hydrated benzaldehyde monoanion bound to zinc via the pro-R oxygen, with a proton residing on the pro-S oxygen; and (MD3) enzyme with NAD+ and hydrated benzaldehyde monoanion bound to zinc via the pro-S oxygen, with a proton residing on the pro-R oxygen. Analyses were done of 800 sample conformations taken in the last 40 ps of dynamics. Structures from MD1 and MD3 were used to define the initial spatial arrangements of reactive functionalities for semiempirical PM3 calculations. Using PM3, model systems were calculated of ground states and some transition states for aldehyde hydration, hydride transfer, and subsequent proton shuttling. With benzaldehyde and zinc-bound hydroxide ion in the active site, the oxygen of Zn(II)-OH resided at a distance of 2.8-5.5 A from the aldehyde carbonyl carbon during the dynamics simulation. This may be compared to the PM3 transition state for attack of the Zn(II)-OH oxygen on the benzaldehyde carbonyl carbon, which has an O...C distance of 1.877 A. HLADH

  20. Catalase increases ethanol oxidation through the purine catabolism in rat liver.

    PubMed

    Villalobos-García, Daniel; Hernández-Muñoz, Rolando

    2017-08-01

    Hepatic ethanol oxidation increases according to its concentration and is raised to near-saturation levels of alcohol dehydrogenase (ADH); therefore, re-oxidation of NADH becomes rate limiting in ethanol metabolism by the liver. Adenosine is able to increase liver ethanol oxidation in both in vivo and in vitro conditions; the enhancement being related with the capacity of the nucleoside to accelerate the transport of cytoplasmic reducing equivalents to mitochondria, by modifying the subcellular distribution of the malate-aspartate shuttle components. In the present study, we explored the putative effects of adenosine and other purines on liver ethanol oxidation mediated by non-ADH pathways. Using the model of high precision-cut rat liver slices, a pronounced increase of ethanol oxidation was found in liver slices incubated with various intermediates of the purine degradation pathway, from adenosine to uric acid (175-230%, over controls). Of these, urate had the strongest (230%), whereas xanthine had the less pronounced effect (178% over controls). The enhancement was not abolished by 4-methylpyrazole, indicating that the effect was independent of alcohol dehydrogenase. Conversely, aminotriazole, a catalase inhibitor, completely abolished the effect, pointing out that this enhanced ethanol oxidation is mediated by catalase activity. It is concluded that the H2O2 needed for catalase activity is derived from the oxidation of (hypo)xanthine by xanthine oxidase and the oxidation of urate by uricase. The present and previous data led us to propose that, depending on the metabolic conditions, adenosine might be able to stimulate the metabolism of ethanol through different pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Efficacy of grape seed and skin extract against doxorubicin-induced oxidative stress in rat liver.

    PubMed

    Mokni, Meherzia; Hamlaoui, Sonia; Kadri, Safouen; Limam, Ferid; Amri, Mohamed; Marzouki, Lamjed; Aouani, Ezzedine

    2015-11-01

    Doxorubicin (Dox) is an anthracycline used in chemotherapy, although it causes toxicity and oxidative stress. Grape seed and skin extract (GSSE) is a mixture of polyphenolic compounds with antioxidant properties. To evaluate the hepato-toxicity of Dox on healthy rats as well as the protective effect of GSSE, rats were treated with GSSE (500mg/kg bw) during 8 days. At the 4th day of treatment, they received a single dose of Dox (20 mg/kg bw). After the treatment (9th day), livers were collected and processed for oxidative stress status. Dox increased MDA (+ 900%), decreased catalase (-60%) and increased peroxidase (+90%) and superoxide dismutase (+100%) activities. In this latter case Dox mainly increased the iron isoform. Furthermore Dox altered intracellular mediators as catalytic free iron (-75%), H₂O₂(-75%) and calcium (+30%). Dox also affected liver function by elevating plasma triacylglycerol and transaminases and liver morphology by altering its typical architecture. Importantly all Dox-induced liver disturbances were alleviated upon GSSE treatment. Dox induced liver toxicity and an oxidative stress mainly characterized by increased lipoperoxidation but not protein carbonylation. GSSE efficiently protected the liver from Dox-induced toxicity and appeared as a safe adjuvant that could be incorporated into chemotherapy protocols.

  2. Changes in Liver Ganglioside Metabolism in Obstructive Cholestasis - the Role of Oxidative Stress.

    PubMed

    Šmíd, V; Petr, T; Váňová, K; Jašprová, J; Šuk, J; Vítek, L; Šmíd, F; Muchová, L

    2016-01-01

    Bile acids have been implicated in cholestatic liver damage, primarily due to their detergent effect on membranes and induction of oxidative stress. Gangliosides can counteract these harmful effects by increasing the rigidity of the cytoplasmic membrane. Induction of haem oxygenase (HMOX) has been shown to protect the liver from increased oxidative stress. The aim of this study was to determine the changes in the synthesis and distribution of liver gangliosides following bile duct ligation (BDL), and to assess the effects of HMOX both on cholestatic liver injury and ganglioside metabolism. Compared to controls, BDL resulted in a significant increase in total as well as complex gangliosides and mRNA expression of corresponding glycosyltransferases ST3GalV, ST8SiaI and B3GalTIV. A marked shift of GM1 ganglioside from the intracellular compartment to the cytoplasmic membrane was observed following BDL. Induction of oxidative stress by HMOX inhibition resulted in a further increase of these changes, while HMOX induction prevented this effect. Compared to BDL alone, HMOX inhibition in combination with BDL significantly increased the amount of bile infarcts, while HMOX activation decreased ductular proliferation. We have demonstrated that cholestasis is accompanied by significant changes in the distribution and synthesis of liver gangliosides. HMOX induction results in attenuation of the cholestatic pattern of liver gangliosides, while HMOX inhibition leads to the opposite effect.

  3. Protective role of erdosteine on vancomycin-induced oxidative stress in rat liver.

    PubMed

    Sahin, Mehmet; Cam, Hakan; Olgar, Seref; Tunc, Sevket Ercan; Arslan, Cagatay; Uz, Efkan; Yilmaz, H Ramazan

    2006-10-01

    Drug-induced liver toxicity is a common cause of liver injury. This study was designed to elucidate whether high dose vancomycin (VCM) induces oxidative stress in liver and to investigate the protective effects of erdosteine, an expectorant agent. Twenty-two young Wistar rats were divided into three groups as follows: control group, VCM, and VCM plus erdosteine. VCM was administered intraperitoneally in the dosage of 200 mg/kg twice daily for 7 days. Erdosteine was administered orally administered once a day at a dose of 10 mg/kg body weight. The activities of antioxidant enzymes such as superoxide dismutase and catalase as well as the concentration of malondialdehyde, as an indicator of lipid peroxidation, were measured to evaluate oxidative stress in homogenates of the liver. VCM administration increased malondialdehyde levels (p < 0.001), superoxide dismutase (p < 0.01) and catalase (p < 0.001) activities. Erdosteine co-administration with VCM injections caused significantly decreased malondialdehyde levels (p < 0.001), superoxide dismutase (p < 0.01) and catalase (p < 0.001) activities in liver tissue when compared with VCM alone. It can be concluded that erdosteine may prevent VCM-induced oxidative changes in liver by reducing reactive oxygen species.

  4. In vivo siRNA delivery of Keap1 modulates death and survival signaling pathways and attenuates concanavalin-A-induced acute liver injury in mice

    PubMed Central

    González-Rodríguez, Águeda; Reibert, Bjorn; Amann, Thomas; Constien, Rainier; Rondinone, Cristina M.; Valverde, Ángela M.

    2014-01-01

    Oxidative stress contributes to the progression of acute liver failure (ALF). Transcription factor nuclear factor-erythroid 2-related factor (Nrf2) serves as an endogenous regulator by which cells combat oxidative stress. We have investigated liver damage and the balance between death and survival signaling pathways in concanavalin A (ConA)-mediated ALF using in vivo siRNA delivery targeting Keap1 in hepatocytes. For that goal, mice were injected with Keap1- or luciferase-siRNA-containing liposomes via the tail vein. After 48 hours, ALF was induced by ConA. Liver histology, pro-inflammatory mediators, antioxidant responses, cellular death, and stress and survival signaling were assessed. Keap1 mRNA and protein levels significantly decreased in livers of Keap1-siRNA-injected mice. In these animals, histological liver damage was less evident than in control mice when challenged with ConA. Likewise, markers of cellular death (FasL and caspases 8, 3 and 1) decreased at 4 and 8 hours post-injection. Nuclear Nrf2 and its target, hemoxygenase 1 (HO1), were elevated in Keap1-siRNA-injected mice compared with control animals, resulting in reduced oxidative stress in the liver. Similarly, mRNA levels of pro-inflammatory cytokines were reduced in livers from Keap1-siRNA-injected mice. At the molecular level, activation of c-jun (NH2) terminal kinase (JNK) was ameliorated, whereas the insulin-like growth factor I receptor (IGFIR) survival pathway was maintained upon ConA injection in Keap1-siRNA-treated mice. In conclusion, our results have revealed a potential therapeutic use of in vivo siRNA technology targeted to Keap1 to combat oxidative stress by modulating Nrf2-mediated antioxidant responses and IGFIR survival signaling during the progression of ALF. PMID:24997191

  5. Dietary moderately oxidized oil induces expression of fibroblast growth factor 21 in the liver of pigs

    PubMed Central

    2012-01-01

    Background Fibroblast growth factor 21 (FGF21), whose expression is induced by peroxisome proliferator-activated receptor α (PPARα), has been recently identified as a novel metabolic regulator which plays a crucial role in glucose homeostasis, lipid metabolism, insulin sensitivity and obesity. Previous studies have shown that administration of oxidized fats leads to an activation of PPARα in the liver. Therefore, the present study investigated the hypothesis that feeding of oxidized fats causes an induction of FGF21 in the liver. Methods Twenty four crossbred pigs were allocated to two groups of 12 pigs each and fed nutritionally adequate diets with either fresh rapeseed oil or oxidized rapeseed oil prepared by heating at a temperature of 175°C for 72 h. Results In pigs fed the oxidized fat mRNA abundance and protein concentrations of FGF21 in liver were significantly increased (P < 0.05), and the protein concentrations of FGF21 in plasma tended to be increased (P < 0.1) in comparison to control pigs. Moreover, pigs fed the oxidized fat had increased transcript levels of the PPARα target genes acyl-CoA oxidase, carnitine palmitoyltransferase-1 and novel organic cation transporter 2 in the liver (P < 0.05), indicative of PPARα activation. Conclusion The present study shows for the first time that administration of an oxidized fat induces the expression of FGF21 in the liver, probably mediated by activation of PPARα. Induction of FGF21 could be involved in several effects observed in animals administered an oxidized fat. PMID:22394566

  6. Chronic Arsenic Exposure-Induced Oxidative Stress is Mediated by Decreased Mitochondrial Biogenesis in Rat Liver.

    PubMed

    Prakash, Chandra; Kumar, Vijay

    2016-09-01

    The present study was executed to study the effect of chronic arsenic exposure on generation of mitochondrial oxidative stress and biogenesis in rat liver. Chronic sodium arsenite treatment (25 ppm for 12 weeks) decreased mitochondrial complexes activity in rat liver. There was a decrease in mitochondrial superoxide dismutase (MnSOD) activity in arsenic-treated rats that might be responsible for increased protein and lipid oxidation as observed in our study. The messenger RNA (mRNA) expression of mitochondrial and nuclear-encoded subunits of complexes I (ND1 and ND2) and IV (COX I and COX IV) was downregulated in arsenic-treated rats only. The protein and mRNA expression of MnSOD was reduced suggesting increased mitochondrial oxidative damage after arsenic treatment. There was activation of Bax and caspase-3 followed by release of cytochrome c from mitochondria suggesting induction of apoptotic pathway under oxidative stress. The entire phenomenon was associated with decrease in mitochondrial biogenesis as evident by decreased protein and mRNA expression of nuclear respiratory factor 1 (NRF-1), nuclear respiratory factor 2 (NRF-2), peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), and mitochondrial transcription factor A (Tfam) in arsenic-treated rat liver. The results of the present study indicate that arsenic-induced mitochondrial oxidative stress is associated with decreased mitochondrial biogenesis in rat liver that may present one of the mechanisms for arsenic-induced hepatotoxicity.

  7. Influence of thermally-oxidized vegetable oils and animal fats on growth performance, liver gene expression, and liver and serum cholesterol and triglycerides in young pigs

    USDA-ARS?s Scientific Manuscript database

    To evaluate the effect of feeding thermally-oxidized vegetable oils and animal fats on growth performance, liver gene expression, and liver and serum fatty acid and cholesterol concentration in young pigs, 102 barrows (6.67 ± 0.03 kg BW) were divided into 3 groups and randomly assigned to dietary tr...

  8. Exercise reduces inflammation and oxidative stress in obesity-related liver diseases.

    PubMed

    Oh, Sechang; Tanaka, Kiyoji; Warabi, Eiji; Shoda, Junichi

    2013-12-01

    Weight reduction remains the most common therapy advocated for the treatment of obesity-related liver diseases. Recently, a beneficial effect of exercise regimens for liver dysfunction, independent of weight reduction, has been reported. Therefore, a retrospective analysis was conducted to determine whether exercise training without dietary restriction in obese, middle-age men influences the pathophysiology of abnormal liver function. A total of 108 subjects who completed a 12-wk exercise training program without any dietary restriction were analyzed in this study; these results were compared with those of 104 subjects who completed a 12-wk dietary restriction program. Furthermore, 42 of these subjects (from both groups) who had abnormal liver function and suspicious liver fibrosis by nonalcoholic fatty liver disease fibrosis score were analyzed to obtain a more concrete outcome for exercise-training effects. In exercise training, although the magnitude of body-weight reduction (-3.1% vs -8.5%), waist circumference (-4.0% vs -7.1%), and visceral adipose tissue area (-12.2% vs -22.5%) was significantly more modest than that achieved by dietary restriction, exercise training elicited equivalent reductions in serum alanine aminotransferase and gamma glutamyl transpeptidase levels (-20.6% vs -16.1% and -25.7% vs -34.0%) and equivalent improvement of insulin resistance (-29.7% vs -26.9%). Moreover, exercise training remarkably increased the serum adiponectin level (+33.4% vs +15.1%). Importantly, for subjects with abnormal liver function and suspicious liver fibrosis, exercise training was effective in reducing the serum levels of inflammation and oxidative stress markers: ferritin and thiobarbituric acid reactive substances (-25.0% vs +1.1% and -33.5% vs -10.5%). Exercise training benefits the management of obesity-related liver diseases independent of detectable weight reduction. Particularly, these effects seem to be acquired through an improvement in the hepatic

  9. Intermittent selective clamping improves rat liver regeneration by attenuating oxidative and endoplasmic reticulum stress

    PubMed Central

    Ben Mosbah, I; Duval, H; Mbatchi, S-F; Ribault, C; Grandadam, S; Pajaud, J; Morel, F; Boudjema, K; Compagnon, P; Corlu, A

    2014-01-01

    Intermittent clamping of the portal trial is an effective method to avoid excessive blood loss during hepatic resection, but this procedure may cause ischemic damage to liver. Intermittent selective clamping of the lobes to be resected may represent a good alternative as it exposes the remnant liver only to the reperfusion stress. We compared the effect of intermittent total or selective clamping on hepatocellular injury and liver regeneration. Entire hepatic lobes or only lobes to be resected were subjected twice to 10 min of ischemia followed by 5 min of reperfusion before hepatectomy. We provided evidence that the effect of intermittent clamping can be damaging or beneficial depending to its mode of application. Although transaminase levels were similar in all groups, intermittent total clamping impaired liver regeneration and increased apoptosis. In contrast, intermittent selective clamping improved liver protein secretion and hepatocyte proliferation when compared with standard hepatectomy. This beneficial effect was linked to better adenosine-5′-triphosphate (ATP) recovery, nitric oxide production, antioxidant activities and endoplasmic reticulum adaptation leading to limit mitochondrial damage and apoptosis. Interestingly, transient and early chaperone inductions resulted in a controlled activation of the unfolded protein response concomitantly to endothelial nitric oxide synthase, extracellular signal-regulated kinase-1/2 (ERK1/2) and p38 MAPK activation that favors liver regeneration. Endoplasmic reticulum stress is a central target through which intermittent selective clamping exerts its cytoprotective effect and improves liver regeneration. This procedure could be applied as a powerful protective modality in the field of living donor liver transplantation and liver surgery. PMID:24603335

  10. Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: a histopathological study.

    PubMed

    Zlatković, Jelena; Todorović, Nevena; Tomanović, Nada; Bošković, Maja; Djordjević, Snežana; Lazarević-Pašti, Tamara; Bernardi, Rick E; Djurdjević, Aleksandra; Filipović, Dragana

    2014-08-01

    Chronic exposure to stress contributes to the etiology of mood disorders, and the liver as a target organ of antidepressant and antipsychotic drug metabolism is vulnerable to drug-induced toxicity. We investigated the effects of chronic administration of fluoxetine (15mg/kg/day) or clozapine (20mg/kg/day) on liver injury via the measurement of liver enzymes, oxidative stress and histopathology in rats exposed to chronic social isolation (21days), an animal model of depression, and controls. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the liver content of carbonyl groups, malonyldialdehyde (MDA), reduced glutathione (GSH), cytosolic glutathione S-transferase (GST) and nitric oxide (NO) metabolites were determined. We also characterized nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2) and CuZn-superoxide dismutase (CuZnSOD) protein expression as well as histopathological changes. Increased serum ALT activity in chronically-isolated and control animals treated with both drugs was found while increased AST activity was observed only in fluoxetine-treated rats (chronically-isolated and controls). Increased carbonyl content, MDA, GST activity and decreased GSH levels in drug-treated controls/chronically-isolated animals suggest a link between drugs and hepatic oxidative stress. Increased NO levels associated with NF-κB activation and the concomitant increased COX-2 expression together with compromised CuZnSOD expression in clozapine-treated chronically-isolated rats likely reinforce oxidative stress, observed by increased lipid peroxidation and GSH depletion. In contrast, fluoxetine reduced NO levels in chronically-isolated rats. Isolation induced oxidative stress but histological changes were similar to those observed in vehicle-treated controls. Chronic administration of fluoxetine in both chronically-isolated and control animals resulted in more or less normal hepatic architecture, while clozapine in both groups

  11. Longitudinal study of circulating oxidized LDL and HDL and fatty liver: the Cardiovascular Risk in Young Finns Study.

    PubMed

    Kaikkonen, Jari E; Kresanov, Petri; Ahotupa, Markku; Jula, Antti; Mikkilä, Vera; Viikari, Jorma S A; Juonala, Markus; Hutri-Kähönen, Nina; Kähönen, Mika; Lehtimäki, Terho; Kangas, Antti J; Soininen, Pasi; Ala-Korpela, Mika; Raitakari, Olli T

    2016-01-01

    Oxidative reactions are thought to play a role in the inflammatory condition called fatty liver. It is unclear whether oxidized lipoprotein lipids or proteins are associated with future fatty liver. In the Cardiovascular Risk in Young Finns Study, we determined the circulating levels of LDL and HDL oxidized lipids and studied their associations with fatty liver assessed by ultrasonography. There were 1286 middle-aged subjects with normal liver and 288 subjects with fatty liver. Analysis of oxidized lipids consisted of conjugated dienes in isolated HDL (oxHDLlipids) and LDL (oxLDLlipids). Oxidized LDL was also measured with a method based on antibodies against oxidized apolipoprotein B (oxLDLprot). After adjustment for age, sex, leisure-time physical activity, body mass index, alcohol intake, smoking, serum LDL and HDL cholesterol as well as particle concentrations, participants with elevated oxLDLlipids (odds ratio for 1-SD change in oxLDLlipids = 1.27, p =0.011) had an increased risk for fatty liver. Similarly, a high oxidation score (oxLDLlipids + oxLDLprot) was directly associated with fatty liver (odds ratio=1.34, p = 0.012). The strongest direct association was seen with a high oxLDLlipids/oxHDLlipids ratio (odds ratio=1.49, p = 0.001). These data suggest that oxidized lipoprotein lipids are linked with the risk of fatty liver in middle-aged adults.

  12. Aminotriazole attenuated carbon tetrachloride-induced oxidative liver injury in mice.

    PubMed

    Deng, Xinyu; Wu, Kunwei; Wan, Jingyuan; Li, Longjiang; Jiang, Rong; Jia, Mengying; Jing, Yuping; Zhang, Li

    2012-09-01

    Carbon tetrachloride (CCl(4)) has been used extensively to study xenobiotic-induced oxidative liver injury. Catalase (CAT) is a major antioxidant enzyme while aminotriazole (ATZ) is commonly used as a CAT inhibitor. In the present study, the effects of ATZ on CCl(4)-induced liver injury were investigated. Our experimental data showed that pretreatment with ATZ significantly decreased CCl(4)-induced elevation of serum aspartate transaminase (AST) and alanine transaminase (ALT) and improved hepatic histopathological abnormality. ATZ dose-dependently inhibited the activity of CAT, but it reduced the content of H(2)O(2) and the levels of malondialdehyde (MDA) in liver tissues. ATZ decreased plasma level of pro-inflammatory cytokines (TNF-α and IL-6) and reduced hepatic levels of myeloperoxidase (MPO). In addition, posttreatment with ATZ also decreased the level of ALT and AST. These data indicated that ATZ effectively alleviated CCl(4)-induced oxidative liver damage. These findings suggested that ATZ might have potential value in preventing oxidative liver injury. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Sesamin ameliorates oxidative liver injury induced by carbon tetrachloride in rat.

    PubMed

    Lv, Dan; Zhu, Chang-Qing; Liu, Li

    2015-01-01

    Sesamin is naturally occurring lignan from sesame oil with putative antioxidant property. The present study was designed to investigate the protective role of sesamin against carbon tetrachloride induced oxidative liver injury. Male Wistar albino rats (180-200 g) were divided in to 5 groups (n=6). Hepatotoxicity was induced by the administration of CCl4 (0.1 ml/100 g bw., 50% v/v with olive oil) intraperitoneally. Sesamin was administered in two different dose (5 and 10 ml/kg bw) to evaluate the hepatoprotective activity. Sesamin significantly reduced the elevated serum liver marker enzymes (P<0.0001). Reduction of TBARS (P<0.01 and P<0.001) followed by enhancement of GSH., SOD and catalase (P<0.0001) in liver homogenate in sesamin treated groups shows the amelioration of oxidative stress induced by CCl4. Histopathological report also supported the hepatoprotection offered by sesamin. Sesamin effects in both the dose were in comparable to reference standard drug silymarin. From these above findings it has been concluded that sesamin ameliorate the oxidative liver injury in terms of reduction of lipid peroxidation and enhancement of liver antioxidant enzymes.

  14. Sesamin ameliorates oxidative liver injury induced by carbon tetrachloride in rat

    PubMed Central

    Lv, Dan; Zhu, Chang-Qing; Liu, Li

    2015-01-01

    Sesamin is naturally occurring lignan from sesame oil with putative antioxidant property. The present study was designed to investigate the protective role of sesamin against carbon tetrachloride induced oxidative liver injury. Male Wistar albino rats (180-200 g) were divided in to 5 groups (n=6). Hepatotoxicity was induced by the administration of CCl4 (0.1 ml/100 g bw., 50% v/v with olive oil) intraperitoneally. Sesamin was administered in two different dose (5 and 10 ml/kg bw) to evaluate the hepatoprotective activity. Sesamin significantly reduced the elevated serum liver marker enzymes (P<0.0001). Reduction of TBARS (P<0.01 and P<0.001) followed by enhancement of GSH., SOD and catalase (P<0.0001) in liver homogenate in sesamin treated groups shows the amelioration of oxidative stress induced by CCl4. Histopathological report also supported the hepatoprotection offered by sesamin. Sesamin effects in both the dose were in comparable to reference standard drug silymarin. From these above findings it has been concluded that sesamin ameliorate the oxidative liver injury in terms of reduction of lipid peroxidation and enhancement of liver antioxidant enzymes. PMID:26191289

  15. Chlorogenic and Caftaric Acids in Liver Toxicity and Oxidative Stress Induced by Methamphetamine

    PubMed Central

    Koriem, Khaled M. M.; Soliman, Rowan E.

    2014-01-01

    Methamphetamine intoxication can cause acute hepatic failure. Chlorogenic and caftaric acids are the major dietary polyphenols present in various foods. The aim of this study was to evaluate the protective role of chlorogenic and caftaric acids in liver toxicity and oxidative stress induced by methamphetamine in rats. Thirty-two male albino rats were divided into 4 equal groups. Group 1, which was control group, was injected (i.p) with saline (1 mL/kg) twice a day over seven-day period. Groups 2, 3, and 4 were injected (i.p) with methamphetamine (10 mg/kg) twice a day over seven-day period, where groups 3 and 4 were injected (i.p) with 60 mg/kg chlorogenic acid and 40 mg/kg caftaric acid, respectively, one day before methamphetamine injections. Methamphetamine increased serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, cholesterol, low-density lipoprotein, and triglycerides. Also, malondialdehyde in serum, liver, and brain and plasma and liver nitric oxide levels were increased while methamphetamine induced a significant decrease in serum total protein, albumin, globulin, albumin/globulin ratio, brain serotonin, norepinephrine and dopamine, blood and liver superoxide dismutase, and glutathione peroxidase levels. Chlorogenic and caftaric acids prior to methamphetamine injections restored all the above parameters to normal values. In conclusion, chlorogenic and caftaric acids before methamphetamine injections prevented liver toxicity and oxidative stress where chlorogenic acid was more effective. PMID:25136360

  16. Chlorogenic and caftaric acids in liver toxicity and oxidative stress induced by methamphetamine.

    PubMed

    Koriem, Khaled M M; Soliman, Rowan E

    2014-01-01

    Methamphetamine intoxication can cause acute hepatic failure. Chlorogenic and caftaric acids are the major dietary polyphenols present in various foods. The aim of this study was to evaluate the protective role of chlorogenic and caftaric acids in liver toxicity and oxidative stress induced by methamphetamine in rats. Thirty-two male albino rats were divided into 4 equal groups. Group 1, which was control group, was injected (i.p) with saline (1 mL/kg) twice a day over seven-day period. Groups 2, 3, and 4 were injected (i.p) with methamphetamine (10 mg/kg) twice a day over seven-day period, where groups 3 and 4 were injected (i.p) with 60 mg/kg chlorogenic acid and 40 mg/kg caftaric acid, respectively, one day before methamphetamine injections. Methamphetamine increased serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, cholesterol, low-density lipoprotein, and triglycerides. Also, malondialdehyde in serum, liver, and brain and plasma and liver nitric oxide levels were increased while methamphetamine induced a significant decrease in serum total protein, albumin, globulin, albumin/globulin ratio, brain serotonin, norepinephrine and dopamine, blood and liver superoxide dismutase, and glutathione peroxidase levels. Chlorogenic and caftaric acids prior to methamphetamine injections restored all the above parameters to normal values. In conclusion, chlorogenic and caftaric acids before methamphetamine injections prevented liver toxicity and oxidative stress where chlorogenic acid was more effective.

  17. Interaction of silicon-based quantum dots with gibel carp liver: oxidative and structural modifications

    NASA Astrophysics Data System (ADS)

    Stanca, Loredana; Petrache, Sorina Nicoleta; Serban, Andreea Iren; Staicu, Andrea Cristina; Sima, Cornelia; Munteanu, Maria Cristina; Zărnescu, Otilia; Dinu, Diana; Dinischiotu, Anca

    2013-05-01

    Quantum dots (QDs) interaction with living organisms is of central interest due to their various biological and medical applications. One of the most important mechanisms proposed for various silicon nanoparticle-mediated toxicity is oxidative stress. We investigated the basic processes of cellular damage by oxidative stress and tissue injury following QD accumulation in the gibel carp liver after intraperitoneal injection of a single dose of 2 mg/kg body weight Si/SiO2 QDs after 1, 3, and 7 days from their administration. QDs gradual accumulation was highlighted by fluorescence microscopy, and subsequent histological changes in the hepatic tissue were noted. After 1 and 3 days, QD-treated fish showed an increased number of macrophage clusters and fibrosis, while hepatocyte basophilia and isolated hepatolytic microlesions were observed only after substantial QDs accumulation in the liver parenchyma, at 7 days after IP injection. Induction of oxidative stress in fish liver was revealed by the formation of malondialdehyde and advanced oxidation protein products, as well as a decrease in protein thiol groups and reduced glutathione levels. The liver enzymatic antioxidant defense was modulated to maintain the redox status in response to the changes initiated by Si/SiO2 QDs. So, catalase and glutathione peroxidase activities were upregulated starting from the first day after injection, while the activity of superoxide dismutase increased only after 7 days. The oxidative damage that still occurred may impair the activity of more sensitive enzymes. A significant inhibition in glucose-6-phosphate dehydrogenase and glutathione-S-transferase activity was noted, while glutathione reductase remained unaltered. Taking into account that the reduced glutathione level had a deep decline and the level of lipid peroxidation products remained highly increased in the time interval we studied, it appears that the liver antioxidant defense of Carassius gibelio does not counteract the

  18. Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis

    PubMed Central

    Ivanov, Alexander V.; Valuev-Elliston, Vladimir T.; Tyurina, Daria A.; Ivanova, Olga N.; Kochetkov, Sergey N.; Bartosch, Birke; Isaguliants, Maria G.

    2017-01-01

    Virally induced liver cancer usually evolves over long periods of time in the context of a strongly oxidative microenvironment, characterized by chronic liver inflammation and regeneration processes. They ultimately lead to oncogenic mutations in many cellular signaling cascades that drive cell growth and proliferation. Oxidative stress, induced by hepatitis viruses, therefore is one of the factors that drives the neoplastic transformation process in the liver. This review summarizes current knowledge on oxidative stress and oxidative stress responses induced by human hepatitis B and C viruses. It focuses on the molecular mechanisms by which these viruses activate cellular enzymes/systems that generate or scavenge reactive oxygen species (ROS) and control cellular redox homeostasis. The impact of an altered cellular redox homeostasis on the initiation and establishment of chronic viral infection, as well as on the course and outcome of liver fibrosis and hepatocarcinogenesis will be discussed The review neither discusses reactive nitrogen species, although their metabolism is interferes with that of ROS, nor antioxidants as potential therapeutic remedies against viral infections, both subjects meriting an independent review. PMID:27965466

  19. The effects of cold-induced stress on liver oxidative injury during binge drinking.

    PubMed

    Ostojić, Jelena Nešović; Mladenović, Dušan; Ninković, Milica; Vučević, Danijela; Bondžić, Kristina; Ješić-Vukićević, Rada; Radosavljević, Tatjana

    2012-04-01

    The aim of our study was to evaluate the effects of cold stress on hepatic oxidative damage during binge drinking in rats. Male Wistar rats were divided into the following groups: group 1: control; group 2: ethanol-treated; group 3: stress-exposed; group 4: stress-exposed and ethanol-treated group. Oxidative and nitrosative stress parameters in the liver were determined spectrophotometrically, 12 h after treatment. Liver malondialdehyde concentration was significantly higher in group 4 when compared with groups 2 and 3. The highest increase in nitric oxide concentration was demonstrated in group 4 in comparison with groups 2 and 3. Superoxide dismutase (SOD) activity was significantly lower in group 4 when compared with groups 2 and 3. Ethanol administration induced a larger decrease in the activity of copper-/zinc-SOD in group 4 in comparison with group 2. Activity of manganese-SOD (Mn-SOD) was significantly higher in groups 3 and 4, when compared with control values, but the greatest increase in the activity of Mn-SOD was demonstrated in group 2. We also evaluated statistically significant decrease in the level of reduced gluthatione in the liver of group 4 in comparison with group 3. Based on our study, it can be concluded that cold-exposed stress and binge ethanol drinking have additive effects in imbalance between pro-oxidant and antioxidant defense system in liver.

  20. The effect of grape seed extract on radiation-induced oxidative stress in the rat liver.

    PubMed

    Cetin, Aysun; Kaynar, Leylagül; Koçyiğit, Ismail; Hacioğlu, Sibel Kabukçu; Saraymen, Recep; Oztürk, Ahmet; Orhan, Okan; Sağdiç, Osman

    2008-06-01

    The tolerance of the liver is considerably low when an effective radiation (RTx) dose needs to be delivered in patients in whom either their liver or whole body area has to be irradiated. The aim of this study was to evaluate the possible protective effect of grape seed extract on liver toxicity induced by RTx in the rat liver. We used four groups, each consisting of 12 healthy male Wistar rats. RTx-grape seed extract group: rats were given grape seed extract (100 mg/kg) orally for seven days, following 8 Gy whole body irradiation, and grape seed extract was maintained for four days. RTx group: the same protocol was applied in this group; however, they received distilled water instead of grape seed extract. Grape seed extract group: only grape seed extract solution was administered for 11 consecutive days in the same fashion. only distilled water (orally) was administered in a similar manner. The level of malondialdehyde, an end product of lipid peroxidation, and the activities of superoxide dismutase and catalase, two important endogenous antioxidants, were evaluated in tissue homogenates. Grape seed extract was seen to protect the cellular membrane from oxidative damage and consequently from protein and lipid oxidation. In the RTx group, malondialdehyde levels were extremely higher than those of the grape seed extract-RTx group (p<0.001). Grape seed extract administration moderately reserved the malondialdehyde levels. RTx therapy decreased superoxide dismutase and catalase activities in the liver homogenates (p<0.001), and these alterations were significantly reversed by grape seed extract treatment (p<0.001). There were no differences between the grape seed extract- RTx, grape seed extract and control groups with regard to antioxidant activity (p>0.05). The levels of antioxidant parameters on RTx-induced liver toxicity were restored to control values with grape seed extract therapy. Grape seed extract may be promising as a therapeutic option in RTx

  1. Liver triglyceride secretion and lipid oxidative metabolism are rapidly altered by leptin in vivo.

    PubMed

    Huang, Wan; Dedousis, Nikolas; Bandi, Archana; Lopaschuk, Gary D; O'Doherty, Robert M

    2006-03-01

    Leptin has potent lipid-lowering effects in peripheral tissues and plasma that are proposed to be important for the prevention of cellular lipotoxicity and insulin resistance. The current study addressed in vivo the effects of acute leptin delivery on liver triglyceride (TG) metabolism, the consequence of hepatic leptin action on whole-body TG homeostasis, and the mechanisms of leptin action. A 120-min iv leptin infusion (plasma leptin, approximately 14 ng/ml) decreased liver TG levels (53 +/- 3%; P = 0.001), but not skeletal muscle TG levels, and increased liver phosphatidylinositol 3-kinase activity (341 +/- 95%; P = 0.01) in lean rats. Leptin had no effect on liver TG levels or phosphatidylinositol 3-kinase activity in diet-induced obese rats. In lean animals, leptin decreased the plasma TG concentration (20 +/- 7%; P = 0.017), the rate of TG accumulation in plasma after tyloxapol administration (26 +/- 6%; P = 0.003), and TG secretion from isolated liver (51 +/- 8%; P = 0.004). To determine possible metabolic fates of depleted hepatic TG, we assessed leptin effects on liver oxidative metabolism. Leptin increased hepatic acetyl-coenzyme A carboxylase phosphorylation (85 +/- 13%; P = 0.006), fatty acid oxidation (49 +/- 7%; P = 0.001) and ketogenesis (69 +/- 15%; P = 0.004). Finally, intracerebroventricular delivery of leptin for 120 min had no effect on liver TG levels, but did increase signal transducer and activator of transcription 3 phosphorylation (162 +/- 40%; P = 0.02). These data present in vivo evidence for a role for leptin in the acute regulation of hepatic TG metabolism, and whole body TG homeostasis. A likely contributing mechanism for these effects is leptin-induced partitioning of TG into oxidative pathways.

  2. Oxidative Stress and DNA Damage Induced by Chromium in Liver and Kidney of Goldfish, Carassius auratus

    PubMed Central

    Velma, Venkatramreddy; Tchounwou, Paul B.

    2013-01-01

    Chromium (Cr) is an abundant element in the Earth’s crust. It exhibits various oxidation states, from divalent to hexavalent forms. Cr has diverse applications in various industrial processes and inadequate treatment of the industrial effluents leads to the contamination of the surrounding water resources. Hexavalent chromium (Cr (VI)) is the most toxic form, and its toxicity has been associated with oxidative stress. The present study was designed to investigate the toxic potential of Cr (VI) in fish. In this research, we investigated the role of oxidative stress in chromium-induced genotoxicity in the liver and kidney cells of goldfish, Carassius auratus. Goldfish were acclimatized to the laboratory conditions and exposed them to 5% and 10% of 96 hr-LC50 (85.7 mg/L) of aqueous Cr (VI) in a continuous flow through system. Fish were sampled every 7 days for a period of 28 days to analyze the lipid hydroperoxides (LHP) levels and genotoxic potentials in the liver and kidney. LHP levels were analyzed by spectrophotometry while genotoxicity was assessed by single cell gel electrophoresis (comet) assay. LHP levels in the liver increased significantly at week 1, followed by a decrease. LHP levels in the kidney increased significantly at weeks 1, 2, and 3, and decreased at week 4 compared to the control. The percentage of DNA damage increased in both liver and kidney at both test concentrations. The results clearly indicate that Cr (VI) induces significant levels of DNA damage in liver and kidney cells of goldfish. The induced LHP levels in both organs were concentration-dependent and were directly correlated with the levels of DNA damage. The two tested Cr (VI) concentrations induced significant levels of oxidative stress in both organs, however the kidney appears to be more vulnerable and sensitive to Cr-induced toxicity than the liver. PMID:23700361

  3. Enzymic oxidation of unconjugated bilirubin by rat liver.

    PubMed Central

    Cardenas-Vazquez, R; Yokosuka, O; Billing, B H

    1986-01-01

    The presence of the enzyme bilirubin oxidase, which degrades bilirubin in vitro, was demonstrated in the liver. Subcellular-fractionation experiments indicate that bilirubin oxidase is located in both the inner and outer membranes of the mitochondria. The mean rate of the reaction is 1.57 +/- 0.38 (S.D.) nmol of bilirubin degraded/min per mg of mitochondrial protein (munits/mg of protein). With respect to the overall breakdown of bilirubin, the enzyme has a Km' of 136 microM-bilirubin and a Vmax.' of 9.13 munits/mg of protein. Its activity is influenced by the ionic strength of the media and is inhibited by KCN, thiol reagents, NADH and albumin. The enzyme is aerobic, and between 1 and 1.5 mol of O2 are consumed per mol of bilirubin degraded. The products of the reaction include propentdyopents. The hepatic bilirubin oxidase activity of the jaundiced Gunn-rat liver is not significantly different from that of the Sprague-Dawley rat, and it is not induced by beta-naphthoflavone. PMID:3790083

  4. Experimental hyperprolinemia induces mild oxidative stress, metabolic changes, and tissue adaptation in rat liver.

    PubMed

    Ferreira, Andréa G K; da Cunha, Aline A; Machado, Fernanda R; Pederzolli, Carolina D; Dalazen, Giovana R; de Assis, Adriano M; Lamers, Marcelo L; dos Santos, Marinilce F; Dutra-Filho, Carlos S; Wyse, Angela T S

    2012-01-01

    The present study investigated the effects of chronic hyperprolinemia on oxidative and metabolic status in liver and serum of rats. Wistar rats received daily subcutaneous injections of proline from their 6th to 28th day of life. Twelve hours after the last injection the rats were sacrificed and liver and serum were collected. Results showed that hyperprolinemia induced a significant reduction in total antioxidant potential and thiobarbituric acid-reactive substances. The activities of the antioxidant enzymes catalase and superoxide dismutase were significantly increased after chronic proline administration, while glutathione (GSH) peroxidase activity, dichlorofluorescin oxidation, GSH, sulfhydryl, and carbonyl content remained unaltered. Histological analyses of the liver revealed that proline treatment induced changes of the hepatic microarchitecture and increased the number of inflammatory cells and the glycogen content. Biochemical determination also demonstrated an increase in glycogen concentration, as well as a higher synthesis of glycogen in liver of hyperprolinemic rats. Regarding to hepatic metabolism, it was observed an increase on glucose oxidation and a decrease on lipid synthesis from glucose. However, hepatic lipid content and serum glucose levels were not changed. Proline administration did not alter the aminotransferases activities and serum markers of hepatic injury. Our findings suggest that hyperprolinemia alters the liver homeostasis possibly by induction of a mild degree of oxidative stress and metabolic changes. The hepatic alterations caused by proline probably do not implicate in substantial hepatic tissue damage, but rather demonstrate a process of adaptation of this tissue to oxidative stress. However, the biological significance of these findings requires additional investigation. Copyright © 2011 Wiley Periodicals, Inc.

  5. Glutathione delays varies as-tocopherol oxidation and subsequent lipid peroxidation in rat liver microsomes

    SciTech Connect

    Robey, S.; Mavis, R.

    1986-05-01

    A method has been developed for in vitro trace radiolabeling of rat liver microsomes with /sup 3/H-..cap alpha..-tocopherol (..cap alpha..T*) which allows virtually complete oxidation of the ..cap alpha..T* under oxidizing conditions. The supernatant of a 16,000 xg centrifugation of homogenized rat liver, containing the cytosolic rat liver vitamin E (VE) transfer protein, was incubated with an ethanolic solution of ..cap alpha..T* for 10 minutes at 37/sup 0/C. Labeled microsomes were collected in the washed 100,000 xg pellet. Microsomes were then incubated with 30 ..mu..M Fe/sup 2 +/ in an NADPH-generating system, and both production of malondialdehyde (MDA) (a product of lipid peroxidation) and oxidation of ..cap alpha..T* were monitored over a time course in the presence and absence of glutathione (GSH). The results indicate virtually complete oxidation of ..cap alpha..T* precedes significant membrane lipid peroxidation, and that addition of 5 mM GSH delays both ..cap alpha..T* oxidation and subsequent MDA production. This suggests that the previously observed VE-dependent heat labile inhibition of microsomal lipid peroxidation by GSH involves maintaining membrane levels of ..cap alpha..-tocopherol.

  6. Involvement of catalase in the protective benefits of metformin in mice with oxidative liver injury.

    PubMed

    Dai, Jie; Liu, Mingwei; Ai, Qing; Lin, Ling; Wu, Kunwei; Deng, Xinyu; Jing, Yuping; Jia, Mengying; Wan, Jingyuan; Zhang, Li

    2014-06-05

    Metformin is a commonly used anti-diabetic drug with AMP-activated protein kinase (AMPK)-dependent hypoglycemic activities. Recent studies have revealed its anti-inflammatory and anti-oxidative properties. In the present study, the anti-oxidative potential of metformin and its potential mechanisms were investigated in a mouse model with carbon tetrachloride (CCl₂)-induced severe oxidative liver injury. Our results showed that treatment with metformin significantly attenuated CCl₂-induced elevation of serum aminotransferases and hepatic histological abnormalities. The alleviated liver injury was associated with decreased hepatic contents of oxidized glutathione (GSSG) and malondialdehyde (MDA). In addition, metformin treatment dose-dependently enhanced the activities of catalase (CAT) and decreased CCl₄-induced elevation of hepatic H₂O₂ levels, but it had no obvious effects on the protein level of CAT. We also found that metformin increased the level of phosphorylated AMP-activated protein kinase (AMPK), but treatment with AMPK activator AICAR had no obvious effects on CAT activity. A molecular docking analysis indicated that metformin might interact with CAT via hydrogen bonds. These data suggested that metformin effectively alleviated CCl₄-induced oxidative liver injury in mice and these hepatoprotective effects might be associated with CAT. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  7. Effects of haloperidol and clozapine administration on oxidative stress in rat brain, liver and serum.

    PubMed

    Andreazza, Ana C; Barakauskas, Vilte E; Fazeli, Salar; Feresten, Abigail; Shao, Li; Wei, Vivien; Wu, Che Hsuan; Barr, Alasdair M; Beasley, Clare L

    2015-03-30

    Antipsychotics remain the standard of care for individuals with schizophrenia, despite their association with adverse effects including extrapyramidal symptoms, metabolic syndrome and agranulocytosis. While the biological mechanisms underlying these side effects remain unresolved, it has been proposed that oxidative stress may play a role in their development. The aim of this study was to evaluate markers of oxidative stress associated with first- and second-generation antipsychotics, focusing on protein and lipid oxidation and expression of the antioxidant proteins peroxiredoxin-2 and peroxiredoxin-6. Following 28-day administration of haloperidol, clozapine or saline to adult rats, brain grey matter, white matter, serum and liver samples were obtained and lipid peroxidation, protein oxidation, peroxiredoxin-2 and peroxiredoxin-6 levels quantified. In grey matter, peroxiredoxin-6 was significantly increased in the haloperidol-exposed animals, with a trend towards increased lipid peroxidation also observed in this group. In liver, lipid peroxidation was increased in the clozapine-exposed animals, with a similar trend noted in the haloperidol group. Antipsychotics did not produce significant changes in serum or white matter. Our results suggest that haloperidol and clozapine may induce oxidative stress in brain and liver, respectively, consistent with the documented adverse effects of these agents. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  8. Treatment with Oxidized Phospholipids Directly Inhibits Nonalcoholic Steatohepatitis and Liver Fibrosis Without Affecting Steatosis.

    PubMed

    Mendel, Itzhak; Yacov, Niva; Shoham, Anat; Ishai, Eti; Breitbart, Eyal

    2016-09-01

    Previous studies demonstrated that toll-like receptors 4 and 2 (TLR-4 and TLR-2), which are expressed on liver-resident Kupffer, hepatic stellate cells, and circulating monocytes, play a role in nonalcoholic fatty liver disease. Lecinoxoids are oxidized phospholipids that antagonize TLR-2- and TLR-4-mediated activation of innate immune cells and inhibit monocyte migration. In this study, we tested the effect of two functionally different lecinoxoids on the development of nonalcoholic steatohepatitis and liver fibrosis in a mouse model. Two-day-old C57BL/6 mice were injected with streptozotocin and fed a high-fat diet from Week 4 after birth. At Week 6 post-birth, lecinoxoids VB-201 or VB-703 were given orally, once daily, for 3 weeks. Telmisartan was administered orally, once daily, for 3 weeks, as positive control. At experiment conclusion, biochemical indices were evaluated. HE stain and quantitative PCR were used to determine the extent of steatosis and steatohepatitis, and Sirius red stain was used to assess liver fibrosis. Treatment with lecinoxoids did not alter the concentration of blood glucose, liver triglycerides, or steatosis compared with solvent-treated mice. However, whereas VB-201 inhibited the development of fibrosis and, to some extent, liver inflammation, VB-703 significantly lessened both liver inflammation and fibrosis. This study indicates that using lecinoxoids to antagonize TLR-2, and more prominently TLR-4, is sufficient to significantly inhibit nonalcoholic steatohepatitis and liver fibrosis. Inhibiting monocyte migration with lecinoxoids that are relatively weak TLR-4 antagonists may alter liver fibrosis and to some extent nonalcoholic steatohepatitis.

  9. Inhibition of retinol oxidation by ethanol in the rat liver and colon

    PubMed Central

    Parlesak, A; Menzl, I; Feuchter, A; Bode, J; Bode, C

    2000-01-01

    BACKGROUND—Epidemiological evidence has been presented for an increased risk of development of colon cancer after chronic alcohol abuse. Alcohol is degraded by cytosolic alcohol dehydrogenases that also are capable of retinol oxidation. Inhibition of retinol oxidation to retinoic acid has been shown to occur in parallel with profound impairment of intracellular retinoid signal transduction and loss of cell differentiation control.
AIMS—In the present study, the change in cytosolic retinol oxidation and retinoic acid formation by ethanol concentrations that occur in body tissues in humans after social drinking was measured in cells from the liver, and small and large intestine of the rat.
RESULTS—The specific catalytic efficiency Vmax/Km (ml/min/g) of cytosolic retinol oxidation in the large intestine (28.9) was found to be distinctly higher than that in the liver (3.4), while the efficiency in the small intestine was negligible (0.20). In the presence of increasing ethanol concentrations (9, 17, and 34 mM), Vmax/Km for retinol oxidation decreased in a dose dependent manner to 7.8% of the initial value in the large intestine and to 12% in the liver. The Vmax/Km of retinoic acid formation in the liver cytosol decreased to 15%.
CONCLUSIONS—Our data demonstrate impairment of hepatic and intestinal cytosolic retinol oxidation and retinoic acid formation by ethanol at concentrations in body tissues after social drinking in humans. The results suggest that the increased risk of developing colorectal neoplasias after alcohol abuse may, at least in part, be caused by impaired retinoid signal transduction.


Keywords: retinol; retinoic acid; ethanol; alcohol; alcohol dehydrogenases; intestine PMID:11076882

  10. Animal models for the study of liver regeneration: role of nitric oxide and prostaglandins.

    PubMed

    Hortelano, Sonsoles; Zeini, Miriam; Casado, Marta; Martín-Sanz, Paloma; Boscá, Lisardo

    2007-01-01

    The mechanisms that permit adult tissues to regenerate are the object of intense study. Liver regeneration is a research area of considerable interest both from pathological and from physiological perspectives. One of the best models of the regenerative process is the two-thirds partial hepatectomy (PH). After PH, the remnant liver starts a series of timed responses that first favor cell growth and then halts hepatocyte proliferation once liver function is fully restored. The mechanisms regulating this process are complex and involve many cellular events. Initiation of liver regeneration requires the injury-related cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6), and involves the activation of cytokine-regulated transcription factors such as NF-kappaB and STAT3. An important event that takes place in the hours immediately after PH is the induction of nitric oxide synthase 2 (NOS-2) and cyclooxygenase 2 (COX-2), and the consequent release of nitric oxide (NO) and prostaglandins (PGs). NO is involved in the vascular readaptation after PH, favoring a general permeability to growth factors throughout the organ. This review examines the mechanisms that regulate NO release during liver regeneration and the animal models used to identify these pathways.

  11. Liver Cholesterol Overload Aggravates Obstructive Cholestasis by Inducing Oxidative Stress and Premature Death in Mice

    PubMed Central

    Nuño-Lámbarri, Natalia; Domínguez-Pérez, Mayra; Baulies-Domenech, Anna; Monte, Maria J.; Marin, Jose J. G.; Rosales-Cruz, Patricia; Souza, Verónica; Miranda, Roxana U.; Bucio, Leticia; Montalvo-Jave, Eduardo E.; Concepción Gutiérrez-Ruiz, María; García-Ruiz, Carmen

    2016-01-01

    Nonalcoholic steatohepatitis is one of the leading causes of liver disease. Dietary factors determine the clinical presentation of steatohepatitis and can influence the progression of related diseases. Cholesterol has emerged as a critical player in the disease and hence consumption of cholesterol-enriched diets can lead to a progressive form of the disease. The aim was to investigate the impact of liver cholesterol overload on the progression of the obstructive cholestasis in mice subjected to bile duct ligation surgery. Mice were fed with a high cholesterol diet for two days and then were subjected to surgery procedure; histological, biochemical, and molecular analyses were conducted to address the effect of cholesterol in liver damage. Mice under the diet were more susceptible to damage. Results show that cholesterol fed mice exhibited increased apoptosis and oxidative stress as well as reduction in cell proliferation. Mortality following surgery was higher in HC fed mice. Liver cholesterol impairs the repair of liver during obstructive cholestasis and aggravates the disease with early fatal consequences; these effects were strongly associated with oxidative stress. PMID:27635189

  12. Non-invasive oxidative stress markers for liver fibrosis development in the evolution of toxic hepatitis.

    PubMed

    Clichici, Simona; Catoi, C; Mocan, T; Filip, A; Login, C; Nagy, A; Daicoviciu, D; Decea, N; Gherman, C; Moldovan, R; Muresan, Adriana

    2011-06-01

    Oxidative stress is related to the liver fibrosis, anticipating the hepatic stellate cells' (HSC) activation. Our aim was to correlate oxidative stress markers with the histological liver alterations in order to identify predictive, noninvasive parameters of fibrosis progression in the evolution of toxic hepatitis.CCl4 in sunflower oil was administered to rats intragastrically, twice a week. After 2, 3, 4 and 8 weeks of treatment, plasma levels of malondialdehyde (MDA), protein carbonyls (PC), hydrogen donor capacity (HD), sulfhydryl groups (SH), and glutathione (GSH) were measured and histological examination of the liver slides was performed. Dynamics of histological disorders was assessed by The Knodell score. Significant elevation of inflammation grade was obtained after the second week of the experiment only (p=0.001), while fibrosis started to become significant (p=0.001) after 1 month of CCl4 administration. Between plasma MDA and liver fibrosis development a good correlation was obtained (r=0.877, p=0.05). Correlation between PC dynamics and liver alterations was marginally significant for inflammation grade (r=0.756, p=0.138). HD evolution revealed a marginally inverse correlation with inflammation grade (r=-0.794, p=0.108). No correlations could be established for other parameters with either inflammation grade or fibrosis stage.Our study shows that MDA elevation offers the best prediction potential for fibrosis, while marginal prediction fiability could be attributed to high levels of plasma PC and low levels of HD.

  13. Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy.

    PubMed

    Yang, Lili; Rozenfeld, Raphael; Wu, Defeng; Devi, Lakshmi A; Zhang, Zhenfeng; Cederbaum, Arthur

    2014-03-01

    Acute alcohol drinking induces steatosis, and effective prevention of steatosis can protect liver from progressive damage caused by alcohol. Increased oxidative stress has been reported as one mechanism underlying alcohol-induced steatosis. We evaluated whether cannabidiol, which has been reported to function as an antioxidant, can protect the liver from alcohol-generated oxidative stress-induced steatosis. Cannabidiol can prevent acute alcohol-induced liver steatosis in mice, possibly by preventing the increase in oxidative stress and the activation of the JNK MAPK pathway. Cannabidiol per se can increase autophagy both in CYP2E1-expressing HepG2 cells and in mouse liver. Importantly, cannabidiol can prevent the decrease in autophagy induced by alcohol. In conclusion, these results show that cannabidiol protects mouse liver from acute alcohol-induced steatosis through multiple mechanisms including attenuation of alcohol-mediated oxidative stress, prevention of JNK MAPK activation, and increasing autophagy.

  14. Geraniol attenuates 2-acetylaminofluorene induced oxidative stress, inflammation and apoptosis in the liver of wistar rats.

    PubMed

    Hasan, Syed Kazim; Sultana, Sarwat

    2015-01-01

    2-Acetylaminofluorene (2-AAF), is a well-known liver toxicant, generally used to induce tumors in laboratory animals. Geraniol (GE), a monoterpene found in essential oils of herbs and fruits, has been known to possess preventive efficacy against chemically induced toxicities. The present study was designed to analyze the protective effect of GE against 2-AAF induced oxidative stress, inflammation, hyperproliferation and apoptotic tissue damage in the liver of female Wistar rats. 2-AAF (0.02% w/w in diet) was administered and subjected to partial hepatectomy, as a mitogenic stimulus for the induction of hyperproliferation of liver tissue. GE was pre-treated orally at two different doses (100 and 200 mg/kg b.wt.) dissolved in corn oil. GE pre-treatment significantly ameliorated 2-AAF induced oxidative damage by diminishing tissue lipid peroxidation accompanied by the increase in enzymatic activities of catalase, glutathione peroxidase, glutathione reductase, superoxide dismutase and reduced glutathione content. The level of serum toxicity markers (AST, ALT, LDH) was found to be decreased. Pre-treatment with GE downregulated the expression of caspase-3,9, COX-2, NFkB, PCNA, iNOS, VEGF and significantly decreased disintegration of DNA. Histological findings further revealed that GE significantly restores the architecture of liver tissue. In the light of the above observations it may be concluded that GE may be used as preventive agent against 2-AAF induced oxidative stress, inflammation, hyperproliferation and apoptotic damage.

  15. Caffeine supplementation modulates oxidative stress markers in the liver of trained rats.

    PubMed

    Barcelos, Rômulo Pillon; Souza, Mauren Assis; Amaral, Guilherme Pires; Stefanello, Silvio Terra; Bresciani, Guilherme; Fighera, Michele Rechia; Soares, Félix Alexandre Antunes; Barbosa, Nilda Vargas

    2014-02-06

    Caffeine has been widely used in sports competitions due to its ergogenic effects. Most of the studies regarding caffeine and exercise have focused on muscle and plasma adaptations, while the impact on the liver is scarcely described. The aim is to analyze the effects of caffeine and exercise training on oxidative stress markers and injury-related parameters in the liver. Rats were divided into sedentary/saline, sedentary/caffeine, exercise/saline, and exercise/caffeine groups. Exercise groups underwent 4 weeks of swimming training, and caffeine (6 mg/kg, p.o.) was supplemented throughout the training protocol. Injury-related liver parameters were assessed in plasma, while redox status and oxidative stress markers were measured on liver homogenates. Exercise training increased muscle citrate synthase activity in the muscle, while in caffeine decreased its activity in both sedentary and trained rats. Aspartate transaminase levels were increased after training, and caffeine intake suppressed this elevation (p<0.05). Caffeine also diminished alanine transaminase levels in both sedentary and exercised rats (p<0.05). Exercise training induced a significant increase on the activity of the enzymes superoxide dismutase and glutathione peroxidase, as an increase on thiobarbituric acid-reactive substances levels was also reached (p<0.05); caffeine intake blunted these alterations. Caffeine intake also suppressed liver catalase activity in both sedentary and exercise groups (p<0.05). Our data suggest that caffeine modified the hepatic responses associated to exercise-induced oxidative stress without affecting the performance, exerting different actions according to the tissue. However, further studies are needed to better understand caffeine's role on liver under exercise training. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. The role of oxidative stress in the development of alcoholic liver disease.

    PubMed

    Galicia-Moreno, M; Gutiérrez-Reyes, G

    2014-01-01

    Alcohol is the most accepted addictive substance worldwide and its consumption is related to multiple health, economic, and social problems. The liver is the organ in charge of ethanol metabolism and it is susceptible to alcohol's toxic effects. To provide a detailed review of the role of oxidative stress in alcoholic liver disease and the mechanisms of damage involved, along with current information on the hepatoprotective effectiveness of the molecules that have been studied. A search of the PubMed database was conducted using the following keywords oxidative stress, alcoholic liver damage, alcoholic cirrhosis, and antioxidants. There was no time limit for gathering all available information on the subject at hand. According to the literature reviewed, oxidative stress plays an important role in the pathogenesis of alcoholic liver damage. Molecules such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), formed during ethanol metabolism, structurally and functionally modify organic molecules. Consequently, biologic processes are altered and hepatocytes are sensitized to the action of cytokines like tumor necrosis factor-α, as well as to the action of endotoxins, activating signaling pathways such as those controlled by nuclear factor kappa B, extracellular signal regulated kinases, and mitogen activated protein kinase. Oxidative stress plays an important role in the development of liver damage resulting from alcohol consumption. The molecules that have currently displayed a hepatoprotective effect in preclinical and clinical trials must be studied further so that their effectiveness can be confirmed and they can possibly be used as adjuvant treatments for this disease. Copyright © 2014 Asociación Mexicana de Gastroenterología. Published by Masson Doyma México S.A. All rights reserved.

  17. Decreased oxidative stress in prehepatic portal hypertensive rat livers following the induction of diabetes.

    PubMed

    Evelson, P; Llesuy, S; Filinger, E; Rodriguez, R R; Lemberg, A; Scorticati, C; Susemihl, M; Villareal, I; Polo, J M; Peredo, H; Perazzo, J C

    2004-03-01

    1. Oxidative stress (OS) is a biological entity indicated as being responsible for several pathologies, including diabetes. Diabetes can also be associated with human cirrhosis. Portal hypertension (PH), a major syndrome in cirrhosis, produces hyperdynamic splanchnic circulation and hyperaemia. The present study was designed to investigate the occurrence of OS in prehepatic PH rat livers following the induction of diabetes. 2. Five groups of rats were used: control, sham operated, chronic diabetes (induced with a single dose of streptozotocin at 60 mg/kg, i.p.), prehepatic PH and chronic diabetic plus prehepatic PH. The occurrence of OS was determined in liver homogenates by measuring hydroperoxide-initiated chemiluminescence and the activity of anti-oxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase). 3. Prehepatic PH produced a significant increase in hydroperoxide-initiated chemiluminescence in the liver compared with control and sham-operated rats, whereas the liver in chronic diabetic rats showed no difference. However, chemiluminescence values decreased almost by 50% in the chronic diabetic plus prehepatic PH group. Concomitantly, the activities of the anti-oxidant enzymes in chronic diabetes, prehepatic PH and chronic diabetic plus prehepatic PH groups were decreased (P < 0.05 vs control and sham-operated groups). 4. Livers from the chronic diabetic group did not show any evidence of the occurrence of OS, whereas the prehepatic PH group showed the occurrence of OS. The association of PH and chronic diabetes resulted in a significant decrease in the occurrence of OS, which could be explained by an anti-oxidant response to an OS.

  18. Biochemical changes and oxidative stress induced by zearalenone in the liver of pregnant rats.

    PubMed

    Zhou, C; Zhang, Y; Yin, S; Jia, Z; Shan, A

    2015-01-01

    The aim of the present research was to examine the toxic influence of different doses of zearalenone (ZEN) on the liver, especially oxidative stress induced by ZEN on the liver. A total of 48 pregnant Sprague-Dawley rats were randomly assigned into 4 treatments groups with 12 animals in each. The rats were fed with a normal diet treated with 0 mg/kg (control), 50 mg/kg (treatment 1), 100 mg/kg (treatment 2), or 150 mg/kg (treatment 3) ZEN in feed on gestation days (GDs) 0-7 and then all the rats were fed with a normal diet on GDs 8-20. The experimental period lasted 21 days. The results showed that exposure to ZEN induced increase in aspartate amino transferase, alanine aminotransferase, and alkaline phosphatase activities and decrease in total protein and albumin content in a dose-dependent manner and also induce decrease in superoxide dismutase and glutathione peroxidase activities and increase in malondialdehyde content in a dose-dependent manner in the serum and the liver. The increased transcription of cytochrome P450 2E1 (CYP2E1) was detected in the liver after exposure to ZEN. These results suggested that ZEN not only caused damage in the liver of pregnant rats in a dose-dependent manner but also induced the messenger RNA expression of CYP2E1 in the liver. © The Author(s) 2014.

  19. Peroxisome Proliferator-Activated Receptor Gamma Exacerbates Concanavalin A-Induced Liver Injury via Suppressing the Translocation of NF-κB into the Nucleus

    PubMed Central

    Ogawa, Yuji; Yoneda, Masato; Tomeno, Wataru; Imajo, Kento; Shinohara, Yoshiyasu; Fujita, Koji; Shibata, Wataru; Kirikoshi, Hiroyuki; Saito, Satoru; Wada, Koichiro; Maeda, Shin; Nakajima, Atsushi

    2012-01-01

    Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to reduce inflammation and attenuate fibrosis in the liver. In this study, we investigated the effects of PPARγ on the liver injury induced by 20 mg/kg Concanavalin A (Con A). The mice were administered one of the three types of PPARγ ligands (pioglitazone, ciglitazone, and troglitazone) for 1 week, and the serum alanine aminotransferase (ALT) levels at 20 h after Con A injection were significantly elevated in the PPARγ ligand-treated mice. Furthermore, the serum ALT levels after Con A injection in the PPARγ hetero-knock-out mice (PPARγ+/− mice) were lower than those in the wild-type mice (WT mice). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) revealed extensive liver damage induced by Con A in the pioglitazone-treated mice. Electrophoresis mobility shift assay (EMSA) revealed that activation of translocation of nuclear factor- (NF-) κB, which is a suppressor of apoptosis, in the nucleus of the hepatocytes was suppressed in the pioglitazone-treated mice after Con A injection. In this study, we showed that PPARγ exacerbated Con A-induced liver injury via suppressing the translocation of NF-κB into the nucleus, thereby inhibiting the suppression of liver cell apoptosis. PMID:23251143

  20. FAT10 suppression stabilizes oxidized proteins in liver cells: Effects of HCV and ethanol.

    PubMed

    Ganesan, Murali; Hindman, Joseph; Tillman, Brittany; Jaramillo, Lee; Poluektova, Larisa I; French, Barbara A; Kharbanda, Kusum K; French, Samuel W; Osna, Natalia A

    2015-12-01

    FAT10 belongs to the ubiquitin-like modifier (ULM) family that targets proteins for degradation and is recognized by 26S proteasome. FAT10 is presented on immune cells and under the inflammatory conditions, is synergistically induced by IFNγ and TNFα in the non-immune (liver parenchymal) cells. It is not clear how viral proteins and alcohol regulate FAT10 expression on liver cells. In this study, we aimed to investigate whether FAT10 expression on liver cells is activated by the innate immunity factor, IFNα and how HCV protein expression in hepatocytes and ethanol-induced oxidative stress affect the level of FAT10 in liver cells. For this study, we used HCV(+) transgenic mice that express structural HCV proteins and their HCV(-) littermates. Mice were fed Lieber De Carli diet (control and ethanol) as specified in the NIH protocol for chronic-acute ethanol feeding. Alcohol exposure enhanced steatosis, induced oxidative stress and decreased proteasome activity in the liversof these mice, with more robust response to ethanol in HCV(+) mice. IFNα induced transcriptional activation of FAT10 in liver cells, which was dysregulated by ethanol feeding. Accordingly, IFNα-activated expression of FAT10 in hepatocytes (measured by indirect immunofluorescent of liver tissue) was also suppressed by ethanol exposure in both HCV(+) and HCV(-) mice. This suppression was accompanied with ethanol-mediated induction of lipid peroxidation marker, 4-HNE. All aforementioned effects of ethanol were attenuated by in vivo feeding of mice with the pro-methylating agent, betaine, which exhibits strong anti-oxidant properties. Based on this study, we hypothesize that FAT10 targets oxidatively modified proteins for proteasomal degradation, and that the reduction in FAT10 levels along with decreased proteasome activity may contribute to stabilization of these altered proteins in hepatocytes. In conclusion, IFNα induced FAT10 expression, which is suppressed by ethanol feeding in both HCV

  1. Oxidative stress and antioxidant status in patients with autoimmune liver diseases.

    PubMed

    Kaffe, Eleanna T; Rigopoulou, Eirini I; Koukoulis, George K; Dalekos, George N; Moulas, Anargyros N

    2015-01-01

    To estimate oxidative stress and antioxidant components during different stages of autoimmune liver diseases and assess their possible implication on disease progression. We determined several markers of oxidative injury (isoprostane, aldehydes, protein carbonyls, 3-nitrotyrosine, and myeloperoxidase) and antioxidant components (glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase) in whole blood, serum, and urine in 49 patients with autoimmune cholestatic liver diseases (AC) and 36 patients with autoimmune hepatitis (AIH) and healthy subjects matched for sex and age. Both AC and AIH patients had increased levels of all lipid and protein oxidative injury products and significantly decreased whole blood glutathione levels compared to controls. AIH patients had significantly higher levels of aldehydes and glutathione peroxidase activity and significantly lower protein carbonyl levels compared to AC patients. Protein carbonyl and isoprostane levels increased and glutathione levels decreased gradually with progression from mild fibrosis to severe fibrosis and cirrhosis in both AC and AIH patients. In addition, both cirrhotic AC and AIH patients had significantly higher protein carbonyls compared to non-cirrhotics. We provide novel findings in support of a major contribution of oxidant/antioxidant imbalance in the progression of liver injury in AC and AIH.

  2. Canine visceral leishmaniasis: relationships between oxidative stress, liver and kidney variables, trace elements, and clinical status.

    PubMed

    Heidarpour, M; Soltani, S; Mohri, M; Khoshnegah, J

    2012-10-01

    The aim of this study was to investigate the role of oxidative stress in the pathology of canine visceral leishmaniasis (CVL). We therefore studied the relationships between oxidative stress markers, liver and kidney variables, trace elements, and clinical status in dogs naturally infected with Leishmania infantum. Two groups of Leishmania-infected dogs [asymptomatic (AD, n = 14) and symptomatic (SD, n = 16)] were assessed and compared with a group of non-infected control dogs (CD, n = 30). A significant decrease (p < 0.001) in serum total antioxidant status (TAS) and albumin concentration (p < 0.05) and a significant increase in serum malondialdehyde (MDA) and blood urea nitrogen (BUN) concentrations (p < 0.001), in the SD group, were observed when compared to CD and AD groups. Dogs of the AD group presented a significant decrease in copper (p < 0.01) and zinc (p < 0.001) concentrations, when compared to CD group, while the SD group presented a significant decrease (p < 0.001) in copper and zinc concentrations, when compared to CD and AD groups. Oxidative stress markers (MDA and TAS) showed significant correlations (p < 0.001) with trace elements (copper and zinc) and liver (alanine aminotransferase) and kidney (BUN and creatinine) variables. The results of the present study revealed that symptomatic dogs showed more severe oxidative stress than asymptomatic and non-infected dogs and enhanced lipid peroxidation may be linked to liver and kidney damage in canine visceral leishmaniasis.

  3. The effect of thiamine and thiamine pyrophosphate on oxidative liver damage induced in rats with cisplatin.

    PubMed

    Turan, Mehmet Ibrahim; Siltelioglu Turan, Isil; Mammadov, Renad; Altınkaynak, Konca; Kisaoglu, Abdullah

    2013-01-01

    The aim of this study was to investigate the effect of thiamine and thiamine pyrophosphate (TPP) on oxidative stress induced with cisplatin in liver tissue. Rats were divided into four groups; thiamine group (TG), TPP + cisplatin group (TPG), healthy animal group (HG), and cisplatin only group (CG). Oxidant and antioxidant parameters in liver tissue and AST, ALT, and LDH levels in rat sera were measured in all groups. Malondialdehyde levels in the CG, TG, TPG, and HG groups were 11 ± 1.4, 9 ± 0.5, 3 ± 0.5, and 2.2 ± 0.48  μ mol/g protein, respectively. Total glutathione levels were 2 ± 0.7, 2.8 ± 0.4, 7 ± 0.8, and 9 ± 0.6 nmol/g protein, respectively. Levels of 8-OH/Gua, a product of DNA damage, were 2.7 ± 0.4 pmol/L, 2.5 ± 0.5, 1.1 ± 0.3, and 0.9 ± 0.3 pmol/L, respectively. A statistically significant difference was determined in oxidant/antioxidant parameters and AST, ALT, and LDH levels between the TPG and CG groups (P < 0.05). No significant difference was determined between the TG and CG groups (P > 0.05). In conclusion, cisplatin causes oxidative damage in liver tissue. TPP seems to have a preventive effect on oxidative stress in the liver caused by cisplatin.

  4. The Effect of Thiamine and Thiamine Pyrophosphate on Oxidative Liver Damage Induced in Rats with Cisplatin

    PubMed Central

    Turan, Mehmet Ibrahim; Siltelioglu Turan, Isil; Mammadov, Renad; Altınkaynak, Konca; Kisaoglu, Abdullah

    2013-01-01

    The aim of this study was to investigate the effect of thiamine and thiamine pyrophosphate (TPP) on oxidative stress induced with cisplatin in liver tissue. Rats were divided into four groups; thiamine group (TG), TPP + cisplatin group (TPG), healthy animal group (HG), and cisplatin only group (CG). Oxidant and antioxidant parameters in liver tissue and AST, ALT, and LDH levels in rat sera were measured in all groups. Malondialdehyde levels in the CG, TG, TPG, and HG groups were 11 ± 1.4, 9 ± 0.5, 3 ± 0.5, and 2.2 ± 0.48 μmol/g protein, respectively. Total glutathione levels were 2 ± 0.7, 2.8 ± 0.4, 7 ± 0.8, and 9 ± 0.6 nmol/g protein, respectively. Levels of 8-OH/Gua, a product of DNA damage, were 2.7 ± 0.4 pmol/L, 2.5 ± 0.5, 1.1 ± 0.3, and 0.9 ± 0.3 pmol/L, respectively. A statistically significant difference was determined in oxidant/antioxidant parameters and AST, ALT, and LDH levels between the TPG and CG groups (P < 0.05). No significant difference was determined between the TG and CG groups (P > 0.05). In conclusion, cisplatin causes oxidative damage in liver tissue. TPP seems to have a preventive effect on oxidative stress in the liver caused by cisplatin. PMID:23841092

  5. Effect of broccoli extract enriched diet on liver cholesterol oxidation in rats subjected to exhaustive exercise.

    PubMed

    Cardenia, Vladimiro; Rodriguez-Estrada, Maria Teresa; Lorenzini, Antonello; Bandini, Erika; Angeloni, Cristina; Hrelia, Silvana; Malaguti, Marco

    2016-04-12

    The effect of broccoli extract (BE)-enriched diet was studied in order to evaluate its ability to counteract liver cholesterol oxidation products (COPs) induced by acute strenuous exercise in rats. Thirty-two female Wistar rats were randomly divided into four groups: control diet without exercise (C), BE-enriched diet without exercise (B), control diet with acute exhaustive exercise (S) and BE-enriched diet with acute exhaustive exercise (BS). The study lasted 45days and on the last day, rats of S and BS groups were forced to run until exhaustion on a treadmill. Glutathione-S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT) and cholesterol oxidation products (COPs) were determined in liver. Exhaustive exercise was clearly responsible for tissue damage, as evidenced by the increase of lactate dehydrogenase (LDH) plasma activity in the S group. Moreover, the exercise protocol reduced CAT activity in liver, while it did not affect GST, GR and GPx. BE-enriched diet raised GST, GR and CAT activities in rats of BS group. The main COPs found were 7α-hydroxycholesterol, 7β-hydroxycholesterol, 7-ketocholesterol, cholestanetriol, 24-hydroxycholesterol and 27-hydroxycholesterol. The BE-enriched diet led to reduced cholesterol oxidation following exhaustive exercise; the highest level of COPs was found in the S group, whereas the BS rats showed the lowest amount. This study indicates that the BE-enriched diet increases antioxidant enzyme activities and exerts an antioxidant effect towards cholesterol oxidation in rat liver, suggesting the use of phytochemicals in the prevention of oxidative damage and in the modulation of the redox environment.

  6. Comparative proteomic analysis of thiol proteins in the liver after oxidative stress induced by diethylnitrosamine.

    PubMed

    Aparicio-Bautista, Diana I; Pérez-Carreón, Julio I; Gutiérrez-Nájera, Nora; Reyes-Grajeda, Juan P; Arellanes-Robledo, Jaime; Vásquez-Garzón, Verónica R; Jiménez-García, Mónica N; Villa-Treviño, Saúl

    2013-12-01

    Conversion of protein -SH groups to disulfides is an early event during protein oxidation, which has prompted great interest in the study of thiol proteins. Chemical carcinogenesis is strongly associated with the formation of reactive oxygen species (ROS). The goal of this study was to detect thiol proteins that are sensitive to ROS generated during diethylnitrosamine (DEN) metabolism in the rat liver. DEN has been widely used to induce experimental hepatocellular carcinoma. We used modified redox-differential gel electrophoresis (redox-DIGE method) and mass spectrometry MALDI-TOF/TOF to identify differential oxidation protein profiles associated with carcinogen exposure. Our analysis revealed a time-dependent increase in the number of oxidized thiol proteins after carcinogen treatment; some of these proteins have antioxidant activity, including thioredoxin, peroxirredoxin 2, peroxiredoxin 6 and glutathione S-transferase alpha-3. According to functional classifications, the identified proteins in our study included chaperones, oxidoreductases, activity isomerases, hydrolases and other protein-binding partners. This study demonstrates that oxidative stress generated by DEN tends to increase gradually through DEN metabolism, causes time-dependent necrosis in the liver and has an oxidative effect on thiol proteins, thereby increasing the number of oxidized thiol proteins. Furthermore, these events occurred during the hepatocarcinogenesis initiation period.

  7. Glycosaminoglycan-targeted iron oxide nanoparticles for magnetic resonance imaging of liver carcinoma.

    PubMed

    Yang, Rui-Meng; Fu, Chao-Ping; Li, Nan-Nan; Wang, Li; Xu, Xiang-Dong; Yang, Ding-Yan; Fang, Jin-Zhi; Jiang, Xin-Qing; Zhang, Li-Ming

    2014-12-01

    To develop an efficient probe for targeted magnetic resonance (MR) imaging of liver carcinoma, the surface modification of superparamagnetic iron oxide nanoparticles (SPIONs) was carried out by conjugating a naturally-occurring glycosaminoglycan with specific biological recognition to human hepatocellular liver carcinoma (HepG2) cells. These modified SPIOs have good water dispersibility, superparamagnetic property, cytocompatibility and high magnetic relaxivity for MR imaging. When incubated with HepG2 cells, they demonstrated significant cellular uptake and specific accumulation, as confirmed by Prussian blue staining and confocal microscopy. The in vitro MR imaging of HepG2 cells and in vivo MR imaging of HepG2 tumors confirmed their effectiveness for targeted MR imaging of liver carcinoma.

  8. Oxidized Low-Density-Lipoprotein Accumulation is Associated with Liver Fibrosis in Experimental Cholestasis

    PubMed Central

    Karadeniz, Güldeniz; Acikgoz, Serefden; Tekin, Ishak Ozel; Tascýlar, Oge; Gun, Banu Dogan; Cömert, Mustafa

    2008-01-01

    OBJECTIVE The aim of the present study was to examine the probable relationship between the accumulation of oxLDL and hepatic fibrogenesis in cholestatic rats. INTRODUCTION There is growing evidence to support the current theories on how oxidative stress that results in lipid peroxidation is involved in the pathogenesis of cholestatic liver injury and fibrogenesis. One of the major and early lipid peroxidation products, OxLDL, is thought to play complex roles in various immuno-inflammatory mechanisms. METHODS A prolonged (21-day) experimental bile duct ligation was performed on Wistar-albino rats. Biochemical analysis of blood, histopathologic evaluation of liver, measurement of the concentration of malondialdehyde (MDA) and superoxide-dismutase (SOD) in liver tissue homogenates, and immunofluorescent staining for oxLDL in liver tissue was conducted in bile-duct ligated (n = 8) and sham-operated rats (n = 8). RESULTS Significantly higher levels of MDA and lower concentrations of SOD were detected in jaundiced rats than in the sham-operated rats. Positive oxLDL staining was also observed in liver tissue sections of jaundiced rats. Histopathological examination demonstrated that neither fibrosis nor other indications of hepatocellular injury were found in the sham-operated group, while features of severe hepatocellular injury, particularly fibrosis, were found in jaundiced rats. CONCLUSION Our results support the finding that either oxLDLs are produced as an intermediate agent during exacerbated oxidative stress or they otherwise contribute to the various pathomechanisms underlying the process of liver fibrosis. Whatever the mechanism, it is clear that an association exists between elevated oxLDL levels and hepatocellular injury, particularly with fibrosis. Further studies are needed to evaluate the potential effects of oxLDLs on the progression of secondary biliary cirrhosis. PMID:18719767

  9. Citric Acid Effects on Brain and Liver Oxidative Stress in Lipopolysaccharide-Treated Mice

    PubMed Central

    Youness, Eman R.; Mohammed, Nadia A.; Morsy, Safaa M. Youssef; Omara, Enayat A.; Sleem, Amany A.

    2014-01-01

    Abstract Citric acid is a weak organic acid found in the greatest amounts in citrus fruits. This study examined the effect of citric acid on endotoxin-induced oxidative stress of the brain and liver. Mice were challenged with a single intraperitoneal dose of lipopolysaccharide (LPS; 200 μg/kg). Citric acid was given orally at 1, 2, or 4 g/kg at time of endotoxin injection and mice were euthanized 4 h later. LPS induced oxidative stress in the brain and liver tissue, resulting in marked increase in lipid peroxidation (malondialdehyde [MDA]) and nitrite, while significantly decreasing reduced glutathione, glutathione peroxidase (GPx), and paraoxonase 1 (PON1) activity. Tumor necrosis factor-alpha (TNF-α) showed a pronounced increase in brain tissue after endotoxin injection. The administration of citric acid (1–2 g/kg) attenuated LPS-induced elevations in brain MDA, nitrite, TNF-α, GPx, and PON1 activity. In the liver, nitrite was decreased by 1 g/kg citric acid. GPx activity was increased, while PON1 activity was decreased by citric acid. The LPS-induced liver injury, DNA fragmentation, serum transaminase elevations, caspase-3, and inducible nitric oxide synthase expression were attenuated by 1–2 g/kg citric acid. DNA fragmentation, however, increased after 4 g/kg citric acid. Thus in this model of systemic inflammation, citric acid (1–2 g/kg) decreased brain lipid peroxidation and inflammation, liver damage, and DNA fragmentation. PMID:24433072

  10. Ceratonia siliqua pod extract ameliorates Schistosoma mansoni-induced liver fibrosis and oxidative stress.

    PubMed

    Al-Olayan, Ebtesam M; El-Khadragy, Manal F; Alajmi, Reem A; Othman, Mohamed S; Bauomy, Amira A; Ibrahim, Shaimaa R; Abdel Moneim, Ahmed E

    2016-11-08

    Schistosomiasis is a prevalent parasitic disease found predominantly in tropical and sub-tropical areas of the developing world, with the second highest socioeconomic and public health burden despite strenuous control efforts. In the present study, we aimed to investigate the ameliorative effects of Ceratonia siliqua pod extract (CPE) on liver fibrosis and oxidative stress in mice infected with Schistosoma mansoni. The schistosomal hepatopathologic mouse model was established by tail immersion with schistosomal cercaria. The extract was given daily for 10 days beginning 42 days post-infection. Liver samples were obtained from mice sacrificed 9 weeks after infection. Liver histopathological changes were observed with hematoxylin-eosin and Masson trichrome staining. Typical schistosomal hepatopathologic changes were induced in the untreated mice. However, the oral administration of CPE was effective in reducing worm number and the egg load in the liver. This treatment also decreased granuloma size and collagen deposition by inhibiting tissue inhibitor of metalloproteinases-2 (TIMP-2) expression. Schistosomal infection induced oxidative stress by increasing lipid peroxidation (LPO) and nitrite/nitrate (nitric oxide; NO) production along with concomitant decreases in glutathione (GSH) and various antioxidant enzymes, including superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. However, treatment of mice with CPE at 300 or 600 mg/kg inhibited LPO and NO production, increased GSH content, and restored the activities of the antioxidant enzymes compared with untreated infected mice. Furthermore, treatment with CPE inhibited apoptosis, as indicated by the reduced Bax expression in hepatic tissue. These data indicated that extracts from Ceratonia siliqua pods may play an important role in combating schistosomal hepatopathology and may inhibit granuloma formation and liver fibrosis through down-regulation of TIMP-2 expression.

  11. Citric acid effects on brain and liver oxidative stress in lipopolysaccharide-treated mice.

    PubMed

    Abdel-Salam, Omar M E; Youness, Eman R; Mohammed, Nadia A; Morsy, Safaa M Youssef; Omara, Enayat A; Sleem, Amany A

    2014-05-01

    Citric acid is a weak organic acid found in the greatest amounts in citrus fruits. This study examined the effect of citric acid on endotoxin-induced oxidative stress of the brain and liver. Mice were challenged with a single intraperitoneal dose of lipopolysaccharide (LPS; 200 μg/kg). Citric acid was given orally at 1, 2, or 4 g/kg at time of endotoxin injection and mice were euthanized 4 h later. LPS induced oxidative stress in the brain and liver tissue, resulting in marked increase in lipid peroxidation (malondialdehyde [MDA]) and nitrite, while significantly decreasing reduced glutathione, glutathione peroxidase (GPx), and paraoxonase 1 (PON1) activity. Tumor necrosis factor-alpha (TNF-α) showed a pronounced increase in brain tissue after endotoxin injection. The administration of citric acid (1-2 g/kg) attenuated LPS-induced elevations in brain MDA, nitrite, TNF-α, GPx, and PON1 activity. In the liver, nitrite was decreased by 1 g/kg citric acid. GPx activity was increased, while PON1 activity was decreased by citric acid. The LPS-induced liver injury, DNA fragmentation, serum transaminase elevations, caspase-3, and inducible nitric oxide synthase expression were attenuated by 1-2 g/kg citric acid. DNA fragmentation, however, increased after 4 g/kg citric acid. Thus in this model of systemic inflammation, citric acid (1-2 g/kg) decreased brain lipid peroxidation and inflammation, liver damage, and DNA fragmentation.

  12. Pretreatment with Fucoidan from Fucus vesiculosus Protected against ConA-Induced Acute Liver Injury by Inhibiting Both Intrinsic and Extrinsic Apoptosis

    PubMed Central

    Li, Jingjing; Chen, Kan; Li, Sainan; Liu, Tong; Wang, Fan; Xia, Yujing; Lu, Jie; Zhou, Yingqun; Guo, Chuanyong

    2016-01-01

    This study aimed to explore the effects of fucoidan from Fucus vesiculosus on concanavalin A (ConA)-induced acute liver injury in mice. Pretreatment with fucoidan protected liver function indicated by ALT, AST and histopathological changes by suppressing inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). In addition, intrinsic and extrinsic apoptosis mediated by Bax, Bid, Bcl-2, Bcl-xL and Caspase 3, 8, and 9 were inhibited by fucoidan and the action was associated with the TRADD/TRAF2 and JAK2/STAT1 signal pathways. Our results demonstrated that fucoidan from Fucus vesiculosus alleviated ConA-induced acute liver injury via the inhibition of intrinsic and extrinsic apoptosis mediated by the TRADD/TRAF2 and JAK2/STAT1 pathways which were activated by TNF-α and IFN-γ. These findings could provide a potential powerful therapy for T cell-related hepatitis. PMID:27035150

  13. Oxidative stress, cardiolipin and mitochondrial dysfunction in nonalcoholic fatty liver disease.

    PubMed

    Paradies, Giuseppe; Paradies, Valeria; Ruggiero, Francesca M; Petrosillo, Giuseppe

    2014-10-21

    Nonalcoholic fatty liver disease (NAFLD) is today considered the most common form of chronic liver disease, affecting a high proportion of the population worldwide. NAFLD encompasses a large spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. Obesity, hyperglycemia, type 2 diabetes and hypertriglyceridemia are the most important risk factors. The pathogenesis of NAFLD and its progression to fibrosis and chronic liver disease is still unknown. Accumulating evidence indicates that mitochondrial dysfunction plays a key role in the physiopathology of NAFLD, although the mechanisms underlying this dysfunction are still unclear. Oxidative stress is considered an important factor in producing lethal hepatocyte injury associated with NAFLD. Mitochondrial respiratory chain is the main subcellular source of reactive oxygen species (ROS), which may damage mitochondrial proteins, lipids and mitochondrial DNA. Cardiolipin, a phospholipid located at the level of the inner mitochondrial membrane, plays an important role in several reactions and processes involved in mitochondrial bioenergetics as well as in mitochondrial dependent steps of apoptosis. This phospholipid is particularly susceptible to ROS attack. Cardiolipin peroxidation has been associated with mitochondrial dysfunction in multiple tissues in several physiopathological conditions, including NAFLD. In this review, we focus on the potential roles played by oxidative stress and cardiolipin alterations in mitochondrial dysfunction associated with NAFLD.

  14. Oxidative stress modulation by Rosmarinus officinalis in CCl4-induced liver cirrhosis.

    PubMed

    Gutiérrez, Rosalinda; Alvarado, José L; Presno, Manuel; Pérez-Veyna, Oscar; Serrano, Carmen J; Yahuaca, Patricia

    2010-04-01

    Rosmarinus officinalis (Lamiaceae) possesses antioxidant activity and hepatoprotective effects, and so may provide a possible therapeutic alternative for chronic liver disease. The effect produced by a methanolic extract of Rosmarinus officinalis on CCl(4)-induced liver cirrhosis in rats was investigated using both prevention and reversion models. Over the course of the development of cirrhosis, the increased enzymatic activities of gamma-glutamyl transpeptidase and alanine aminotransferase, and the rise in bilirubin levels caused by CCl(4) administration, were prevented by Rosmarinus officinalis co-administration. When the cirrhosis by oxidative stress was evaluated as an increase on liver lipoperoxidation, total lipid peroxides, nitric oxide in serum, and loss of erythrocyte plasma membrane stability, R. officinalis was shown to prevent such alterations. On cirrhotic animals treated with CCl(4), histological studies showed massive necrosis, periportal inflammation and fibrosis which were modified by R. officinalis. These benefits on experimental cirrhosis suggest a potential therapeutic use for R. officinalis as an alternative for liver cirrhosis. Copyright (c) 2009 John Wiley & Sons, Ltd.

  15. Effect of sweetener and flavoring agent on oxidative indices, liver and kidney function levels in rats.

    PubMed

    Amin, Kamal A; Al-muzafar, Hessa M; Abd Elsttar, Adel H

    2016-01-01

    Food additives while attract consumers, improve quality, control weight and replace sugar, may affect seriously children and adults health. Here, we investigated the adverse effects of saccharin and methylsalicyltaes as sweetener and flavoring agent on lipid profile, blood glucose, renal, hepatic function and oxidative stress/antioxidants (lipid peroxidation, catalase and reduced glutathione in liver tissues). Saccharin and methylsalicylate were administered orally in young male albino rats at low and high dose for 30 days. Rats were divided into 5 groups, 1st control group, 2nd and 3rd (low and high saccharin-treated groups) and 4th and 5th (low and high methylsalicylate-treated group). Serum total cholesterol, triglyceride, glucose levels and body weight gain were found decreased in saccharin high dose group compared to control. Rats consumed high dose of saccharin showed a significant decrease in serum triglycerides, cholesterol and LDL levels. Low and high doses of saccharin exhibited a significant increase in liver function marker of ALT, AST, ALP activity, total proteins and albumin levels and renal function test (urea and creatinine levels) in comparison with control group. Further, saccharin at high dose induced significant decrease in liver GSH levels, catalase and SOD activity and increase in hepatic MDA level. Overall saccharin harmfully altered biochemical markers in liver and kidney at higher as well as lower doses. Whereas, methyl salicylates did not pose a risk for renal function and hepatic oxidative markers.

  16. Oxidative stress, cardiolipin and mitochondrial dysfunction in nonalcoholic fatty liver disease

    PubMed Central

    Paradies, Giuseppe; Paradies, Valeria; Ruggiero, Francesca M; Petrosillo, Giuseppe

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is today considered the most common form of chronic liver disease, affecting a high proportion of the population worldwide. NAFLD encompasses a large spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. Obesity, hyperglycemia, type 2 diabetes and hypertriglyceridemia are the most important risk factors. The pathogenesis of NAFLD and its progression to fibrosis and chronic liver disease is still unknown. Accumulating evidence indicates that mitochondrial dysfunction plays a key role in the physiopathology of NAFLD, although the mechanisms underlying this dysfunction are still unclear. Oxidative stress is considered an important factor in producing lethal hepatocyte injury associated with NAFLD. Mitochondrial respiratory chain is the main subcellular source of reactive oxygen species (ROS), which may damage mitochondrial proteins, lipids and mitochondrial DNA. Cardiolipin, a phospholipid located at the level of the inner mitochondrial membrane, plays an important role in several reactions and processes involved in mitochondrial bioenergetics as well as in mitochondrial dependent steps of apoptosis. This phospholipid is particularly susceptible to ROS attack. Cardiolipin peroxidation has been associated with mitochondrial dysfunction in multiple tissues in several physiopathological conditions, including NAFLD. In this review, we focus on the potential roles played by oxidative stress and cardiolipin alterations in mitochondrial dysfunction associated with NAFLD. PMID:25339807

  17. Dioscin alleviates dimethylnitrosamine-induced acute liver injury through regulating apoptosis, oxidative stress and inflammation.

    PubMed

    Zhang, Weixin; Yin, Lianhong; Tao, Xufeng; Xu, Lina; Zheng, Lingli; Han, Xu; Xu, Youwei; Wang, Changyuan; Peng, Jinyong

    2016-07-01

    In our previous study, the effects of dioscin against alcohol-, carbon tetrachloride- and acetaminophen-induced liver damage have been found. However, the activity of it against dimethylnitrosamine (DMN)-induced acute liver injury remained unknown. In the present study, dioscin markedly decreased serum ALT and AST levels, significantly increased the levels of SOD, GSH-Px, GSH, and decreased the levels of MDA, iNOS and NO. Mechanism study showed that dioscin significantly decreased the expression levels of IL-1β, IL-6, TNF-α, IκBα, p50 and p65 through regulating TLR4/MyD88 pathway to rehabilitate inflammation. In addition, dioscin markedly up-regulated the expression levels of SIRT1, HO-1, NQO1, GST and GCLM through increasing nuclear translocation of Nrf2 against oxidative stress. Furthermore, dioscin significantly decreased the expression levels of FasL, Fas, p53, Bak, Caspase-3/9, and upregulated Bcl-2 level through decreasing IRF9 level against apoptosis. In conclusion, dioscin showed protective effect against DMN-induced acute liver injury via ameliorating apoptosis, oxidative stress and inflammation, which should be developed as a new candidate for the treatment of acute liver injury in the future.

  18. Feeding oxidized fat during pregnancy up-regulates expression of PPARα-responsive genes in the liver of rat fetuses

    PubMed Central

    Ringseis, Robert; Gutgesell, Anke; Dathe, Corinna; Brandsch, Corinna; Eder, Klaus

    2007-01-01

    Background Feeding oxidized fats causes activation of peroxisome proliferator-activated receptor α (PPARα) in the liver of rats. However, whether feeding oxidized fat during pregnancy also results in activation of PPARα in fetal liver is unknown. Thus, this study aimed to explore whether feeding oxidized fat during pregnancy causes a PPARα response in fetal liver. Two experiments with pregnant rats which were administered three different diets (control; oxidized fat; clofibrate as positive control) in a controlled feeding regimen during either late pregnancy (first experiment) or whole pregnancy (second experiment) were performed. Results In both experiments pregnant rats treated with oxidized fat or clofibrate had higher relative mRNA concentrations of the PPARα-responsive genes acyl-CoA oxidase (ACO), cytochrome P450 4A1 (CYP4A1), L-type carnitin-palmitoyl transferase I (L-CPT I), medium-chain acyl-CoA dehydrogenase (MCAD), and long-chain acyl-CoA dehydrogenase (LCAD) in the liver than control rats (P < 0.05). In addition, in both experiments fetuses of the oxidized fat group and the clofibrate group also had markedly higher relative mRNA concentrations of ACO, CYP4A1, CPT I, MCAD, and LCAD in the liver than those of the control group (P < 0.05), whereas the relative mRNA concentrations of PPARα, SREBP-1c, and FAS did not differ between treatment groups. In the second experiment treatment with oxidized fat also reduced triacylglycerol concentrations in the livers of pregnant rats and fetuses (P < 0.05). Conclusion The present study demonstrates for the first time that components of oxidized fat with PPARα activating potential are able to induce a PPARα response in the liver of fetuses. Moreover, the present study shows that feeding oxidized fat during whole pregnancy, but not during late pregnancy, lowers triacylglycerol concentrations in fetal livers. PMID:17352811

  19. Resveratrol, a red wine polyphenol, attenuates ethanol-induced oxidative stress in rat liver.

    PubMed

    Kasdallah-Grissa, Abir; Mornagui, Bessem; Aouani, Ezzedine; Hammami, Mohamed; El May, Michelle; Gharbi, Najoua; Kamoun, Abdelaziz; El-Fazaâ, Saloua

    2007-02-20

    The involvement of oxidative stress in the pathogenesis of alcoholic diseases in the liver has been repeatedly confirmed. Resveratrol, a natural phytoalexin present in grape skin and red wine possesses a variety of biological activities including antioxidant. This study was conducted to evaluate whether resveratrol has a preventive effect on the main indicators of hepatic oxidative status as an expression of the cellular damage caused by free radicals, and on antioxidant defence mechanism during chronic ethanol treatment. Wistar rats were treated daily with 35% ethanol solution (3 g/kg/day i.p.) during 6 weeks and fed basal diet or basal diet containing 5 g/kg resveratrol. Control rats were treated with i.p. saline and fed basal diet. Experimentally, chronic ethanol administration leads to hepatotoxicity as monitored by the increase in the level of hepatic marker enzymes and the appearance of fatty change, necrosis, fibrosis and inflammation in liver sections. Ethanol also enhanced the formation of MDA in the liver indicating an increase in lipid peroxidation, a major end-point of oxidative damage, and caused drastic alterations in antioxidant defence systems. Particularly the activities of hepatic superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were found reduced by ethanol treatment while glutathione reductase (GR) activity was unchanged. Dietary supplementation with resveratrol during ethanol treatment inhibited hepatic lipid peroxidation and ameliorated SOD, GPx and CAT activities in the liver. Conclusively, we can suggest that resveratrol could have a beneficial effect in inhibiting the oxidative damage induced by chronic ethanol administration, which was proved by the experiments that we conducted on rats.

  20. Berberis vulgaris L. effects on oxidative stress and liver injury in lead-intoxicated mice.

    PubMed

    Laamech, Jawhar; El-Hilaly, Jaouad; Fetoui, Hamadi; Chtourou, Yassine; Gouitaa, Hanane; Tahraoui, Adel; Lyoussi, Badiaa

    2017-03-01

    Background Berberis vulgaris L. (BV), commonly known as "Aghriss" in Moroccan pharmacopoeia, is used to cure liver disorders and other diseases. The present study aimed to investigate the protective effect of BV aqueous extract against lead-induced toxicity in mice liver. Methods Sixty IOPS mice were divided into six groups and were treated as follows: group 1 (normal control) received double distilled water; group 2 (toxic control) received lead acetate (5 mg/kg body weight/day) in double distilled water for 40 days; groups 3-6 received BV aqueous extract at doses of 25, 50, 100 and 150 mg/kg body weight , respectively, once daily for 30 days from 11 day after beginning of lead acetate exposure to the end of the experiment. Results Toxic control group showed a significant alteration of serum alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), total cholesterol (TC), total bilirubin (TB), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH). Histological assessment of lead-intoxicated mice liver revealed alterations in hepatocytes and focal necrosis. BV treatment significantly prevented lead accumulation, increased ALT, AST, TC, and TB, inhibited lipid peroxidation and protein carbonyls(PCO) formation. Additionally, BV extract normalized the antioxidant enzymes (CAT, SOD and GPx), GSH and architecture of liver tissues. Conclusions BV aqueous extract exerts significant hepatoprotective effects against lead-induced oxidative stress and liver dysfunction. The BV effect may be mediated through the enhancement of antioxidant status, lead-chelating abilities and free radicals quenching.

  1. [Acute fatty liver in pregnancy: revealing fetal fatty acid oxidation disorders].

    PubMed

    Lamireau, D; Feghali, H; Redonnet-Vernhet, I; Mesli, S; Carles, D; Brissaud, O

    2012-03-01

    Acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome are serious maternal illnesses occurring in the third trimester of pregnancy with significant perinatal and maternal mortality. AFLP may result from mitochondrial defects in the beta-oxidation of fatty acids, in particular a deficiency of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) in the fetus. Clinical findings in AFLP vary and its diagnosis is complicated by a significant overlap in clinical and biochemical features with HELLP syndrome. We report the case of 2 siblings who died, the first one in the neonatal period of asphyxia with multivisceral presentation and the second one from sudden death at 7 months. Autopsy of the latter infant revealed hepatic steatosis associated with cardiomyopathy, which led to suspicion of a fatty acid oxidation deficiency. Mutation analysis demonstrated that both children were homozygous for the common mutation c.1528G>C and the parents were heterozygous for this same mutation. This case demonstrates the importance of screening mothers with acute fatty liver disease of pregnancy and their children at birth for a metabolic disease. This article proposes several metabolic tests for mother and child suspected of having beta-oxidation of a fatty acid disorder.

  2. Exogenous Superoxide Dismutase: Action on Liver Oxidative Stress in Animals with Streptozotocin-Induced Diabetes

    PubMed Central

    Di Naso, Fábio Cangeri; Simões Dias, Alexandre; Porawski, Marilene; Marroni, Norma Anair Possa

    2011-01-01

    Aim. To investigate the effects of exogenous antioxidant copper zinc superoxide dismutase (Cu/Zn SOD) on oxidative stress in the experimental model of diabetes mellitus (DM). Methods. Twenty eight male Wistar rats divided in four groups were used: control (CO), controls treated with SOD (CO + SOD), diabetics (DM), and diabetics treated with SOD (DM + SOD). SOD (orgotein, 13 mg/Kg body weight was administered. DM was induced by a single streptozotocin injection (i.p., 70 mg/kg), and 60 days later, we evaluated liver oxidative stress. Results. Liver lipoperoxidation was increased in the DM group and significantly decreased in the DM + SOD group. Nitrite and nitrate measures were reduced in the DM and increased in the DM + SOD group, while iNOS expression in the DM group was 32% greater than in the CO and 53% greater in the DM + SOD group than in the DM group (P < .01). P65 expression was 37% higher in the DM (P < .05), and there was no significant difference between the DM and DM + SOD groups. Conclusion. SOD treatment reduced liver oxidative stress in diabetic animals, even though it did not change NFκB. SOD also increased NO, probably by the increased dismutation of the superoxide radical. The iNOS expression increase, which became even more evident after SOD administration. PMID:21437212

  3. Increased sensitivity of apolipoprotein E knockout mice to copper-induced oxidative injury to the liver.

    PubMed

    Chen, Yuan; Li, Bin; Zhao, Ran-ran; Zhang, Hui-feng; Zhen, Chao; Guo, Li

    2015-04-10

    Apolipoprotein E (ApoE) genotypes are related to clinical presentations in patients with Wilson's disease, indicating that ApoE may play an important role in the disease. However, our understanding of the role of ApoE in Wilson's disease is limited. High copper concentration in Wilson's disease induces excessive generation of free oxygen radicals. Meanwhile, ApoE proteins possess antioxidant effects. We therefore determined whether copper-induced oxidative damage differ in the liver of wild-type and ApoE knockout (ApoE(-/-)) mice. Both wild-type and ApoE(-/-) mice were intragastrically administered with 0.2 mL of copper sulfate pentahydrate (200 mg/kg; a total dose of 4 mg/d) or the same volume of saline daily for 12 weeks, respectively. Copper and oxidative stress markers in the liver tissue and in the serum were assessed. Our results showed that, compared with the wild-type mice administered with copper, TBARS as a marker of lipid peroxidation, the expression of oxygenase-1 (HO-1), NAD(P)H dehydrogenase, and quinone 1 (NQO1) significantly increased in the ApoE(-/-) mice administered with copper, meanwhile superoxide dismutase (SOD) activity significantly decreased. Thus, it is concluded that ApoE may protect the liver from copper-induced oxidative damage in Wilson's disease.

  4. Metabolism of (-)-cis- and (-)-trans-rose oxide by cytochrome P450 enzymes in human liver microsomes.

    PubMed

    Nakahashi, Hiroshi; Yamamura, Yuuki; Usami, Atsushi; Rangsunvigit, Pramoch; Malakul, Pomthong; Miyazawa, Mitsuo

    2015-12-01

    The in vitro metabolism of (-)-cis- and (-)-trans-rose oxide was investigated using human liver microsomes and recombinant cytochrome P450 (P450 or CYP) enzymes for the first time. Both isomers of rose oxide were incubated with human liver microsomes, and the formation of the respective 9-oxidized metabolite were determined using gas chromatography-mass spectrometry (GC-MS). Of 11 different recombinant human P450 enzymes used, CYP2B6 and CYP2C19 were the primary enzymes catalysing the metabolism of (-)-cis- and (-)-trans-rose oxide. CYP1A2 also efficiently oxidized (-)-cis-rose oxide at the 9-position but not (-)-trans-rose oxide. α-Naphthoflavone (a selective CYP1A2 inhibitor), thioTEPA (a CYP2B6 inhibitor) and anti-CYP2B6 antibody inhibited (-)-cis-rose oxide 9-hydroxylation catalysed by human liver microsomes. On the other hand, the metabolism of (-)-trans-rose oxide was suppressed by thioTEPA and anti-CYP2B6 at a significant level in human liver microsomes. However, omeprazole (a CYP2C19 inhibitor) had no significant effects on the metabolism of both isomers of rose oxide. Using microsomal preparations from nine different human liver samples, (-)-9-hydroxy-cis- and (-)-9-hydroxy-trans-rose oxide formations correlated with (S)-mephenytoin N-demethylase activity (CYP2B6 marker activity). These results suggest that CYP2B6 plays important roles in the metabolism of (-)-cis- and (-)-trans-rose oxide in human liver microsomes.

  5. [Curcumin alleviated liver oxidative stress injury of rat induced by paraquat].

    PubMed

    Han, Wenwen; Wu, Dong; Liu, Hong; Lu, Yang; Wang, Lei; Hong, Guangliang; Qiu, Qiaomeng; Lu, Zhongqiu

    2014-05-01

    To investigate the effect of curcumin on liver injury in rats induced by paraquat-mediated oxidative stress and the mechanism underlying its effect. Sixty rats were randomly divided into 4 groups: control group, curcumin control group (curcumin 50 mg/kg), paraquat group (2% paraquat solution 100 mg/kg), and curcumin intervention group (curcumin 50 mg/kg at 15 min, 24 h, or 48 h after paraquat exposure). On days 1, 3, or 7 after paraquat administration, and liver tissue was collected thereafter. The content of malonaldehyde (MDA) and the activities of superoxide dismutase activity (SOD) and catalase (CAT) in the liver tissue were determined by chemical colorimetry. The activities of heme oxygenase 1 (HO-1) and quinone oxidoreductase 1 (NQO-1) in the liver tissue were determined by ELISA. The mRNA and protein levels of NF-E2-related factor 2 (Nrf2) were determined by RT-PCR and Western blot, respectively. The pathological changes of liver tissue were examined by optical microscopy. No significant change was observed between the control group and the curcumin control group in any examination of this study (P > 0.05). Both paraquat group and curcumin intervention group showed increase in MDA content, decreases in SOD and CAT activities, increases in HO-1 and NQO-1 activities, and increases in the protein and mRNA levels of Nrf2, in comparison with the control group (P < 0.05 for all except HO-1 activity in paraquat group on day 7). In comparison with the parquet group on the same day, the curcumin intervention group showed decrease in MDA content, increases in the activities of SOD, CAT, HO-1, and NQO-1, and increases in the mRNA and protein levels of Nrf2 on days 1, 3, and 7 (P < 0.05). The pathological examination revealed that the damage of liver tissue in the paraquat group was the most serious on the 3rd day after paraquat exposure, and the damage was consistently alleviated by curcumin intervention on days 1, 3, and 7, as compared with the paraquat group

  6. Brain and liver oxidative stress after sertraline and haloperidol treatment in mice.

    PubMed

    Abdel-Salam, Omar M E; Youness, Eman R; Khadrawy, Yasser Ashry; Sleem, Amany A

    2013-01-01

    Haloperidol is a classic antipsychotic drug known for its propensity to cause extrapyramidal side effects. Sertraline is an antidepressant drug which has been reported to cause extrapyramidal symptoms. We aimed to see whether treatment with sertraline would worsen the effect of haloperidol on oxidative stress in the brains of mice. Sertraline (10 or 20 mg/kg), haloperidol (2 mg/kg), haloperidol combined with sertraline or saline was administered daily via the subcutaneous route and mice were euthanized 10 days later when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (nitrite) levels, total antioxidant capacity (TAC), acetylcholinesterase (AChE), catalase and paraoxonase 1 (PON1) activities were determined in the brain and liver. Sertraline monotherapy did not alter GSH, MDA, TAC or nitrite in the brain. Haloperidol decreased GSH and TAC and increased MDA and nitrite. The combined treatment with sertraline and haloperidol resulted in increased MDA, but to a lesser extent than haloperidol monotherapy. A significant increase in GSH and TAC and decreased nitrite was observed after the combination treatment was compared with haloperidol monotherapy. Catalase activity decreased with sertraline or haloperidol treatment. PON1 activity decreased with sertraline and haloperidol monotherapy and showed a further decrease with the combination therapy compared with haloperidol monotherapy. AChE activity decreased after haloperidol and increased with the combination treatment compared with haloperidol monotherapy. In the liver, GSH was unaltered after sertraline, haloperidol or their combination. MDA increased with sertraline, haloperidol and their combination. TAC decreased after combination therapy. Nitric oxide increased after sertraline, haloperidol or their combination. PON1 activity decreased with sertraline, haloperidol and with sertraline-haloperidol co-treatment. Sertraline did not worsen brain oxidative stress

  7. Oxidative modification enhances lipoprotein(a)-induced overproduction of plasminogen activator inhibitor-1 in cultured vascular endothelial cells.

    PubMed

    Ren, S; Man, R Y; Angel, A; Shen, G X

    1997-01-03

    Elevated levels of plasma lipoprotein (a) [Lp(a)] have been considered as a strong risk factor for premature cardiovascular diseases. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of plasminogen activators (PA). Increases in PAI-1 levels with or without a reduction in PA levels have been frequently found in coronary artery disease patients. The present paper examined the effects of oxidized Lp(a) on the production of PAI-1 in cultured human umbilical vein endothelial cells (HUVEC). Lp(a) and Lp(a)-free, low density lipoprotein (LDL) were prepared using lysine-Sepharose 4B affinity chromatography. Incubations with 10(-8) M levels of native Lp(a) moderately increased the levels of biologically active PAI-1 in post-culture medium of HUVEC compared to that with equimolar concentrations of native Lp(a)-free LDL. The release of PAI-1 induced by Lp(a) was enhanced by oxidative modification with copper ion. The stimulation of oxidized Lp(a) on PAI-1 production reached plateau in EC treated with 10-20 nM oxidized Lp(a) modified by microM CuSO4. Treatment with 0.2 micrograms/ml of actinomycin D significantly reduced native and oxidized Lp(a)-induced PAI-1 overproduction in EC. Increases in the steady state levels of PAI-1 mRNA were detected in native or oxidized Lp(a)-treated EC. The effect of Lp(a)-free oxidized LDL on PAI-1 production was significantly weaker than the equimolar amount of oxidized Lp(a) but stronger than that of native LDL. Treatments with oxidized Lp(a) increased cell-associated PAI-1 to a similar extent as that in native Lp(a)-treated EC. The results of the present paper demonstrate that oxidative modification enhances Lp(a)-induced PAI-1 production in vascular endothelial cells at RNA transcription level, which suggests that oxidization potentially amplifies the anti-fibrinolytic and thrombotic effect of Lp(a).

  8. N-acetyl-cysteine inhibits liver oxidative stress markers in BALB/c mice infected with Leishmania amazonensis

    PubMed Central

    Gasparotto, Juciano; Kunzler, Alice; Senger, Mario Roberto; de Souza, Celeste da Silva Freitas; de Simone, Salvatore Giovanni; Bortolin, Rafael Calixto; Somensi, Nauana; Dal-Pizzol, Felipe; Moreira, José Claudio Fonseca; Abreu-Silva, Ana Lúcia; Calabrese, Kátia da Silva; Silva, Floriano Paes; Gelain, Daniel Pens

    2017-01-01

    BACKGROUND Leishmaniasis is a parasitosis caused by several species of the genus Leishmania. These parasites present high resistance against oxidative stress generated by inflammatory cells. OBJECTIVES To investigate oxidative stress and molecular inflammatory markers in BALB/c mice infected with L. amazonensis and the effect of antioxidant treatment on these parameters. METHODS Four months after infection, oxidative and inflammatory parameters of liver, kidneys, spleen, heart and lungs from BALB/c mice were assessed. FINDINGS In liver, L. amazonensis caused thiol oxidation and nitrotyrosine formation; SOD activity and SOD2 protein content were increased while SOD1 protein content decreased. The content of the cytokines IL-1β, IL-6, TNF-α, and the receptor of advanced glycation endproducts (RAGE) increased in liver. Treatment with the antioxidant N-acetyl-cysteine (20 mg/kg b.w) for five days inhibited oxidative stress parameters. MAIN CONCLUSIONS L. amazonensis induces significant alterations in the redox status of liver but not in other organs. Acute antioxidant treatment alleviates oxidative stress in liver, but it had no effect on pro-inflammatory markers. These results indicate that the pathobiology of leishmaniasis is not restricted to the cutaneous manifestations and open perspectives for the development of new therapeutic approaches to the disease, especially for liver function. PMID:28177049

  9. N-acetyl-cysteine inhibits liver oxidative stress markers in BALB/c mice infected with Leishmania amazonensis.

    PubMed

    Gasparotto, Juciano; Kunzler, Alice; Senger, Mario Roberto; Souza, Celeste da Silva Freitas de; Simone, Salvatore Giovanni de; Bortolin, Rafael Calixto; Somensi, Nauana; Dal-Pizzol, Felipe; Moreira, José Claudio Fonseca; Abreu-Silva, Ana Lúcia; Calabrese, Kátia da Silva; Silva, Floriano Paes; Gelain, Daniel Pens

    2017-02-01

    Leishmaniasis is a parasitosis caused by several species of the genus Leishmania. These parasites present high resistance against oxidative stress generated by inflammatory cells. To investigate oxidative stress and molecular inflammatory markers in BALB/c mice infected with L. amazonensis and the effect of antioxidant treatment on these parameters. Four months after infection, oxidative and inflammatory parameters of liver, kidneys, spleen, heart and lungs from BALB/c mice were assessed. In liver, L. amazonensis caused thiol oxidation and nitrotyrosine formation; SOD activity and SOD2 protein content were increased while SOD1 protein content decreased. The content of the cytokines IL-1β, IL-6, TNF-α, and the receptor of advanced glycation endproducts (RAGE) increased in liver. Treatment with the antioxidant N-acetyl-cysteine (20 mg/kg b.w) for five days inhibited oxidative stress parameters. L. amazonensis induces significant alterations in the redox status of liver but not in other organs. Acute antioxidant treatment alleviates oxidative stress in liver, but it had no effect on pro-inflammatory markers. These results indicate that the pathobiology of leishmaniasis is not restricted to the cutaneous manifestations and open perspectives for the development of new therapeutic approaches to the disease, especially for liver function.

  10. Effect of hydrogen-rich water on oxidative stress, liver function, and viral load in patients with chronic hepatitis B.

    PubMed

    Xia, Chunxiang; Liu, Wenwu; Zeng, Dongxiao; Zhu, Liyao; Sun, Xiaoli; Sun, Xuejun

    2013-10-01

    To investigate effects of hydrogen-rich water (HRW) on oxidative stress, liver function and HBV DNA in patients with chronic hepatitis B (CHB). Sixty patients with CHB were randomly assigned into routine treatment group or hydrogen treatment group in which patients received routine treatment alone or additional oral HRW (1200-1800 mL/day, twice daily), respectively, for 6 consecutive weeks. Serum oxidative stress, liver function, and HBV DNA level were detected before and after treatment. Thirty healthy subjects served as controls. When compared with controls, oxidative stress was obvious in CHB patients, and the liver function also significantly impaired. After treatment, the oxidative stress remained unchanged in routine treatment group, but markedly improved in hydrogen treatment group. The liver function was improved significantly and the HBV DNA reduced markedly after corresponding treatments. Although a significant difference was noted in the oxidative stress between two groups after treatment, the liver function and HBV DNA level were comparable after treatment and both had improved tendencies. HRW significantly attenuates oxidative stress in CHB patients, but further study with long-term treatment is required to confirm the effect of HRW on liver function and HBV DNA level. © 2013 Wiley Periodicals, Inc.

  11. Crocetin protects ultraviolet A-induced oxidative stress and cell death in skin in vitro and in vivo.

    PubMed

    Ohba, Takuya; Ishisaka, Mitsue; Tsujii, Saori; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Kubo, Koya; Umigai, Naofumi; Iwawaki, Takao; Hara, Hideaki

    2016-10-15

    Crocetin, the aglycone of crocin, is a carotenoid found in fruits of gardenia (Gardeina jasminoides Ellis) and saffron (Crocus sativus L.). We investigated the protective effects of crocetin against ultraviolet-A (UV-A)-induced skin damage and explored the underlying mechanism. Human skin-derived fibroblasts cells (NB1-RGB) were damaged by exposure to UV-A irradiation (10J/cm(2)). Crocetin protected these cells against cell death and reduced the production of reactive oxygen species induced by UV-A irradiation. Crocetin treatment also suppressed induction of caspase-3 activation by UV-A irradiation. The effects of crocetin against oxidative stress were also examined by imaging of Keap1-dependent oxidative stress detector (OKD) mice. UV-A irradiation upregulated oxidative stress in the OKD mice skin, while crocetin administration (100mg/kg, p.o.) ameliorated this oxidative stress. Crocetin administration also decreased lipid peroxidation in the skin. These findings suggest that crocetin its observed protective effects against UV-A induced skin damage by reducing reactive oxygen species production and cell apoptosis.

  12. Effects of sodium arsenate exposure on liver fatty acid profiles and oxidative stress in rats.

    PubMed

    Kharroubi, Wafa; Dhibi, Madiha; Haouas, Zohra; Chreif, Imed; Neffati, Fadoua; Hammami, Mohamed; Sakly, Rachid

    2014-02-01

    The present study aimed to evaluate the effect of arsenic on liver fatty acids (FA) composition, hepatotoxicity and oxidative status markers in rats. Male rats were randomly devised to six groups (n=10 per group) and exposed to sodium arsenate at a dose of 1 and 10 mg/l for 45 and 90 days. Arsenate exposure is associated with significant changes in the FA composition in liver. A significant increase of saturated fatty acids (SFA) in all treated groups (p<0.01) and trans unsaturated fatty acids (trans UFA) in rats exposed both for short term for 10 mg/l (p<0.05) and long term for 1 and 10 mg/l (p<0.001) was observed. However, the cis UFA were significantly decreased in these groups (p<0.05). A markedly increase of indicator in cell membrane viscosity expressed as SFA/UFA was reported in the treated groups (p<0.001). A significant increase in the level of malondialdehyde by 38.3 % after 90 days of exposure at 10 mg/l was observed. Compared to control rats, significant liver damage was observed at 10 mg/l of arsenate by increasing plasma marker enzymes after 90 days. It is through the histological investigations in hepatic tissues of exposed rats that these damage effects of arsenate were confirmed. The antioxidant perturbations were observed to be more important at groups treated by the high dose (p<0.05). An increase in the level of protein carbonyls was observed in all treated groups (p<0.05). The present study provides evidence for a direct effect of arsenite on FA composition disturbance causing an increase of SFA and TFAs isomers, liver dysfunction and oxidative stress. Therefore, arsenate can lead to hepatic damage and propensity towards liver cancer.

  13. Fatty liver and anti-oxidant enzyme activities along with peroxisome proliferator-activated receptors γ and α expressions in the liver of Wilson's disease.

    PubMed

    Nagasaka, Hironori; Miida, Takashi; Inui, Ayano; Inoue, Ikuo; Tsukahara, Hirokazu; Komatsu, Haruki; Hiejima, Eitaro; Fujisawa, Tomoo; Yorifuji, Tohru; Hiranao, Ken-ichi; Okajima, Hideaki; Inomata, Yukihiro

    2012-11-01

    The mechanisms of liver damage and steatosis in Wilson's disease (WD) presenting accumulation of copper generating oxidants remain unclear. Recent studies have shown that peroxisome proliferator-activated receptors (PPARs), in particular PPARs α and γ, regulate fat content of the liver together with the anti-oxidant and anti-inflammation systems. However, such PPARs have never been studied in WD. We examined PPARs along with the liver damage and steatosis of WD using liver specimens from affected patients exhibiting mild liver damage (group I, n = 5), moderate or greater liver damage (group II, n = 10) and fulminant hepatic failure (group III, n = 5), and from asymptomatic carriers (group H, n = 4). PPAR α expression was increased over the control levels in groups H and I but was decreased in groups II and III in parallel with the progression of liver damage (group H = I>II>III). PPAR γ expression was inversely increased (group Hoxidant system in the liver of WD. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Effect of galangin supplementation on oxidative damage and inflammatory changes in fructose-fed rat liver.

    PubMed

    Sivakumar, Allur Subramaniyan; Anuradha, Carani Venkatraman

    2011-09-05

    The study examined the effects of galangin (GA) on oxidative stress, inflammatory cytokine levels and nuclear factor-kappa B (NF-κB) activation in fructose-fed rat liver. Adult male albino Wistar rats were divided into 4 groups. Groups 1 and 4 received the control diet containing starch as the source of carbohydrate while groups 2 and 3 were fed a diet containing fructose. Groups 3 and 4 additionally received GA (100μg/kg, p.o) from the 15th day. At the end of 60 days, the levels of plasma glucose, insulin and triglycerides, insulin sensitivity indices and oxidative stress markers in the liver were determined. Cytokines of interest were assayed by ELISA and RT-PCR and NF-κB p65 nuclear translocation by Western blot and RT-PCR. Compared to control diet-fed animals, fructose-fed animals developed hyperglycemia, hyperinsulinemia, hypertriglyceridemia and insulin resistance (IR) (all p<0.01). GA prevented the rise in plasma glucose, insulin and triglycerides and improved insulin sensitivity. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels in plasma and the mRNA and protein levels of TNF-α and transforming growth factor-β1(TGF-β(1)) in liver were significantly higher in fructose-fed rats than control rats. However, treatment with GA downregulated the expression of these cytokines. Translocation of NF-κB into the nucleus was also increased in fructose diet-fed animals, which was prevented by GA. These results suggest that GA prevents oxidative damage and has a downregulatory effect on the inflammatory pathway in liver of fructose-fed rats.

  15. Peroxiredoxin III and sulfiredoxin together protect mice from pyrazole-induced oxidative liver injury.

    PubMed

    Bae, Soo Han; Sung, Su Haeng; Lee, Hye Eun; Kang, Ha Tan; Lee, Se Kyoung; Oh, Sue Young; Woo, Hyun Ae; Kil, In Sup; Rhee, Sue Goo

    2012-11-15

    To define the mechanisms underlying pyrazole-induced oxidative stress and the protective role of peroxiredoxins (Prxs) and sulfiredoxin (Srx) against such stress. Pyrazole increased Srx expression in the liver of mice in a nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent manner and induced Srx translocation from the cytosol to the endoplasmic reticulum (ER) and mitochondria. Pyrazole also induced the expression of CYP2E1, a primary reactive oxygen species (ROS) source for ethanol-induced liver injury, in ER and mitochondria. However, increased CYP2E1 levels only partially accounted for the pyrazole-mediated induction of Srx, prompting the investigation of CYP2E1-independent ROS generation downstream of pyrazole. Indeed, pyrazole increased ER stress, which is known to elevate mitochondrial ROS. In addition, pyrazole up-regulated CYP2E1 to a greater extent in mitochondria than in ER. Accordingly, among Prxs I to IV, PrxIII, which is localized to mitochondria, was preferentially hyperoxidized in the liver of pyrazole-treated mice. Pyrazole-induced oxidative damage to the liver was greater in PrxIII(-/-) mice than in wild-type mice. Such damage was also increased in Srx(-/-) mice treated with pyrazole, underscoring the role of Srx as the guardian of PrxIII. The roles of Prxs, Srx, and ER stress have not been previously studied in relation to pyrazole toxicity. The concerted action of PrxIII and Srx is important for protection against pyrazole-induced oxidative stress arising from the convergent induction of CYP2E1-derived and ER stress-derived ROS in mitochondria.

  16. Peroxiredoxin III and Sulfiredoxin Together Protect Mice from Pyrazole-Induced Oxidative Liver Injury

    PubMed Central

    Sung, Su Haeng; Lee, Hye Eun; Kang, Ha Tan; Lee, Se Kyoung; Oh, Sue Young; Woo, Hyun Ae; Kil, In Sup

    2012-01-01

    Abstract Aims: To define the mechanisms underlying pyrazole-induced oxidative stress and the protective role of peroxiredoxins (Prxs) and sulfiredoxin (Srx) against such stress. Results: Pyrazole increased Srx expression in the liver of mice in a nuclear factor erythroid 2–related factor 2 (Nrf2)-dependent manner and induced Srx translocation from the cytosol to the endoplasmic reticulum (ER) and mitochondria. Pyrazole also induced the expression of CYP2E1, a primary reactive oxygen species (ROS) source for ethanol-induced liver injury, in ER and mitochondria. However, increased CYP2E1 levels only partially accounted for the pyrazole-mediated induction of Srx, prompting the investigation of CYP2E1-independent ROS generation downstream of pyrazole. Indeed, pyrazole increased ER stress, which is known to elevate mitochondrial ROS. In addition, pyrazole up-regulated CYP2E1 to a greater extent in mitochondria than in ER. Accordingly, among Prxs I to IV, PrxIII, which is localized to mitochondria, was preferentially hyperoxidized in the liver of pyrazole-treated mice. Pyrazole-induced oxidative damage to the liver was greater in PrxIII−/− mice than in wild-type mice. Such damage was also increased in Srx−/− mice treated with pyrazole, underscoring the role of Srx as the guardian of PrxIII. Innovation: The roles of Prxs, Srx, and ER stress have not been previously studied in relation to pyrazole toxicity. Conclusion: The concerted action of PrxIII and Srx is important for protection against pyrazole-induced oxidative stress arising from the convergent induction of CYP2E1-derived and ER stress-derived ROS in mitochondria. Antioxid. Redox Signal. 17, 1351–1361. PMID:22490042

  17. Modulatory role of Pterocarpus santalinus against alcohol-induced liver oxidative/nitrosative damage in rats.

    PubMed

    Bulle, Saradamma; Reddy, Vaddi Damodara; Padmavathi, Pannuru; Maturu, Paramahamsa; N Ch, Varadacharyulu

    2016-10-01

    Pterocarpus santalinus, a traditional medicinal plant has shown protective mechanisms against various complications. The aim of the present study is to evaluate therapeutic efficacy of P. santalinus heartwood methanolic extract (PSE) against alcohol-induced oxidative/nitrosative stress leading to hepatotoxicity. In-vitro studies revealed that PSE possess strong DPPH (1,1-diphenyl-2-picryl hydrazyl) and nitric oxide radical scavenging activity. For in vivo studies male albino Wistar rats were treated with 20% alcohol (5g/kg b.wt/day) and PSE (250mg/kg b.wt/day) for 60days. Results showed that alcohol administration significantly altered plasma lipid profile with marked increase in the levels of plasma transaminases (ALT and AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma glutamyl transferase (γGT). Moreover, lipid peroxides, nitric oxide (NOx) levels in plasma and liver were increased with increased iNOS protein expression in liver was noticed in alcohol administered rats and these levels were significantly brought back close to normal level by PSE administration except iNOS protein expression. Alcohol administration also decreased the content of reduced glutathione (GSH) and activities of glutathione peroxidase (GPx), glutathione-s transferase (GST), glutathione reductase (GR), superoxide dismutase (SOD) and catalase (CAT) in liver, which were significantly enhanced by administration of PSE. The active compounds pterostilbene, lignan and lupeols present in PSE might have shown protection against alcohol-induced hepatic damage by possibly reducing the rate of lipid peroxidation, NOx levels and increasing the antioxidant defence mechanism in alcohol administered rats. Both biochemical and histopathological results in the alcohol-induced liver damage model emphasize beneficial action of PSE as a hepatoprotective agent. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  18. Protective effects of erdosteine on rotenone-induced oxidant injury in liver tissue.

    PubMed

    Terzi, Alpaslan; Iraz, Mustafa; Sahin, Semsettin; Ilhan, Atilla; Idiz, Nuri; Fadillioglu, Ersin

    2004-09-01

    Rotenone, an insecticide of botanical origin, causes toxicity through inhibition of complex I of the respiratory chain in mitochondria. This study was undertaken to determine whether rotenone-induced liver oxidant injury is prevented by erdosteine, a mucolytic agent showing antioxidant properties. There were four groups of Male Wistar Albino rats: group one was untreated as control; the other groups were treated with erdosteine (50 mg/kg per day, orally), rotenone (2.5 mg/mL once and 1 mL/kg per day for 60 days, i.p.) or rotenone plus erdosteine, respectively. Rotenone treatment without erdosteine increased xanthine oxidase (XO) enzyme activity and also increased lipid peroxidation in liver tissue (P < 0.05). The rats treated with rotenone plus erdosteine produced a significant decrease in lipid peroxidation and XO activities in comparison with rotenone group (P < 0.05). Erdosteine treatment with rotenone led to an increase in catalase (CAT) and superoxide dismutase (SOD) activities in comparison with the rotenone group (P < 0.05). There was no significant difference in nitric oxide (NO) level between groups. There were negative correlations between CAT activity and malondialdehyde (MDA) level (r = -0.934, P < 0.05) with between CAT and SOD activities (r = -0.714, P < 0.05), and a positive correlation between SOD activity and MDA level (r = 0.828, P < 0.05) in rotenone group. In the rotenone plus erdosteine group, there was a negative correlation between XO activity and NO level in liver tissue (r = -0.833, P < 0.05). In the light of these findings, erdosteine may be a protective agent for rotenone-induced liver oxidative injury in rats.

  19. Effects of zinc oxide nanoparticles on Kupffer cell phagosomal motility, bacterial clearance, and liver function

    PubMed Central

    Watson, Christa Y; Molina, Ramon M; Louzada, Andressa; Murdaugh, Kimberly M; Donaghey, Thomas C; Brain, Joseph D

    2015-01-01

    Background Zinc oxide engineered nanoparticles (ZnO ENPs) have potential as nanomedicines due to their inherent properties. Studies have described their pulmonary impact, but less is known about the consequences of ZnO ENP interactions with the liver. This study was designed to describe the effects of ZnO ENPs on the liver and Kupffer cells after intravenous (IV) administration. Materials and methods First, pharmacokinetic studies were conducted to determine the tissue distribution of neutron-activated 65ZnO ENPs post-IV injection in Wistar Han rats. Then, a noninvasive in vivo method to assess Kupffer cell phagosomal motility was employed using ferromagnetic iron particles and magnetometry. We also examined whether prior IV injection of ZnO ENPs altered Kupffer cell bactericidal activity on circulating Pseudomonas aeruginosa. Serum and liver tissues were collected to assess liver-injury biomarkers and histological changes, respectively. Results We found that the liver was the major site of initial uptake of 65ZnO ENPs. There was a time-dependent decrease in tissue levels of 65Zn in all organs examined, refecting particle dissolution. In vivo magnetometry showed a time-dependent and transient reduction in Kupffer cell phagosomal motility. Animals challenged with P. aeruginosa 24 hours post-ZnO ENP injection showed an initial (30 minutes) delay in vascular bacterial clearance. However, by 4 hours, IV-injected bacteria were cleared from the blood, liver, spleen, lungs, and kidneys. Seven days post-ZnO ENP injection, creatine phosphokinase and aspartate aminotransferase levels in serum were significantly increased. Histological evidence of hepatocyte damage and marginated neutrophils were observed in the liver. Conclusion Administration of ZnO ENPs transiently inhibited Kupffer cell phagosomal motility and later induced hepatocyte injury, but did not alter bacterial clearance from the blood or killing in the liver, spleen, lungs, or kidneys. Our data show that

  20. Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis

    PubMed Central

    Iyer, Malliga R.; Liu, Ziyi; Cao, Zongxian; Jourdan, Tony; Erdelyi, Katalin; Godlewski, Grzegorz; Szanda, Gergő; Liu, Jie; Park, Joshua K.; Mukhopadhyay, Bani; Rosenberg, Avi Z.; Liow, Jeih-San; Lorenz, Robin G.; Pacher, Pal; Innis, Robert B.

    2016-01-01

    Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment. Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis. CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects. Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases. Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group. In mouse models of fibrosis induced by CCl4 or bile duct ligation, the hybrid CB1R/iNOS antagonist surpassed the antifibrotic efficacy of the CB1R antagonist rimonabant or the iNOS inhibitor 1400W, without inducing anxiety-like behaviors or CB1R occupancy in the CNS. The hybrid inhibitor also targeted CB1R-independent, iNOS-mediated profibrotic pathways, including increased PDGF, Nlrp3/Asc3, and integrin αvβ6 signaling, as judged by its ability to inhibit these pathways in cnr1–/– but not in nos2–/– mice. Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis. PMID:27525312

  1. Molecular evidence of offspring liver dysfunction after maternal exposure to zinc oxide nanoparticles.

    PubMed

    Hao, Yanan; Liu, Jing; Feng, Yanni; Yu, Shuai; Zhang, Weidong; Li, Lan; Min, Lingjiang; Zhang, Hongfu; Shen, Wei; Zhao, Yong

    2017-08-15

    Recently, reproductive, embryonic and developmental toxicity have been considered as one important sector of nanoparticle (NP) toxicology, with some studies already suggesting varying levels of toxicity and possible transgenerational toxic effects. Even though many studies have investigated the toxic effects of zinc oxide nanoparticles (ZnO NPs), little is known of their impact on overall reproductive outcome and transgenerational effects. Previously we found ZnO NPs caused liver dysfunction in lipid synthesis. This investigation, for the first time, explored the liver dysfunction at the molecular level of gene and protein expression in offspring after maternal exposure to ZnO NPs. Three pathways were investigated: lipid synthesis, growth related factors and cell toxic biomarkers/apoptosis at 5 different time points from embryonic day-18 to postnatal day-20. It was found that the expression of 15, 16, and 16 genes in lipid synthesis, growth related factors and cell toxic biomarkers/apoptosis signalling pathway respectively in F1 animal liver were altered by ZnO NPs compared to ZnSO4. The proteins in these signalling pathways (five in each pathways analyzed) in F1 animal liver were also changed by ZnO NPs compared to ZnSO4. The results suggest that ZnO NPs caused maternal liver defects can also be detected in offspring that might result in problems on offspring liver development, mainly on lipid synthesis, growth, and lesions or apoptosis. Along with others, this study suggests that ZnO NPs may pose reproductive, embryonic and developmental toxicity; therefore, precautions should be taken with regard to human exposure during daily life. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Protective effects of selenium on oxidative damage and oxidative stress related gene expression in rat liver under chronic poisoning of arsenic.

    PubMed

    Xu, Zhao; Wang, Zhou; Li, Jian-jun; Chen, Chen; Zhang, Ping-chuan; Dong, Lu; Chen, Jing-hong; Chen, Qun; Zhang, Xiao-tian; Wang, Zhi-lun

    2013-08-01

    Arsenic (As) is a toxic metalloid existing widely in the environment, and chronic exposure to it through contaminated drinking water has become a global problem of public health. The present study focused on the protective effects of selenium on oxidative damage of chronic arsenic poisoning in rat liver. Rats were divided into four groups at random and given designed treatments for 20 weeks. The oxidative damage of liver tissue was evaluated by lipid peroxidation and antioxidant enzymes. Oxidative stress related genes were detected to reflect the liver stress state at the molecular level. Compared to the control and Na2SeO3 groups, the MDA content in liver tissue was decreased and the activities of antioxidant enzymes were increased in the Na2SeO3 intervention group. The mRNA levels of SOD1, CAT, GPx and Txnrd1 were increased significantly (P<0.05) in the combined Na2SeO3+NaAsO2 treatment group. The expressions of HSP70 and HO-1 were significantly (P<0.05) increased in the NaAsO2 group and reduced in the combined treatment group. The results indicate that long-term intake of NaAsO2 causes oxidative damage in the rat liver, and Na2SeO3 protects liver cells by adjusting the expression of oxidative stress related genes to improve the activities of antioxidant enzymes. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  3. High fat diet aggravates arsenic induced oxidative stress in rat heart and liver.

    PubMed

    Dutta, Mousumi; Ghosh, Debosree; Ghosh, Arnab Kumar; Bose, Gargi; Chattopadhyay, Aindrila; Rudra, Smita; Dey, Monalisa; Bandyopadhyay, Arkita; Pattari, Sanjib K; Mallick, Sanjaya; Bandyopadhyay, Debasish

    2014-04-01

    Arsenic is a well known global groundwater contaminant. Exposure of human body to arsenic causes various hazardous effects via oxidative stress. Nutrition is an important susceptible factor which can affect arsenic toxicity by several plausible mechanisms. Development of modern civilization led to alteration in the lifestyle as well as food habits of the people both in urban and rural areas which led to increased use of junk food containing high level of fat. The present study was aimed at investigating the effect of high fat diet on heart and liver tissues of rats when they were co-treated with arsenic. This study was established by elucidating heart weight to body weight ratio as well as analysis of the various functional markers, oxidative stress biomarkers and also the activity of the antioxidant enzymes. Histological analysis confirmed the biochemical investigations. From this study it can be concluded that high fat diet increased arsenic induced oxidative stress. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Oxidation of methyl groups by grass grubs and vertebrate liver enzymes.

    PubMed

    Hook, G E; Smith, J N

    1967-02-01

    1. Oxidation rates of p-nitrotoluene, p-acetamidotoluene and p-toluidine by intact grass grubs and vertebrate liver preparations were measured. 2. The effect of p-substitution in increasing the rate of conversion of the methyl into a carboxy group was in the order acetamido> nitro[unk] amino in mice and grass grubs. 3. Rates of oxidation of the N-methyl group in some alkylaryl N-methylcarbamates was measured and the effect of ring substituents in increasing the rate was in the order hydrogen> o-methyl or o-isopropyl> p-methyl or p-isopropyl> m-methyl or m-isopropyl. 4. Rates of oxidation of the N-methyl groups were similar to those of the p-substituted toluenes.

  5. Supplementing antioxidants to pigs fed diets high in oxidants: I. Effects on growth performance, liver function, and oxidative status.

    PubMed

    Lu, T; Harper, A F; Zhao, J; Estienne, M J; Dalloul, R A

    2014-12-01

    The objective of the study was to determine the effects of a dietary antioxidant blend (ethoxyquin and propyl gallate) and vitamin E on growth performance, liver function, and oxidative status in pigs fed diets high in oxidants. Crossbred barrows (n=100, 10.91±0.65 kg BW, 36±2 d of age, Landrace×Duroc) were allotted to 5 treatments on the basis of BW (5 replicate pens per treatment, 4 pigs per pen). Treatments included 1) HO, high-oxidant diet containing 5% oxidized soybean oil and 10% PUFA source (providing 2.05% docosahexaenoic acid in the diet), 2) VE, the HO diet with 11 IU/kg of added vitamin E, 3) AOX, the HO diet with antioxidant blend (135 mg/kg), 4) VE+AOX, the HO diet with both vitamin E and antioxidant blend, and 5) SC, a standard corn-soy control diet. The trial lasted for 118 d; on d 83, the HO diet pigs were switched to the SC diet because the animals were displaying very poor health. Compared with SC pigs, HO pigs had decreased ADG (0.92 vs. 0.51 kg for d 26 to 55, 1.29 vs. 0.34 kg for d 56 to 82; P<0.05) and ADFI (1.84 vs. 0.96 kg for d 26 to 55, 3.41 vs. 1.14 kg for d 56 to 82; P<0.05). However, switching the HO pigs to the SC diet resulted in HO pigs having a greater ADG than VE-fed pigs from d 83 to 118 (0.90 vs. 0.60 kg; P<0.05). The antioxidant blend restored pig performance to a level similar that of pigs fed the SC diet (P>0.05) with greater G:F for the entire period (0.44 vs. 0.38; P<0.05). A greater liver to BW ratio was found in HO compared with other treatments on d 55 and in VE on d 118. Total bilirubin concentration in plasma of HO pigs on d 55 was greater than that in VE+AOX pigs (P<0.05), whereas on d 118, bilirubin concentration in VE was higher than those in VE+AOX and SC (P<0.05). A similar trend was observed in aspartate transaminase. Plasma concentrations of thiobarbituric acid reactive substances (TBARS) and carbonyl were elevated (P<0.05) in the HO pigs compared with the SC pigs on d 55 but not on d 118. Liver TBARS and

  6. Glucuronidation versus oxidation of the flavonoid galangin by human liver microsomes and hepatocytes.

    PubMed

    Otake, Yoko; Hsieh, Faye; Walle, Thomas

    2002-05-01

    In a previous study, we used human liver microsomes for the first time to study cytochrome P450 (P450)-mediated oxidation of the flavonoid galangin. The combination of CYP1A2 and CYP2C9 produced a V(max)/K(m) value of 13.6 +/- 1.1 microl/min/mg of protein. In the present extended study, we determined glucuronidation rates for galangin with the same microsomes. Two major and one minor glucuronide were identified by liquid chromatography/mass spectrometry. The V(max)/K(m) values for the two major glucuronides conjugated in the 7- and 3-positions were 155 +/- 30 and 427 +/- 26 microl/min/mg of protein, thus, exceeding that of oxidation by 11 and 31 times, respectively. This highly efficient glucuronidation appeared to be catalyzed mainly by the UDP-glucuronosyltransferase (UGT)1A9 isoform but also by UGT1A1 and UGT2B15. Sulfation of galangin by the human liver cytosol, mediated mainly but not exclusively by sulfotransferase (SULT) 1A1, also appeared to be efficient. These conclusions were strongly supported by experiments using the S9 fraction of the human liver, in which all three metabolic pathways could be directly compared. When galangin metabolism was examined in fresh plated hepatocytes from six donors, glucuronidation clearly predominated followed by sulfation. Oxidation occurred only to a minor extent in two of the donors. This study for the first time establishes that glucuronidation and sulfation of galangin, and maybe other flavonoids, are more efficient than P450-mediated oxidation, clearly being the metabolic pathways of choice in intact cells and therefore likely also in vivo.

  7. Graft reconditioning with nitric oxide gas in rat liver transplantation from cardiac death donors.

    PubMed

    Kageyama, Shoichi; Yagi, Shintaro; Tanaka, Hirokazu; Saito, Shunichi; Nagai, Kazuyuki; Hata, Koichiro; Fujimoto, Yasuhiro; Ogura, Yasuhiro; Tolba, Rene; Shinji, Uemoto

    2014-03-27

    Liver transplant outcomes using grafts donated after cardiac death (DCD) remain poor. We investigated the effects of ex vivo reconditioning of DCD grafts with venous systemic oxygen persufflation using nitric oxide gas (VSOP-NO) in rat liver transplants. Orthotopic liver transplants were performed in Lewis rats, using DCD grafts prepared using static cold storage alone (group-control) or reconditioning using VSOP-NO during cold storage (group-VSOP-NO). Experiment I: In a 30-min warm ischemia model, graft damage and hepatic expression of inflammatory cytokines, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and endothelin-1 (ET-1) were examined, and histologic analysis was performed 2, 6, 24, and 72 hr after transplantation. Experiment II: In a 60-min warm ischemia model, grafts were evaluated 2 hr after transplantation (6 rats/group), and survival was assessed (7 rats/group). Experiment I: Group-VSOP-NO had lower alanine aminotransferase (ALT) (P<0.001), hyaluronic acid (P<0.05), and malondialdehyde (MDA) (P<0.001), hepatic interleukin-6 expression (IL-6) (P<0.05), and hepatic tumor necrosis factor-alpha (TNF-α) expression (P<0.001). Hepatic eNOS expression (P<0.001) was upregulated, whereas hepatic iNOS (P<0.01) and ET-1 (P<0.001) expressions were downregulated. The damage of hepatocyte and sinusoidal endothelial cells (SECs) were lower in group-VSOP-NO.Experiment II: VSOP-NO decreased ET-1 and 8-hydroxy-2'deoxyguanosine (8-OHdG) expression and improved survival after transplantation by 71.4% (P<0.01). These results suggest that VSOP-NO effectively reconditions warm ischemia-damaged grafts, presumably by decreasing ET-1 upregulation and oxidative damage.

  8. Oxidative Stress and Cell Apoptosis in Caprine Liver Induced by Molybdenum and Cadmium in Combination.

    PubMed

    Yang, Fan; Zhang, Caiying; Zhuang, Yu; Gu, Xiaolong; Xiao, Qingyang; Guo, Xiaoquan; Hu, Guoliang; Cao, Huabin

    2016-09-01

    To investigate the effects of co-exposure to molybdenum (Mo) and cadmium (Cd) on oxidative stress and cell apoptosis in caprine livers, 36 Boer goats were randomly divided into four groups with nine goats in each group. Three groups were randomly assigned with one of three oral treatments of CdCl2 (0.5 mg Cd kg(-1)·BW) and [(NH4)6Mo7O24·4H2O] (15 mg Mo kg(-1)·BW, 30 mg Mo kg(-1)·BW, 45 mg Mo kg(-1)·BW), while the control group received deionized water. Liver tissues on days 0, 25, and 50 were subjected to determine antioxidant activity indexes and the messenger RNA (mRNA) expression levels of ceruloplasmin (CP), cysteinyl aspartate-specific proteinase-3 (caspase-3), second mitochondria-derived activator of caspases (Smac), and cytochrome-C (Cyt-C) genes. The results showed that significant reductions were observed in total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) activities (P < 0.05), while activities or contents of malondialdehyde (MDA), nitric oxide (NO), and nitric oxide synthase (NOS) were increased (P < 0.05). The mRNA expression levels of CP, caspase-3, Smac, and Cyt-C genes were upregulated (P < 0.05). In addition, histopathological lesions showed different degrees of vacuolar degeneration and edematous and mitochondrial swelling. The results suggest that co-exposure to Mo and Cd could induce oxidative stress and cell apoptosis possibly associated with mitochondrial intrinsic pathway in goat liver and show possible synergistic effects between the two elements.

  9. Saikokeishito Extract Exerts a Therapeutic Effect on alpha-Naphthylisothiocyanate-Induced Liver Injury in Rats through Attenuation of Enhanced Neutrophil Infiltration and Oxidative Stress in the Liver Tissue.

    PubMed

    Ohta, Yoshiji; Kongo-Nishimura, Mutsumi; Hayashi, Takahiro; Kitagawa, Akira; Matsura, Tatsuya; Yamada, Kazuo

    2007-01-01

    We examined whether Saikokeishito extract (TJ-10), a traditional Japanese herbal medicine, exerts a therapeutic effect on alpha-naphthylisothiocyanate (ANIT)-induced liver injury in rats through attenuation of enhanced neutrophil infiltration and oxidative stress in the liver tissue. In rats treated once with ANIT (75 mg/kg, i.p.), liver injury with cholestasis occurred 24 h after treatment and progressed at 48 h. When ANIT-treated rats orally received TJ-10 (0.26, 1.3 or 2.6 g/kg) at 24 h after the treatment, progressive liver injury with cholestasis was significantly attenuated at 48 h after the treatment at the dose of 1.3 or 2.6 g/kg. At 24 h after ANIT treatment, increases in hepatic lipid peroxide and reduced glutathione contents and myeloperoxidase activity occurred with decreases in hepatic superoxide dismutase and glutathione reductase activities. At 48 h after ANIT treatment, these changes except for reduced glutathione were enhanced with decreases in catalase, Se-glutathione peroxidase, and glucose-6-phosphate dehydrogenase activities. TJ-10 (1.3 or 2.6 g/kg) post-administered to ANIT-treated rats attenuated these changes found at 48 h after the treatment significantly. These results indicate that TJ-10 exerts a therapeutic effect on ANIT-induced liver injury in rats possibly through attenuation of enhanced neutrophil infiltration and oxidative stress in the liver tissue.

  10. Oxidation of carbon tetrachloride, bromotrichloromethane, and carbon tetrabromide by rat liver microsomes to electrophilic halogens

    SciTech Connect

    Mico, B.A.; Branchflower, R.V.; Pohl, L.R.; Pudzianowski, A.T.; Loew, G.H.

    1982-01-11

    In order to determine whether CCl/sub 4/, CBrCl/sub 3/, CBr/sub 4/ or CHCl/sub 3/ undergo oxidative metabolism to electrophilic halogens by liver microsomes, they were incubated with liver microsomes from phenobarbital pretreated rats in the presence of NADPH and 2,6-dimethylphenol. The analysis of the reaction mixtures by capillary gas chromatography mass spectrometry revealed that 4-chloro-2,6-dimethylphenol was a metabolite of CCl/sub 4/ and CBrCl/sub 3/ whereas 4-bromo-2,6-dimethylphenol was a metabolite of CBr/sub 4/. The formation of the metabolites was significantly decreased when the reactions were conducted with heat denatured microsomes, in the absence of NADPH or under an atmosphere of N/sub 2/. These results indicate that the chlorines of CBrCl/sub 3/ and CCl/sub 4/ and the bromines of CBr/sub 4/ are oxidatively metabolized by rat liver microsomes to electrophilic and potentially toxic metabolites.

  11. Downregulation of Glutathione Biosynthesis Contributes to Oxidative Stress and Liver Dysfunction in Acute Kidney Injury

    PubMed Central

    Siow, Yaw L.; Isaak, Cara K.

    2016-01-01

    Ischemia-reperfusion is a common cause for acute kidney injury and can lead to distant organ dysfunction. Glutathione is a major endogenous antioxidant and its depletion directly correlates to ischemia-reperfusion injury. The liver has high capacity for producing glutathione and is a key organ in modulating local and systemic redox balance. In the present study, we investigated the mechanism by which kidney ischemia-reperfusion led to glutathione depletion and oxidative stress. The left kidney of Sprague-Dawley rats was subjected to 45 min ischemia followed by 6 h reperfusion. Ischemia-reperfusion impaired kidney and liver function. This was accompanied by a decrease in glutathione levels in the liver and plasma and increased hepatic lipid peroxidation and plasma homocysteine levels. Ischemia-reperfusion caused a significant decrease in mRNA and protein levels of hepatic glutamate-cysteine ligase mediated through the inhibition of transcription factor Nrf2. Ischemia-reperfusion inhibited hepatic expression of cystathionine γ-lyase, an enzyme responsible for producing cysteine (an essential precursor for glutathione synthesis) through the transsulfuration pathway. These results suggest that inhibition of glutamate-cysteine ligase expression and downregulation of the transsulfuration pathway lead to reduced hepatic glutathione biosynthesis and elevation of plasma homocysteine levels, which, in turn, may contribute to oxidative stress and distant organ injury during renal ischemia-reperfusion. PMID:27872680

  12. Chlorogenic acid ameliorates endotoxin-induced liver injury by promoting mitochondrial oxidative phosphorylation

    SciTech Connect

    Zhou, Yan; Ruan, Zheng; Zhou, Lili; Shu, Xugang; Sun, Xiaohong; Mi, Shumei; Yang, Yuhui; Yin, Yulong

    2016-01-22

    Acute or chronic hepatic injury is a common pathology worldwide. Mitochondrial dysfunction and the depletion of adenosine triphosphate (ATP) play important roles in liver injury. Chlorogenic acids (CGA) are some of the most abundant phenolic acids in human diet. This study was designed to test the hypothesis that CGA may protect against chronic lipopolysaccharide (LPS)-induced liver injury by modulating mitochondrial energy generation. CGA decreased the activities of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. The contents of ATP and adenosine monophosphate (AMP), as well as the ratio of AMP/ATP, were increased after CGA supplementation. The activities of enzymes that are involved in glycolysis were reduced, while those of enzymes involved in oxidative phosphorylation were increased. Moreover, phosphorylated AMP-activated protein kinase (AMPK), and mRNA levels of AMPK-α, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial DNA transcription factor A were increased after CGA supplementation. Collectively, these findings suggest that the hepatoprotective effect of CGA might be associated with enhanced ATP production, the stimulation of mitochondrial oxidative phosphorylation and the inhibition of glycolysis. - Highlights: • Dietary supplementation with chlorogenic acid (CGA) improved endotoxin-induced liver injury. • Chlorogenic acid enhances ATP increase and shifts energy metabolism, which is correlated with up-regulation AMPK and PGC-1α. • The possible mechanism of CGA on mitochondrial biogenesis was correlated with up-regulation AMPK and PGC-1α.

  13. Grape seed and skin extract mitigates garlic-induced oxidative stress in rat liver.

    PubMed

    Hamlaoui-Gasmi, Sonia; Mokni, Meherzia; Limam, Nadia; N'guessan, Prudence; Carrier, Alice; Limam, Ferid; Amri, Mohamed; Aouani, Ezzedine; Marzouki, Lamjed

    2012-05-01

    Garlic is a commonly used spice in folk medicine that can exert adverse health effects when given at a high dose. Grape seed and skin extract (GSSE) exhibits a variety of beneficial effects even at a high dose. In the present study we evaluated the toxicity of high-dose garlic treatment on liver and the protective effect of GSSE. Rats were intraperitoneally administered either with garlic extract (5 g·(kg body weight)(-1)) or GSSE (500 mg·(kg body weight)(-1)) or a combination of garlic and GSSE at the same doses daily for 1 month. Plasma and hepatic levels of cholesterol, triacylglycerol, and transaminases and liver antioxidant status were evaluated. Data showed that a high garlic dose induced liver toxicity and a pro-oxidative status characterized by increased malondialdehyde and decreased antioxidant enzyme activities as catalase, peroxidase, and superoxide dismutase. Garlic increased intracellular H(2)O(2) but decreased free iron and Ca(2+). GSSE alone or in co-treatment with garlic had the reverse effect and counteracted almost all garlic-induced deleterious impacts to near control levels. In conclusion, a high garlic dose induced a pro-oxidative state characterized by the Fenton reaction between H(2)O(2) and free iron, inducing Ca(2+) depletion, while GSSE exerted antioxidant properties and Ca(2+) repletion.

  14. Melatonin administration ameliorates cadmium-induced oxidative stress and morphological changes in the liver of rat.

    PubMed

    El-Sokkary, Gamal H; Nafady, Allam A; Shabash, Elhammaly H

    2010-03-01

    The oxidative status and the morphological changes of liver of rats exposed to cadmium (5 mg Cd/kg body weight subcutaneously) for 22 days and the protective role of melatonin (10mg/kg b.w.) against the toxicity of cadmium was studied. The concentration of malondialdehyde (MDA), as an indicator of lipid peroxidation, activity of the antioxidant enzyme superoxide dismutase (SOD) as well as the concentration of glutathione (GSH) was measured in the liver. The morphological changes were investigated using both light and electron microscopes. The exposure to Cd led to an increase of MDA levels and a decrease of both the activity of SOD and GSH concentration in the liver. In contrast, melatonin administration restored the previous changes to nearly the normal levels. Morphologically, Cd led to different histopathological changes such as loss of normal architecture of the parenchymatous tissue, cytoplasmic vacuolization, cellular degeneration and necrosis, congested blood vessels, destructed cristae mitochondria, fat globules, severe glycogen depletion, lipofuscin pigments, and collagenous fibers formation. Again, melatonin administration counteracts all changes and the tissue appears more or less normal. The rate of recovery was faster when melatonin was administered for treatment after the exposure to cadmium than if the animals left without any treatment. The results suggest that melatonin may be useful as an antioxidant in combating free radical-induced oxidative stress and tissue injury that is a result of cadmium toxicity. (c) 2009 Elsevier Inc. All rights reserved.

  15. Induction of oxidative stress and related transcriptional effects of sodium fluoride in female zebrafish liver.

    PubMed

    Mukhopadhyay, Debdip; Chattopadhyay, Ansuman

    2014-07-01

    The effects of sodium fluoride (NaF) exposure on the induction of oxidative stress and alteration of gene expressions were studied in the liver of female zebrafish (Danio rerio). Zebrafish, exposed to 15 ppm NaF for 30 and 90 days, exhibited liver histopathology including hyperplassia, cytoplasmic degeneration and nuclear fragmentation. Antioxidant enzyme (GST, CAT, SOD) activities in the liver altered significantly; the mRNA levels for the genes encoding antioxidant proteins, such as Gst, Cat, Cu/ZnSod, MnSod as well as Gpx were significantly upregulated at 30 days NaF-treatment along with the stress marker gene Hsp70 and phase I detoxyfying gene Cyp1A1. Moreover, the transcriptional pattern of Ucp2, related to mitochondrial reactive oxygen species (ROS) production, upregulated significantly at 90 days NaF-treatment. ROS generation was evidensed by fluoroscence microscopy. The results of this study will help to understand the mechanism of oxidative stress induced by NaF in fish.

  16. Direct and indirect effects of kisspeptin on liver oxidant and antioxidant systems in young male rats.

    PubMed

    Aydin, M; Oktar, S; Yonden, Z; Ozturk, O H; Yilmaz, B

    2010-06-01

    Kisspeptin is a recently discovered hypothalamic peptide which plays an important role in the central control of reproductive functions. We have investigated direct and indirect effects of kisspeptin on the liver oxidative stress in young male rats. Twenty-four rats were divided into four groups (n = 6/group). First group served as control and received saline. Kisspeptin-10 was administered to the animals in the second group (20 nmol/rat/day), for a period of 7 days. Rats were given only one dose gosereline (0.9 mg/rat), a GnRH agonist in the third group. The last group received kisspeptin-10 with gosereline. The activities of catalase, superoxide dismutase (SOD), xanthine oxidase (XO), adenosine deaminase (AD) and level of malondialdehyde were studied in liver tissue. Serum samples were separated for total antioxidant capacity (TAC), total oxidant status (TOS), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, blood urea nitrogen (BUN), colesterol, high-density lipoprotein (HDL) and triglyceride. Kisspeptin increased the activities of SOD and catalase (p < 0.05). When compared to the control group, the levels of malondialdehyde, TOS and AST were lower, but levels of BUN, cholesterole, HDL and AD were higher in the other three groups (p < 0.05). In conclusion, our findings suggest that kisspeptin may have antioxidant and thus protective effects on the liver tissue. 2010 John Wiley & Sons, Ltd.

  17. Betaine treatment decreased oxidative stress, inflammation, and stellate cell activation in rats with alcoholic liver fibrosis.

    PubMed

    Bingül, İlknur; Başaran-Küçükgergin, Canan; Aydın, A Fatih; Çoban, Jale; Doğan-Ekici, Işın; Doğru-Abbasoğlu, Semra; Uysal, Müjdat

    2016-07-01

    The aim of this study was to investigate the effect of betaine (BET) on alcoholic liver fibrosis in rats. Fibrosis was experimentally generated with ethanol plus carbon tetrachloride (ETH+CCl4) treatment. Rats were treated with ETH (5% v/v in drinking water) for 14 weeks. CCl4 was administered intraperitoneally (i.p.) 0.2mL/kg twice a week to rats in the last 6 weeks with/without commercial food containing BET (2% w/w). Serum hepatic damage markers, tumor necrosis factor-α, hepatic triglyceride (TG) and hydroxyproline (HYP) levels, and oxidative stress parameters were measured together with histopathologic observations. In addition, α-smooth muscle-actin (α-SMA), transforming growth factor-β1 (TGF-β1) and type I collagen (COL1A1) protein expressions were assayed immunohistochemically to evaluate stellate cell (HSC) activation. mRNA expressions of matrix metalloproteinase-2 (MMP-2) and its inhibitors (TIMP-1 and TIMP-2) were also determined. BET treatment diminished TG and HYP levels; prooxidant status and fibrotic changes; α-SMA, COL1A1 and TGF-β protein expressions; MMP-2, TIMP-1 and TIMP-2 mRNA expressions in the liver of fibrotic rats. In conclusion, these results indicate that the antifibrotic effect of BET may be related to its suppressive effects on oxidant and inflammatory processes together with HSC activation in alcoholic liver fibrosis.

  18. Dietary Supplementation of Calendula officinalis Counteracts the Oxidative Stress and Liver Damage Resulted from Aflatoxin

    PubMed Central

    Hamzawy, Mohamed A.; El-Denshary, Ezzeldein S. M.; Hassan, Nabila S.; Mannaa, Fathia A.; Abdel-Wahhab, Mosaad A.

    2013-01-01

    This study was conducted to evaluate the total phenolic compounds, the antioxidant properties, and the hepatorenoprotective potential of Calendula officinalis extract against aflatoxins (AFs-) induced liver damage. Six groups of male Sprague-Dawley rats were treated for 6 weeks included the control; the group fed AFs-contaminated diet (2.5 mg/kg diet); the groups treated orally with Calendula extract at low (CA1) and high (CA2) doses (500 and 1000 mg/kg b.w); the groups treated orally with CA1 and CA2 one week before and during AFs treatment for other five weeks. The results showed that the ethanol extract contained higher phenolic compounds and posses higher 1,1-diphenyl 1-2-picryl hydrazyl (DPPH) radical scavenging activity than the aqueous extract. Animals fed AFs-contaminated diet showed significant disturbances in serum biochemical parameters, inflammatory cytokines, and the histological and histochemical pictures of the liver accompanied by a significant increase in malondialdehyde (MDA) and a significant decrease in superoxide dismutase (SOD) and glutathione peroxidase (GPx) in liver. Calendula extract succeeded to improve the biochemical parameters, inflammatory cytokines, decreased the oxidative stress, and improved the histological pictures in the liver of rats fed AFs-contaminated diet in a dose-dependent manner. It could be concluded that Calendula extract has potential hepatoprotective effects against AFs due to its antioxidant properties and radical scavenging activity. PMID:24959547

  19. Mitochondrial oxidative stress and dysfunction induced by isoniazid: study on isolated rat liver and brain mitochondria.

    PubMed

    Ahadpour, Morteza; Eskandari, Mohammad Reza; Mashayekhi, Vida; Haj Mohammad Ebrahim Tehrani, Kamaleddin; Jafarian, Iman; Naserzadeh, Parvaneh; Hosseini, Mir-Jamal

    2016-01-01

    Isoniazid (INH or isonicotinic hydrazide) is used for the treatment and prophylaxis of tuberculosis. Liver and brain are two important target organs in INH toxicity. However, the exact mechanisms behind the INH hepatotoxicity or neurotoxicity have not yet been completely understood. Considering the mitochondria as one of the possible molecular targets for INH toxicity, the aim of this study was to evaluate the mechanisms of INH mitochondrial toxicity on isolated mitochondria. Mitochondria were isolated by differential ultracentrifugation from male Sprague-Dawley rats and incubated with different concentrations of INH (25-2000 μM) for the investigation of mitochondrial parameters. The results indicated that INH could interact with mitochondrial respiratory chain and inhibit its activity. Our results showed an elevation in mitochondrial reactive oxygen species (ROS) formation, lipid peroxidation and mitochondrial membrane potential collapse after exposure of isolated liver mitochondria in INH. However, different results were obtained in brain mitochondria. Noteworthy, significant glutathione oxidation, adenosine triphosphate (ATP) depletion and lipid peroxidation were observed in higher concentration of INH, as compared to liver mitochondria. In conclusion, our results suggest that INH may initiate its toxicity in liver mitochondria through interaction with electron transfer chain, lipid peroxidation, mitochondrial membrane potential decline and cytochrome c expulsion which ultimately lead to cell death signaling.

  20. Avermectin induced liver injury in pigeon: mechanisms of apoptosis and oxidative stress.

    PubMed

    Zhu, Wen-Jun; Li, Ming; Liu, Ci; Qu, Jian-Ping; Min, Ya-Hong; Xu, Shi-Wen; Li, Shu

    2013-12-01

    Extensive use of avermectin (AVM) can result in environment pollution, and it is important to evaluate the potential impact this antibiotic has on ecological systems. Few published literatures have discussed the liver injury mechanisms induced by AVM on birds. In this study, pigeons were exposed to feed containing AVM (0, 20, 40 and 60 mg/kg diet) for 30, 60, 90 days respectively. The results showed that AVM increased the number of apoptosis and the expression level of caspase-3, 8, fas mRNA in the liver of pigeons. Ultrastructural alterations, including mitochondrial damage and chromatin aggregation, become severe with increase exposure dose. Exposure to AVM induced significant changes in antioxidant enzyme {superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)} activities and malondialdehyde (MDA) content, augmented protein carbonyl (PCO) content and DNA-protein crosslink (DPC) coefficient, in a concentration-dependent manner in the liver of pigeons. Our results show that AVM has toxic effect in pigeon liver, and the mechanism of injury caused by AVM is closely related to apoptosis and oxidative stress.

  1. Oxidative Stress as a Critical Factor in Nonalcoholic Fatty Liver Disease Pathogenesis.

    PubMed

    Spahis, Schohraya; Delvin, Edgard; Borys, Jean-Michel; Levy, Emile

    2017-04-01

    Nonalcoholic fatty liver disease (NAFLD), characterized by liver triacylglycerol build-up, has been growing in the global world in concert with the raised prevalence of cardiometabolic disorders, including obesity, diabetes, and hyperlipemia. Redox imbalance has been suggested to be highly relevant to NAFLD pathogenesis. Recent Advances: As a major health problem, NAFLD progresses to the more severe nonalcoholic steatohepatitis (NASH) condition and predisposes susceptible individuals to liver and cardiovascular disease. Although NAFLD represents the predominant cause of chronic liver disorders, the mechanisms of its development and progression remain incompletely understood, even if various scientific groups ascribed them to the occurrence of insulin resistance, dyslipidemia, inflammation, and apoptosis. Nevertheless, oxidative stress (OxS) more and more appears as the most important pathological event during NAFLD development and the hallmark between simple steatosis and NASH manifestation. The purpose of this article is to summarize recent developments in the understanding of NAFLD, essentially focusing on OxS as a major pathogenetic mechanism. Various attempts to translate reactive oxygen species (ROS) scavenging by antioxidants into experimental and clinical studies have yielded mostly encouraging results. Although augmented concentrations of ROS and faulty antioxidant defense have been associated to NAFLD and related complications, mechanisms of action and proofs of principle should be highlighted to support the causative role of OxS and to translate its concept into the clinic. Antioxid. Redox Signal. 26, 519-541.

  2. The oxidative dealkylation of insecticidal phosphoric acid triesters by mammalian liver enzymes

    PubMed Central

    Donninger, C.; Hutson, D. H.; Pickering, B. A.

    1972-01-01

    1. The dealkylation of the insecticidal phosphoric acid triester, 2-chloro-1-(2,4-dichlorophenyl)vinyl diethyl phosphate, proceeds in mammalian liver slices via an oxidative mechanism and not by hydrolysis. 2. The enzyme that catalyses the reaction is located in the microsomal fraction of liver homogenate and is dependent for activity on molecular oxygen and NADPH. 3. There are large species differences between rat, mouse, rabbit and dog in the activity of the enzymes, the relative rates of dealkylation being 1, 8, 24 and 88 respectively in liver slices. 4. Dimethyl and di-isopropyl phosphate triesters are also dealkylated by rabbit liver microsomal preparations. 5. The mechanism of dealkylation involves hydroxylation at the α-carbon atom of an alkyl group, which is removed as the corresponding aldehyde, and is thus analogous to that of similar reactions catalysed by the microsomal mixed-function oxidases. 6. The relevance of these findings in the toxicology of phosphoric acid triesters is discussed. PMID:5075276

  3. Evidence of oxidative stress in brain and liver of young rats submitted to experimental galactosemia.

    PubMed

    Castro, Márcia B; Ferreira, Bruna K; Cararo, José Henrique; Chipindo, Adália E; Magenis, Marina L; Michels, Monique; Danielski, Lucinéia G; de Oliveira, Marcos R; Ferreira, Gustavo C; Streck, Emilio L; Petronilho, Fabricia; Schuck, Patrícia F

    2016-12-01

    Galactosemia is a disorder of galactose metabolism, leading to the accumulation of this carbohydrate. Galactosemic patients present brain and liver damage. For evaluated oxidative stress, 30-day-old males Wistar rats were divided into two groups: galactose group, that received a single injection of this carbohydrate (5 μmol/g), and control group, that received saline 0.9 % in the same conditions. One, twelve or twenty-four hours after the administration, animals were euthanized and cerebral cortex, cerebellum, and liver were isolated. After one hour, it was found a significant increase in TBA-RS levels, nitrate and nitrite and protein carbonyl contents in cerebral cortex, as well as protein carbonyl content in the cerebellum and in hepatic level of TBA-RS, and a significant decrease in nitrate and nitrite contents in cerebellum. TBA-RS levels were also found increased in all studied tissues, as well as nitrate and nitrite contents in cerebral cortex and cerebellum, that also present increased protein carbonyl content and impairments in the activity of antioxidant enzymes of rats euthanized at twelve hours. Finally, animals euthanized after twenty-four hours present an increase of TBA-RS levels in studied tissues, as well as the protein carbonyl content in cerebellum and liver. These animals also present an increased nitrate and nitrite content and impairment of antioxidant enzymes activities. Taken together, our data suggest that acute galactose administration impairs redox homeostasis in brain and liver of rats.

  4. NOX2-generated oxidative stress is associated with severity of ultrasound liver steatosis in patients with non-alcoholic fatty liver disease

    PubMed Central

    2014-01-01

    Background Chronic oxidative stress is one of the key mechanisms responsible for disease progression in non-alcoholic fatty liver disease. However, so far, few studies reported increased circulating levels of oxidative stress markers in patients with non-alcoholic fatty liver and no study has been performed with newer markers of systemic oxidative stress. The aim was to assess the relationship between urinary 8-iso-prostaglandin F2α and serum soluble NOX2-derived peptide and the severity of liver steatosis in subjects with non-alcoholic fatty liver. Methods The study was performed in 264 consecutive patients referred for suspected metabolic disease. Steatosis was defined according to Hamaguchi ultrasonographic criteria. Oxidative stress was assessed by urinary 8-iso- prostaglandin F2α and serum soluble NOX2-derived peptide levels. Results Patients with non-alcoholic fatty liver had higher (p < 0.001) mean values of urinary 8-iso-PGF2α and of serum soluble NOX2-derived peptide, alanine aminotransferase, Cytokeratin-18 and homeostasis model of insulin resistance and lower values of serum adiponectin as compared to those without. Prevalence of metabolic syndrome and of its clinical features was significantly higher in patients with non-alcoholic fatty liver. Same findings were also observed after the exclusion of obese subjects, or subjects with diabetes or with metabolic syndrome and in those not taking statin medication. In addition, the levels of urinary 8-iso-PGF2α were independent predictors of non-alcoholic fatty liver and a strong association of urinary 8-iso-PGF2α and of serum soluble NOX2-derived peptide with the severity of steatosis at ultrasound was also observed. Conclusions We demonstrated increased markers of oxidative stress in subjects with non-alcoholic fatty liver. Urinary 8-iso-PGF2α and serum soluble NOX2-derived peptide levels were independent from obesity, diabetes and metabolic syndrome and increased with the severity of liver

  5. Metabolism of allylbenzene 2',3'-oxide and estragole 2',3'-oxide in the isolated perfused rat liver.

    PubMed

    Luo, G; Guenthner, T M

    1995-02-01

    The metabolism of allylbenzene 2',3'-oxide, estragole 2',3'-oxide, allylbenzene and estragole was studied in the isolated perfused rat liver. Formation of dihydrodiol and glutathione conjugate metabolites was detected for both epoxides and the presence of dihydrodiol metabolites after perfusion of allylbenzene or estragole indicated the formation of allylic epoxide intermediates in the intact liver. A comparison of elimination kinetics for parent compounds and epoxides indicated that epoxides were relatively rapidly detoxified and probably do not accumulate on formation in vivo. Acute toxicity of epoxides, measured as the release of alanine aminotransferase activity into the perfusate, or genetic toxicity, determined as covalent binding of radiolabeled epoxide to DNA, were not observed. It was concluded that both epoxide hydrolases and glutathione S-transferases can effectively detoxify the allylic epoxides derived from either allylbenzene or estragole and effectively prevent cellular or genetic toxicity of these reactive intermediates. Epoxide hydrolases appear to play the major role in the detoxication of these epoxides in vivo.

  6. For Better or Worse, Iron Overload by Superparamagnetic Iron Oxide Nanoparticles as a MRI Contrast Agent for Chronic Liver Diseases.

    PubMed

    Zhou, Qibing; Wei, Yushuang

    2017-01-17

    Superparamagnetic iron oxide nanoparticles (SPIONs) have recently been used as an effective magnetic resonance imaging (MRI) contrast agent for the noninvasive diagnosis of chronic liver diseases including nonalcohol fatty liver diseases, nonalcohol steatohepatitis, and cirrhosis as well as liver tumors. However, the potential risk of the iron overload by SPIONs has been highly underestimated in chronic liver diseases. While most of SPIONs have been shown safe in the healthy group, significant toxicity potential by the iron overload has been revealed through immunotoxicity, lipid peroxidation, and fatty acid and cholesterol metabolism in cirrhosis as a high risk factor. As a result, the systems toxicology assessments of SPIONs are crucial in both healthy ones and chronic liver disease models to determine the margin of safety. In addition, the challenge of the iron overload by SPIONs requires better designed SPIONs as MRI contrast agents for chronic liver diseases such as the biodegradable nanocluster assembly with urine clearance.

  7. Dietary supplementation of pyrroloquinoline quinone disodium protects against oxidative stress and liver damage in laying hens fed an oxidized sunflower oil-added diet.

    PubMed

    Wang, J; Zhang, H J; Xu, L; Long, C; Samuel, K G; Yue, H Y; Sun, L L; Wu, S G; Qi, G H

    2016-07-01

    The protective effects of dietary pyrroloquinoline quinone disodium (PQQ.Na2) supplementation against oxidized sunflower oil-induced oxidative stress and liver injury in laying hens were examined. Three hundred and sixty 53-week-old Hy-Line Gray laying hens were randomly allocated into one of the five dietary treatments. The treatments included: (1) a diet containing 2% fresh sunflower oil; (2) a diet containing 2% thermally oxidized sunflower oil; (3) an oxidized sunflower oil diet with 100 mg/kg of added vitamin E; (4) an oxidized sunflower oil diet with 0.08 mg/kg of PQQ.Na2; and (5) an oxidized sunflower oil diet with 0.12 mg/kg of PQQ.Na2. Birds fed the oxidized sunflower oil diet showed a lower feed intake compared to birds fed the fresh oil diet or oxidized oil diet supplemented with vitamin E (P=0.009). Exposure to oxidized sunflower oil increased plasma malondialdehyde (P<0.001), hepatic reactive oxygen species (P<0.05) and carbonyl group levels (P<0.001), but decreased plasma glutathione levels (P=0.006) in laying hens. These unfavorable changes induced by the oxidized sunflower oil diet were modulated by dietary vitamin E or PQQ.Na2 supplementation to levels comparable to the fresh oil group. Dietary supplementation with PQQ.Na2 or vitamin E increased the activities of total superoxide dismutase and glutathione peroxidase in plasma and the liver, when compared with the oxidized sunflower oil group (P<0.05). PQQ.Na2 or vitamin E diminished the oxidized sunflower oil diet induced elevation of liver weight (P=0.026), liver to BW ratio (P=0.001) and plasma activities of alanine aminotransferase (P=0.001) and aspartate aminotransferase (P<0.001) and maintained these indices at the similar levels to the fresh oil diet. Furthermore, oxidized sunflower oil increased hepatic DNA tail length (P<0.05) and tail moment (P<0.05) compared with the fresh oil group. Dietary supplementation of PQQ.Na2 or vitamin E decreased the oxidized oil diet induced DNA tail length

  8. Ring-Oxidative Biotransformation and Drug Interactions of Propofol in the Livers of Rats

    PubMed Central

    Tai, Yu-Ting; Lin, Yi-Ling; Chang, Chia-Chen; Cherng, Yih-Giun; Don, Ming-Jaw; Chen, Ruei-Ming

    2015-01-01

    Propofol, an intravenous anesthetic agent, is widely used for inducing and maintaining anesthesia during surgical procedures and for sedating intensive care unit patients. In the clinic, rapid elimination is one of the major advantages of propofol. Meanwhile, the biotransformation and drug interactions of propofol in rat livers are still little known. In this study, we evaluated the ring-oxidative metabolism of propofol in phenobarbital-treated rat livers and possible drug interactions. Administration of phenobarbital to male Wistar rats significantly increased levels of hepatic cytochrome P450 (CYP) 2B1/2 and microsomal pentoxyresorufin O-dealkylase (PROD) activity. Analyses by high-performance liquid chromatography and liquid chromatography mass spectroscopy revealed that propofol was metabolized by phenobarbital-treated rat liver microsomes into 4-hydroxypropofol. In comparison, PROD activity and 4-hydroxy-propofol production from propofol metabolism were suppressed by orphenodrine, an inhibitor of CYP2B1/2, and a polyclonal antibody against rat CYP2B1/2 protein. Furthermore, exposure of rats to propofol did not affect the basal or phenobarbital-enhanced levels of hepatic CYP2B1/2 protein. Meanwhile, propofol decreased the dealkylation of pentoxyresorufin by phenobarbital-treated rat liver microsomes in a concentration-dependent manner. Taken together, this study shows that rat hepatic CYP2B1/2 plays a critical role in the ring-oxidative metabolism of propofol into 4-hydroxypropofol, and this anesthetic agent can inhibit CYP2B1/2 activity without affecting protein synthesis. PMID:25710017

  9. Two-photon dual imaging platform for in vivo monitoring cellular oxidative stress in liver injury

    PubMed Central

    Wang, Haolu; Zhang, Run; Bridle, Kim R.; Jayachandran, Aparna; Thomas, James A.; Zhang, Wenzhu; Yuan, Jingli; Xu, Zhi Ping; Crawford, Darrell H. G.; Liang, Xiaowen; Liu, Xin; Roberts, Michael S.

    2017-01-01

    Oxidative stress reflects an imbalance between reactive oxygen species (ROS) and antioxidants, which has been reported as an early unifying event in the development and progression of various diseases and as a direct and mechanistic indicator of treatment response. However, highly reactive and short-lived nature of ROS and antioxidant limited conventional detection agents, which are influenced by many interfering factors. Here, we present a two-photon sensing platform for in vivo dual imaging of oxidative stress at the single cell-level resolution. This sensing platform consists of three probes, which combine the turn-on fluorescent transition-metal complex with different specific responsive groups for glutathione (GSH), hydrogen peroxide (H2O2) and hypochlorous acid (HOCl). By combining fluorescence intensity imaging and fluorescence lifetime imaging, these probes totally remove any possibility of crosstalk from in vivo environmental or instrumental factors, and enable accurate localization and measurement of the changes in ROS and GSH within the liver. This precedes changes in conventional biochemical and histological assessments in two distinct experimental murine models of liver injury. The ability to monitor real-time cellular oxidative stress with dual-modality imaging has significant implications for high-accurate, spatially configured and quantitative assessment of metabolic status and drug response. PMID:28349954

  10. Olanzapine alleviates oxidative stress in the liver of socially isolated rats.

    PubMed

    Stanisavljevic, Andrijana; Peric, Ivana; Pantelic, Marija; Filipovic, Dragana M

    2016-12-22

    Olanzapine, an antipsychotic drug, is used to treat depressive disorder, but its effects on the liver, the main site of drug metabolism, still remain elusive. We studied the effects of 3 weeks of olanzapine treatment (7.5 mg/kg per day) on the malondialdehyde (MDA) and protein carbonyl (PCO) contents, protein expression of copper/zinc superoxide dismutase (CuZnSOD), and activity of total superoxide dismutase (SOD), as well as catalase (CAT) protein expression and activity levels in the liver cytosol of rats exposed to 6 weeks of chronic social isolation (CSIS), which causes depressive- and anxiety-like behaviors. Increased cytosolic MDA in CSIS rats (vehicle- or olanzapine-treated) indicated hepatic oxidative stress. Increase in PCO and CAT activity associated with unchanged total SOD activity following CSIS also confirm the presence of oxidative stress. Chronic olanzapine treatment in CSIS prevented increase in PCO without an effect on MDA content. Increased SOD activity in olanzapine-treated (controls and CSIS) groups compared with corresponding vehicle-treated groups and decreased CAT activity in olanzapine-treated CSIS rats compared with vehicle-treated CSIS group was found. The data suggest that chronic olanzapine treatment has a protective effect on hepatic protein oxidation and improves antioxidant defense. The beneficial effects of olanzapine may be due to its free radical scavenging properties and antioxidant activity.

  11. Oxidative stress and trace elements in camel (Camelus dromedarius) with liver cystic echinococcosis.

    PubMed

    Heidarpour, M; Mohri, M; Borji, H; Moghdass, E

    2012-07-06

    Status of certain oxidative stress indices and zinc, copper and iron concentrations in blood were estimated in camel with liver cystic echinococcosis. In comparison to healthy control, the index of serum lipid peroxidation assessed by the malondialdehyde (MDA) level was significantly higher in the parasitized group. However, mean serum total antioxidant status (TAS) and erythrocyte glutathione peroxidase (GPx) were significantly lower in the parasitized group. Serum zinc concentration in camels with liver cystic echinococcosis was significantly lower than healthy control. In parasitized camels, a significant positive correlation of MDA with gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST) and bilirubin was observed. By contrast, MDA was inversely correlated with the values of packed cell volume (PCV), serum albumin and zinc. From the present study, it was concluded that cystic echinococcosis in camel is associated with oxidative stress. The resulting oxidative stress seems to have a role in the injury of hepatocytes, changes of trace elements and destruction of erythrocytes. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. [Tissue oxygen exchange and oxidative processes in long-livers: age peculiarities].

    PubMed

    Korkushko, O V; Ivanov, L A; Shatilo, V B

    2012-01-01

    This work was undertaken to study tissue oxygen exchange and oxidative processes in the long-lived individuals who were assumed as the physiologically aging individuals. Oxygen tension was assessed in forearm subcutaneous cellular tissue by means of the polarographic method while performing 10 min oxygen inhalation tests (with spontaneous oxygemogram recording) and a 10 min clamping of vessels. The obtained data served as the tissue oxygen exchange indicator. This approach made us possible to evaluate the oxygen delivery and oxygen uptake. To study qualitative characteristics of oxidative processes, we assessed vacat-oxygen of the blood and urine and estimated the underoxidation coefficient proposed by Muller. We have found that tissue respiration intensity falls, the amount of underoxidated products of the blood and urine rises, and the underoxidation coefficient increases in aging. The decrease of tissue oxygen respiration intensity in subcutaneous cellular tissue reflects the development of tissue hypoxia associated with reduced activity of the enzymes, being involved in oxygen exchange. An age-related decrease of tissue perfusion leads to the formation of circulatory hypoxia and also contributes considerably to tissue hypoxia formation. The revealed changes in the tissue oxygen exchange and oxidative processes in the long-livers are generally correspondent to those that can be seen in the people of 80-89 years. This finding speaks in favor of the physiological aging in the long-livers.

  13. Two-photon dual imaging platform for in vivo monitoring cellular oxidative stress in liver injury.

    PubMed

    Wang, Haolu; Zhang, Run; Bridle, Kim R; Jayachandran, Aparna; Thomas, James A; Zhang, Wenzhu; Yuan, Jingli; Xu, Zhi Ping; Crawford, Darrell H G; Liang, Xiaowen; Liu, Xin; Roberts, Michael S

    2017-03-28

    Oxidative stress reflects an imbalance between reactive oxygen species (ROS) and antioxidants, which has been reported as an early unifying event in the development and progression of various diseases and as a direct and mechanistic indicator of treatment response. However, highly reactive and short-lived nature of ROS and antioxidant limited conventional detection agents, which are influenced by many interfering factors. Here, we present a two-photon sensing platform for in vivo dual imaging of oxidative stress at the single cell-level resolution. This sensing platform consists of three probes, which combine the turn-on fluorescent transition-metal complex with different specific responsive groups for glutathione (GSH), hydrogen peroxide (H2O2) and hypochlorous acid (HOCl). By combining fluorescence intensity imaging and fluorescence lifetime imaging, these probes totally remove any possibility of crosstalk from in vivo environmental or instrumental factors, and enable accurate localization and measurement of the changes in ROS and GSH within the liver. This precedes changes in conventional biochemical and histological assessments in two distinct experimental murine models of liver injury. The ability to monitor real-time cellular oxidative stress with dual-modality imaging has significant implications for high-accurate, spatially configured and quantitative assessment of metabolic status and drug response.

  14. Oxidative phosphorylation of liver mitochondria from mice acclimatized to hypobaric hypoxia

    NASA Astrophysics Data System (ADS)

    Leon-Velarde, F.; Whittembury, J.; Monge, C.

    1986-09-01

    Mice exposed to intermittent hypobaric hypoxia for 20 hours a day, 6 days a week, develop extracellular adaptive responses similar to those found in humans exposed to oxygen tension equivalent to that found at an altitude of 4500 m. Isolated liver mitochondria from these animals show no significant differences in rates of substrate-stimulated respiration, ADP-stimulated respiration and the respiratory control ratio (RCR), when compared with sea level controls. Undetectable or negligible differences in these parameters are also noted when sea level animals are exposed for one hour to severe hypoxia (7% O2). We therefore conclude that the oxidative phosphorylation capacity of the isolated mouse liver mitochondria remains unaltered in both acute and chronic hypoxia. However the in vivo oxygen consumption by mice at this degree of hypoxia was markedly reduced. Lack of observable changes in oxidative phosphorylation could be accounted for by extracellular adaptations in mitochondria isolated from acclimatized animals. This explanation, however, is not consistent with the lack of changes on oxidative phosphorylation in mitochondria isolated from mice undergoing acute hypoxia at sea level. It is then suggested that isolated mitochondrial preparations are of limited value for investigating biochemical mechanisms underlying the variation of cellular respiration occurring in vivo.

  15. Polyphenolic fraction of Algerian propolis reverses doxorubicin induced oxidative stress in liver cells and mitochondria.

    PubMed

    Wided, Kebsa; Hassiba, Rouibah; Mesbah, Lahouel

    2014-11-01

    Doxorubicin (DOX) is a potent anticancer drug; its use has been limited by its hepatotoxicity, which is due to free radicals generation. Propolis, a honeybee product very rich in flavonoids and therapeutic possibilities, has gained popularity as a food and alternative medicine. The present study treats DOX pro-oxidant effect on hepatic cells and mitochondrial functions. The prophylactic effect of propolis ethanolic extract (EEP) against DOX induced mitochondrial oxidative stress has also been investigated. We find that doxorubicin at the amount of 10mg/Kg altered liver mitochondrial functions as attested by the overproduction of superoxide anion (O2(2-)) by mitochondrial respiratory chain complex III. The hepatic tissue from DOX treated rats showed also a marked depletion in reduced GSH contents and an inhibition in (Mn-SOD), (Cu-Zn SOD) and (CAT) enzymatic activities. DOX increase cytosolic and mitochondrial lipid peroxidation as attested by the MDA content. These results are reversed after one mount per os pretreatment by EEP at the amount of 100mg/kg. Propolis polyphenolic fraction protects liver tissue from oxidative stress by protecting mitochondrial functions and reinforcement of enzymatic and non enzymatic antioxidants.

  16. Complex responses to Si quantum dots accumulation in carp liver tissue: Beyond oxidative stress.

    PubMed

    Serban, Andreea Iren; Stanca, Loredana; Sima, Cornelia; Staicu, Andrea Cristina; Zarnescu, Otilia; Dinischiotu, Anca

    2015-09-05

    The use of quantum dots (QDs) in biomedical applications is limited due to their inherent toxicity caused by the heavy metal core of the particles. Consequently, silicon-based QDs are expected to display diminished toxicity. We investigated the in vivo effects induced by Si/SiO2 QDs intraperitoneally injected in crucian carp liver. The QDs contained a crystalline Si core encased in a SiO2 shell, with a size between 2.75 and 11.25nm and possess intrinsic fluorescence (Ex 325nm/Em ∼690nm). Tissue fluorescence microscopy analysis revealed the presence of QDs in the liver for at least 2weeks after injection. Although protein and lipid oxidative stress markers showed the onset of oxidative stress, the hepatic tissue exhibited significant antioxidant adaptations (increase of antioxidant enzymes, recovery of glutathione levels), sustained by the activation of Hsp30 and Hsp70 chaperoning proteins. The increased activity of cyclooxigenase-2 (COX-2) and matrix metalloproteinases (MMPs) support the idea that Si/SiO2 QDs have a potential to induce inflammatory response, a scenario also indicated by the profile of Hsp60 and Hsp90 heat shock proteins. MMPs profile and the recovery of oxidative stress markers suggested a tissue remodelation phase after 3weeks from QDs administration.

  17. Mitochondrial and peroxisomal fatty acid oxidation in liver homogenates and isolated hepatocytes from control and clofibrate-treated rats.

    PubMed

    Mannaerts, G P; Debeer, L J; Thomas, J; De Schepper, P J

    1979-06-10

    Mitochondrial and peroxisomal fatty acid oxidation were compared in whole liver homogenates. Oxidation of 0.2 mM palmitoyl-CoA or oleate by mitochondria increased rapidly with increasing molar substrate:albumin ratios and became saturated at ratios below 3, while peroxisomal oxidation increased more slowly and continued to rise to reach maximal activity in the absence of albumin. Under the latter condition mitochondrial oxidation was severely depressed. In homogenates from normal liver peroxisomal oxidation was lower than mitochondrial oxidation at all ratios tested except when albumin was absent. In contrast with mitochondrial oxidation, peroxisomal oxidation did not produce ketones, was cyanide-insensitive, was not dependent on carnitine, and was not inhibited by (+)-octanoylcarnitine, malonyl-CoA and 4-pentenoate. Mitochondrial oxidation was inhibited by CoASH concentrations that were optimal for peroxisomal oxidation. In the presence of albumin, peroxisomal oxidation was stimulated by Triton X-100 but unaffected by freeze-thawing; both treatments suppressed mitochondrial oxidation. Clofibrate treatment increased mitochondrial and peroxisomal oxidation 2- and 6- to 8-fold, respectively. Peroxisomal oxidation remained unchanged in starvation and diabetes. Fatty acid oxidation was severely depressed by cyanide and (+)-octanoylcarnitine in hepatocytes from normal rats. Hepatocytes from clofibrate-treated rats, which displayed a 3- to 4-fold increase in fatty acid oxidation, were less inhibited by (+)-octanoylcarnitine. Hydrogen peroxide production was severalfold higher in hepatocytes from treated animals oxidizing fatty acids than in control hepatocytes. Assuming that all H2O2 produced during fatty acid oxidation was due to peroxisomal oxidation, it was calculated that the contribution of the peroxisomes to fatty acid oxidation was less than 10% both in cells from control and clofibrate-treated animals.

  18. Biochemical properties of rat liver mitochondrial aldehyde dehydrogenase with respect to oxidation of formaldehyde.

    PubMed

    Cinti, D L; Keyes, S R; Lemelin, M A; Denk, H; Schenkman, J B

    1976-03-25

    The oxidation of formaldehyde by rat liver mitochondria in the presence of 50 mM phosphate was enhanced 2-fold by exogenous NAD+. Absolute requirement of NAD+ for formaldehyde oxidation was demonstrated by depleting the mitochondria of their NAD+ content (4.6 nmol/mg of protein), followed by reincorporation of the NAD+ into the depleted mitochondria. Aldehyde (formaldehyde) dehydrogenase activity was completely abolished in the depleted mitochondria, but the enzyme activity was restored to control levels following reincorporation of the pyridine nucleotide. Phosphate stimulation of formaldehyde oxidation could not be explained fully by the phosphate-induced swelling which enhances membrane permeability to NAD+, since stimulation of the enzyme activity by increased phosphate concentrations was still observed in the absence of exogenous NAD+. The Km for formaldehyde oxidation by the mitochondria was found to be 0.38 nM, a value similar to that obtained with varying concentrations of NAD+; both Vmax values were very similar, giving a value of 70 to 80 nmol/min/mg of protein. The pH optimum for the mitochondrial enzyme was 8.0. Inhibition of the enzyme activity by anaerobiosis was apparently due to the inability of the respiratory chain to oxidize the generated NADH. The inhibition of mitochondrial formaldehyde oxidation by succinate was found to be due to a lowering of the NAD+ level in the mitochondria. Succinate also inhibited acetaldehyde oxidation by the mitochondria. Malonate, a competitive inhibitor of succinic dehydrogenase, blocked the inhibitory effect of succinate. The respiratory chain inhibitors, rotenone, and antimycin A plus succinate, strongly inhibited formaldehyde oxidation by apparently the same mechanism, although the crude enzyme preparation (freed from the membrane) was slightly sensitive to rotenone. The mitochondria were subfractionated, and 85% of the enzyme activity was found in the inner membrane fraction (mitoplast). Furthermore, separation

  19. Cell transplantation after oxidative hepatic preconditioning with radiation and ischemia-reperfusion leads to extensive liver repopulation

    NASA Astrophysics Data System (ADS)

    Malhi, Harmeet; Gorla, Giridhar R.; Irani, Adil N.; Annamaneni, Pallavi; Gupta, Sanjeev

    2002-10-01

    The inability of transplanted cells to proliferate in the normal liver hampers cell therapy. We considered that oxidative hepatic DNA damage would impair the survival of native cells and promote proliferation in transplanted cells. Dipeptidyl peptidase-deficient F344 rats were preconditioned with whole liver radiation and warm ischemia-reperfusion followed by intrasplenic transplantation of syngeneic F344 rat hepatocytes. The preconditioning was well tolerated, although serum aminotransferase levels rose transiently and hepatic injury was observed histologically, along with decreased catalase activity and 8-hydroxy adducts of guanine, indicating oxidative DNA damage. Transplanted cells did not proliferate in the liver over 3 months in control animals and animals preconditioned with ischemia-reperfusion alone. Animals treated with radiation alone showed some transplanted cell proliferation. In contrast, the liver of animals preconditioned with radiation plus ischemia-reperfusion was replaced virtually completely over 3 months. Transplanted cells integrated in the liver parenchyma and liver architecture were preserved normally. These findings offer a paradigm for repopulating the liver with transplanted cells. Progressive loss of cells experiencing oxidative DNA damage after radiation and ischemia-reperfusion injury could be of significance for epithelial renewal in additional organs.

  20. Exposure to the insecticide endosulfan induces liver morphology alterations and oxidative stress in fruit-eating bats (Artibeus lituratus).

    PubMed

    Oliveira, Jerusa Maria; Brinati, Alessandro; Miranda, Liany Divina Lima; Morais, Danielle Barbosa; Zanuncio, José Cola; Gonçalves, Reggiani Vilela; Peluzio, Maria do Carmo Gouveia; Freitas, Mariella Bontempo

    2017-02-01

    Exposure to pesticides may increase the generation of reactive oxygen species (ROS), leading to oxidation of cell membrane lipids and proteins. Although fruit bats are potentially exposed to pesticides during their entire lifespan, the impacts of this exposure are still poorly investigated. We examined the effects of low, commercially recommended concentrations (0, 1.05 and 2.1 g/l) of an organochlorine insecticide endosulfan (EDS) formulation on oxidative responses in the liver and kidneys of Neotropical fruit bats (Artibeus lituratus), as well as possible liver morphological alterations following a 35-day oral exposure. Superoxide dismutase activity was significantly decreased upon exposure to 1.05 g/l of EDS in the liver and kidneys, catalase was decreased in the liver of 2.1 g/l EDS-exposed bats, while glutathione S-transferase was increased in the liver of 2.1 g/l EDS-exposed bats. Protein carbonyls increased following the exposure to the highest EDS dose tested. Endosulfan-induced morphological alterations in the liver included cell degeneration and cell death, with apparent cytoplasm lipid accumulation (steatosis) and pyknotic nuclei, karyolysis and deposit of collagen fibres. Our findings suggest that exposure to low concentrations of EDS induced a certain extent of oxidative damage in fruit bats, which may have led to liver morphological alterations. © 2017 The Authors. International Journal of Experimental Pathology © 2017 International Journal of Experimental Pathology.

  1. Liver Damage in Patients with HCV/HIV Coinfection Is Linked to HIV-Related Oxidative Stress

    PubMed Central

    Huang, Xiangbo; Liang, Hua; Fan, Xueying; Zhu, Liyan; Shen, Tao

    2016-01-01

    HIV infection aggravates the progression of liver damage in HCV-coinfected patients, with the underlying pathogenesis being multifactorial. Although high level of oxidative stress has been observed frequently in patients infected with HIV or HCV, the status of oxidative stress in HIV/HCV coinfection and its contribution to HCV liver damage have not been determined. This study involved 363 HBsAg-negative, anti-HCV-positive former blood donors recruited from a village in central China in July 2005; of these, 140 were positive for HIV. Of these 363 subjects, 282 were successfully followed up through July 2009. HIV/HCV-coinfected subjects had higher rates of end-stage liver disease-related death than those monoinfected with HCV. Liver ultrasound manifestations were poor in HIV-positive than in HIV-negative individuals, in both chronic HCV carriers and those with resolved HCV. Serum concentrations of total glutathione (tGSH), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), GSSG, and reduced GSH were higher in HIV-positive than HIV-negative subjects. GSSG concentrations were higher in HIV-infected subjects with abnormal ALT/AST levels than in those with normal ALT/AST levels and were associated with poorer liver ultrasound manifestations. These finding indicated that HIV infection accelerated HCV-associated liver damage in HIV/HCV-coinfected individuals. Increased oxidative stress, induced primarily by HIV coinfection, may contribute to aggravated liver damage. PMID:26881041

  2. Accelerated CCl4-Induced Liver Fibrosis in Hjv-/- Mice, Associated with an Oxidative Burst and Precocious Profibrogenic Gene Expression

    PubMed Central

    Sebastiani, Giada; Gkouvatsos, Kostas; Maffettone, Carmen; Busatto, Graziella; Guido, Maria; Pantopoulos, Kostas

    2011-01-01

    Hereditary hemochromatosis is commonly associated with liver fibrosis. Likewise, hepatic iron overload secondary to chronic liver diseases aggravates liver injury. To uncover underlying molecular mechanisms, hemochromatotic hemojuvelin knockout (Hjv-/-) mice and wild type (wt) controls were intoxicated with CCl4. Hjv-/- mice developed earlier (by 2-4 weeks) and more acute liver damage, reflected in dramatic levels of serum transaminases and ferritin and the development of severe coagulative necrosis and fibrosis. These responses were associated with an oxidative burst and early upregulation of mRNAs encoding α1-(I)-collagen, the profibrogenic cytokines TGF-β1, endothelin-1 and PDGF and, notably, the iron-regulatory hormone hepcidin. Hence, CCl4-induced liver fibrogenesis was exacerbated and progressed precociously in Hjv−/− animals. Even though livers of naïve Hjv−/− mice were devoid of apparent pathology, they exhibited oxidative stress and immunoreactivity towards α-SMA antibodies, a marker of hepatic stellate cells activation. Furthermore, they expressed significantly higher (2–3 fold vs. wt, p<0.05) levels of α1-(I)-collagen, TGF-β1, endothelin-1 and PDGF mRNAs, indicative of early fibrogenesis. Our data suggest that hepatic iron overload in parenchymal cells promotes oxidative stress and triggers premature profibrogenic gene expression, contributing to accelerated onset and precipitous progression of liver fibrogenesis. PMID:21966437

  3. Acrolein, a highly toxic aldehyde generated under oxidative stress in vivo, aggravates the mouse liver damage after acetaminophen overdose.

    PubMed

    Arai, Tomoya; Koyama, Ryo; Yuasa, Makoto; Kitamura, Daisuke; Mizuta, Ryushin

    2014-01-01

    Although acetaminophen-induced liver injury in mice has been extensively studied as a model of human acute drug-induced hepatitis, the mechanism of liver injury remains unclear. Liver injury is believed to be initiated by metabolic conversion of acetaminophen to the highly reactive intermediate N-acetyl p-benzoquinoneimine, and is aggravated by subsequent oxidative stress via reactive oxygen species (ROS), including hydrogen peroxide (H2O2) and the hydroxyl radical (•OH). In this study, we found that a highly toxic unsaturated aldehyde acrolein, a byproduct of oxidative stress, has a major role in acetaminophen-induced liver injury. Acetaminophen administration in mice resulted in liver damage and increased acrolein-protein adduct formation. However, both of them were decreased by treatment with N-acetyl-L-cysteine (NAC) or sodium 2-mercaptoethanesulfonate (MESNA), two known acrolein scavengers. The specificity of NAC and MESNA was confirmed in cell culture, because acrolein toxicity, but not H2O2 or •OH toxicity, was inhibited by NAC and MESNA. These results suggest that acrolein may be more strongly correlated with acetaminophen-induced liver injury than ROS, and that acrolein produced by acetaminophen-induced oxidative stress can spread from dying cells at the primary injury site, causing damage to the adjacent cells and aggravating liver injury.

  4. [Peculiarities of disturbances in oxidation and phosphorylation processes in rat liver under the effect of mononitrophenols].

    PubMed

    Kolodib, F A; Vasilenko, N M

    1976-01-01

    It is determined that ortho- and n-nitrophenol introduced into the stomach (0.80 and 0.11 g/kg, respectively) inhibit the activity of cytochrome oxydase (by 21% at an average), cause an increase in the content of NADH (by 35 and 27%) and a decrease in ATP (by 38 and 36%, respectively), split the oxidation and phosphorylation processes in the rat liver tissue. The content of NAD+, AMP and ADP, lactate, the activity of K+, Na+-ATPase and lactate dehydrogenase do not change.

  5. Nocturnal hypoxia-induced oxidative stress promotes progression of pediatric non-alcoholic fatty liver disease.

    PubMed

    Sundaram, Shikha S; Halbower, Ann; Pan, Zhaoxing; Robbins, Kristen; Capocelli, Kelley E; Klawitter, Jelena; Shearn, Colin T; Sokol, Ronald J

    2016-09-01

    Oxidative stress is proposed as a central mediator in NAFLD pathogenesis, but the specific trigger for reactive oxygen species generation has not been clearly delineated. In addition, emerging evidence shows that obesity related obstructive sleep apnea (OSA) and nocturnal hypoxia are associated with NAFLD progression in adults. The aim of this study was to determine if OSA/nocturnal hypoxia-induced oxidative stress promotes the progression of pediatric NAFLD. Subjects with biopsy proven NAFLD and lean controls were studied. Subjects underwent polysomnograms, liver histology scoring, laboratory testing, urine F(2)-isoprostanes (measure of lipid peroxidation) and 4-hydroxynonenal liver immunohistochemistry (in situ hepatic lipid peroxidation). We studied 36 adolescents with NAFLD and 14 lean controls. The OSA/hypoxia group (69% of NAFLD subjects) had more severe fibrosis (64% stage 0-2; 36% stage 3) than those without OSA/hypoxia (100% stage 0-2), p=0.03. Higher F(2)-isoprostanes correlated with apnea/hypoxia index (r=0.39, p=0.03), % time SaO2 <90% (r=0.56, p=0.0008) and inversely with SaO2 nadir (r=-0.46, p=0.008). OSA/hypoxia was most severe in subjects with the greatest 4HNE staining (p=0.03). Increasing F(2)-isoprostanes(r=0.32, p=0.04) and 4HNE hepatic staining (r=0.47, p=0.007) were associated with worsening steatosis. Greater oxidative stress occurred in subjects with definite NASH as measured by F(2)-isoprostanes (p=0.06) and hepatic 4HNE (p=0.03) compared to those with borderline/not NASH. These data support the role of nocturnal hypoxia as a trigger for localized hepatic oxidative stress, an important factor associated with the progression of NASH and hepatic fibrosis in obese pediatric patients. Obstructive sleep apnea and low nighttime oxygen are associated with NAFLD progression in adults. In this study, we show that adolescents with NAFLD who have OSA and low oxygen have significant scar tissue in their livers. NAFLD subjects affected by OSA and low

  6. Purification of Arsenic (+3 Oxidation State) Methyltransferase from Rat Liver Cytosol

    PubMed Central

    Drobna, Zuzana; Styblo, Miroslav; Thomas, David J.

    2015-01-01

    Demonstrating the enzymatic basis of arsenic methylation is critical to further studies of the pathway for the conversion of inorganic arsenic into a variety of methylated metabolites. This protocol describes a procedure for the purification of an arsenic methyltransferase from rat liver cytosol. Purification of this enzyme and subsequent cloning of its gene has permitted studies of enzyme structure and function and has lead to the identification of orthologous genes in genomes of organisms ranging in complexity from sea urchins to humans. These proteins are referred to as arsenic (+3 oxidation state) methyltransferases. PMID:20949431

  7. A Single Zidovudine (AZT) Administration Delays Hepatic Cell Proliferation by Altering Oxidative State in the Regenerating Rat Liver.

    PubMed

    Butanda-Ochoa, Armando; Hernández-Espinosa, Diego Rolando; Olguín-Martínez, Marisela; Sánchez-Sevilla, Lourdes; Rodríguez, Mario R; Chávez-Rentería, Benito; Aranda-Fraustro, Alberto; Hernández-Muñoz, Rolando

    2017-01-01

    The 3'-azido-3'-deoxythymidine or Zidovudine (AZT) was the first antiretroviral drug used in the treatment of HIV patients, which has good effectiveness but also hepatotoxic side effects that include cell cycle arrest and oxidative/nitrative mitochondrial damage. Whether such an oxidative damage may affect the proliferative-regenerative capacity of liver remains to be clearly specified at doses commonly used in the clinical practice. In this study, we described the oxidative-proliferative effect of AZT administered at a common clinical dose in rat liver submitted to 70% partial hepatectomy (PH). The results indicate that AZT significantly decreased DNA synthesis and the number of mitosis in liver subjected to PH in a synchronized way with the promotion of organelle-selective lipid peroxidation events (especially those observed in plasma membrane and cytosolic fractions) and with liver enzyme release to the bloodstream. Then at the dose used in clinical practice AZT decreased liver regeneration but stimulates oxidative events involved during the proliferation process in a way that each membrane system inside the cell preserves its integrity in order to maintain the cell proliferative process. Here, the induction of large amounts of free ammonia in the systemic circulation could become a factor capable of mediating the deleterious effects of AZT on PH-induced rat liver regeneration.

  8. A Single Zidovudine (AZT) Administration Delays Hepatic Cell Proliferation by Altering Oxidative State in the Regenerating Rat Liver

    PubMed Central

    Butanda-Ochoa, Armando; Hernández-Espinosa, Diego Rolando; Olguín-Martínez, Marisela; Sánchez-Sevilla, Lourdes; Rodríguez, Mario R.; Chávez-Rentería, Benito; Aranda-Fraustro, Alberto

    2017-01-01

    The 3′-azido-3′-deoxythymidine or Zidovudine (AZT) was the first antiretroviral drug used in the treatment of HIV patients, which has good effectiveness but also hepatotoxic side effects that include cell cycle arrest and oxidative/nitrative mitochondrial damage. Whether such an oxidative damage may affect the proliferative-regenerative capacity of liver remains to be clearly specified at doses commonly used in the clinical practice. In this study, we described the oxidative-proliferative effect of AZT administered at a common clinical dose in rat liver submitted to 70% partial hepatectomy (PH). The results indicate that AZT significantly decreased DNA synthesis and the number of mitosis in liver subjected to PH in a synchronized way with the promotion of organelle-selective lipid peroxidation events (especially those observed in plasma membrane and cytosolic fractions) and with liver enzyme release to the bloodstream. Then at the dose used in clinical practice AZT decreased liver regeneration but stimulates oxidative events involved during the proliferation process in a way that each membrane system inside the cell preserves its integrity in order to maintain the cell proliferative process. Here, the induction of large amounts of free ammonia in the systemic circulation could become a factor capable of mediating the deleterious effects of AZT on PH-induced rat liver regeneration. PMID:28479956

  9. Effects of triterpenoid from Schisandra chinensis on oxidative stress in alcohol-induced liver injury in rats.

    PubMed

    Li, Bin; Zhu, Lijie; Wu, Ting; Zhang, Jiachen; Jiao, Xinyao; Liu, Xiuying; Wang, Yanqun; Meng, Xianjun

    2015-03-01

    Alcohol-induced oxidative stress plays a crucial role in the pathological development of alcoholic liver disease. The aim of this study was to investigate the effects of triterpenoid from Schisandra chinensis on oxidative stress in alcohol-induced liver injury in rats. We found that the administration of triterpenoid attenuated alcohol-induced oxidative stress in multiple organs including liver. Moreover, the impaired liver function and histological changes resulted from alcohol consumption was improved by triterpenoid treatment. Finally, we found that pretreatment with triterpenoid from Schisandra chinensis to alcohol-fed rats increased the expression level of haem oxygenase-1 (HO-1) while inhibited the induction of cytochrome P-450 2E1 (CYP2E1) in liver microsomes. Further assays revealed that the microsomal activity of HO-1 was accordingly induced whereas CYP2E1 was suppressed in rats received triterpenoid intervention. Our findings suggest that triterpenoid from Schisandra chinensis may protect against alcohol-induced liver injury through ameliorating oxidative stress in rats.

  10. Newcastle disease virus (NDV) induces protein oxidation and nitration in brain and liver of chicken: Ameliorative effect of vitamin E.

    PubMed

    Venkata Subbaiah, Kadiam C; Valluru, Lokanatha; Rajendra, Wudayagiri; Ramamurthy, Chiteti; Thirunavukkarusu, Chinnasamy; Subramanyam, Rajagopal

    2015-07-01

    The present study was aimed at investigating the therapeutic efficacy of vitamin E on oxidative injury in brain and liver of Newcastle disease virus (NDV) challenged chickens. We have analyzed the xanthine oxidase (XOD) activity; uric acid (UA) levels and superoxide radical generation by using electron spin resonance spectroscopy. Further, protein oxidation, nitration and apoptosis were evaluated in the brain and liver of the control, NDV-infected and NDV+Vit. E treated groups. A significant elevation was observed in XOD activity and UA levels in brain (p<0.001) and liver (p<0.05) of NDV infected birds when compared to controls. Further, significant increase in the production of superoxides, enhanced intracellular protein carbonyls and nitrates were observed in the brain and liver of NDV-infected birds over healthy subjects. Apoptosis studies also suggested that a larger number of TUNEL positive cells were observed in brain and a moderately in liver of NDV-infected chickens. However, all these perturbations were significantly ameliorated in NDV+Vit. E treated chickens as compared to NDV-infected birds. Taken together, our results suggested that NDV-induced neuronal and hepatic damage at least in part mediates oxidative stress and on the other hand, supplementation of vitamin E mitigates NDV-induced oxidative damage thereby protects brain and liver of chickens. These findings could provide new insights into the understanding of NDV pathogenesis and therapeutic effects of dietary antioxidants.

  11. Antifibrotic effect of meloxicam in rat liver: role of nuclear factor kappa B, proinflammatory cytokines, and oxidative stress.

    PubMed

    Hassan, Memy H; Ghobara, Mohamed M

    2016-09-01

    This study was aimed at investigating the antifibrotic effect of meloxicam in CCl4-induced liver fibrosis and elucidating its underlying mechanism. Forty male rats were equally randomized for 8-week treatment with corn oil (negative control), CCl4 (to induce liver fibrosis), and/or meloxicam. Meloxicam effectively ameliorated the CCl4-induced alterations in liver histology, liver weight to body weight ratio, liver functions, and serum markers for liver fibrosis (hyaluronic acid, laminin, and PCIII). Meloxicam significantly abrogated CCl4-induced elevation of messenger RNA (mRNA) expressions for collagen I and alpha smooth muscle actin (α-SMA) and hepatic contents of hydroxyproline, transforming growth factor beta (TGF-β), and tissue inhibitor of matrix metalloproteases (TIMP-1). Meloxicam mitigated CCl4-induced elevation in hepatic levels of nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), total nitric oxide (NO), interleukin-l beta (IL 1β), and prostaglandin E2 (PGE2). Meloxicam modulated CCl4-induced disturbance of liver cytochrome P450 subfamily 2E1 (CYP2E1) and glutathione-S-transferase (GST). The attenuation of meloxicam to liver fibrosis was associated with suppression of oxidative stress via reduction of lipid peroxides along with induction of reduced glutathione content and enhancement of superoxide dismutase, glutathione peroxidase, and catalase activities. This study provides an evidence for antifibrotic effect of meloxicam against CCl4-induced liver fibrosis in rat. The antifibrotic mechanism of meloxicam could be through decreasing NF-κB level and subsequent proinflammatory cytokine production (TNF-α, NO, IL-1 beta, and PGE2) and, hence, collagen deposition through inhibition of TIMP-1 and TGF-β. Abrogation of oxidative stress and modulation of liver-metabolizing enzymes (CYP2E1 and GST) were also involved.

  12. Melatonin treatment protects liver of Zucker rats after ischemia/reperfusion by diminishing oxidative stress and apoptosis.

    PubMed

    Kireev, Roman; Bitoun, Samuel; Cuesta, Sara; Tejerina, Alejandro; Ibarrola, Carolina; Moreno, Enrique; Vara, Elena; Tresguerres, Jesus A F

    2013-02-15

    Fatty livers occur in up to 20% of potential liver donors and increase cellular injury during the ischemia/reperfusion phase, so any intervention that could enable a better outcome of grafts for liver transplantation would be very useful. The effect of melatonin on liver ischemia/reperfusion injury in a rat model of obesity and hepatic steatosis has been investigated. Forty fa/fa Zucker rats were divided in 4 groups. 3 groups were subjected to 35 min of warm hepatic ischemia and 36 h of reperfusion. One experimental group remained untreated and 2 were given 10mg/kg melatonin intraperitoneally or orally. Another group was sham-operated. Plasma ALT, AST and hepatic content of ATP, MDA, hydroxyalkenals, NOx metabolites, antioxidant enzyme activity, caspase-9 and DNA fragmentation were determined in the liver. The expression of iNOS, eNOS, Bcl2, Bax, Bad and AIF were determined by RT-PCR Melatonin was effective at decreasing liver injury by both ways as assessed by liver transaminases, markers of apoptosis, of oxidative stress and improved liver ATP content. Melatonin administration decreased the activities or levels of most of the parameters measured in a beneficial way, and our study identified also some of the mechanisms of protection. We conclude that administration of melatonin improved liver function, as well as markers of pro/antioxidant status and apoptosis following ischemia/reperfusion in obese rats with fatty liver. These data suggest that this substance could improve outcome in patients undergoing liver transplantation who receive a fatty liver implant and suggest the need of clinical trials with it in liver transplantation. Copyright © 2012 Elsevier B.V. All rights reserved.

  13. Enhancement of lindane-induced liver oxidative stress and hepatotoxicity by thyroid hormone is reduced by gadolinium chloride.

    PubMed

    Simon-Giavarotti, Karin A; Giavarotti, Leandro; Gomes, Ligia F; Lima, Alessandra F; Veridiano, Adriano M; Garcia, Eduardo A; Mora, Oswaldo A; Fernández, Virginia; Videla, Luis A; Junqueira, Virginia B C

    2002-10-01

    The role of Kupffer cells in the hepatocellular injury and oxidative stress induced by lindane (20 mg/kg; 24h) in hyperthyroid rats (daily doses of 0.1 mg L-3,3',5-triiodothyronine (T3)/kg for three consecutive days) was assessed by the simultaneous administration of gadolinium chloride (GdCl3; 2 doses of 10mg/kg on alternate days). Hyperthyroid animals treated with lindane exhibit enhanced liver microsomal superoxide radical (O2.-) production and NADPH cytochrome c reductase activity, with lower levels of cytochrome P450, superoxide dismutase (SOD) and catalase activity, and glutathione (GSH) content over control values. These changes are paralleled by a substantial increase in the lipid peroxidation potential of the liver and in the O2.- generation/ SOD activity ratio, thus evidencing a higher oxidative stress status that correlates with the development of liver injury characterized by neutrophil infiltration and necrosis. Kupffer cell inactivation by GdCl3 suppresses liver injury in lindane/T3-treated rats with normalization of altered oxidative stress-related parameters, excepting the reduction in the content of GSH and in catalase activity. It is concluded that lindane hepatotoxicity in hyperthyroid state, that comprises an enhancement in the oxidative stress status of the liver, is largely dependent on Kupffer cell function, which may involve generation of mediators leading to pro-oxidant and inflammatory processes.

  14. Involvement of Oxidative Stress and Inflammation in Liver Injury Caused by Perfluorooctanoic Acid Exposure in Mice

    PubMed Central

    Yang, Bei; Zou, Weiying; Hu, Zhenzhen; Liu, Fangming; Zhou, Ling; Yang, Shulong; Kuang, Haibin; Wu, Lei; Wei, Jie; Wang, Jinglei; Zou, Ting; Zhang, Dalei

    2014-01-01

    Perfluorooctanoic acid (PFOA) is widely present in the environment and has been reported to induce hepatic toxicity in animals and humans. In this study, mice were orally administered different concentrations of PFOA (2.5, 5, or 10 mg/kg/day). Histological examination showed that the exposure to PFOA for 14 consecutive days led to serious hepatocellular injury and obvious inflammatory cell infiltration. In addition, malondialdehyde formation and hydrogen peroxide generation, indicators of oxidative stress, were significantly induced by PFOA treatment in the liver of mice. Furthermore, hepatic levels of interleukin-6, cyclooxygenase-2, and C-reactive protein, markers of inflammatory response, were markedly increased by exposure to PFOA in mice. These results demonstrated that PFOA-induced hepatic toxicity may be involved in oxidative stress and inflammatory response in mice. PMID:24724082

  15. Current status of superparamagnetic iron oxide contrast agents for liver magnetic resonance imaging

    PubMed Central

    Wang, Yi-Xiang J

    2015-01-01

    Five types of superparamagnetic iron oxide (SPIO), i.e. Ferumoxides (Feridex® IV, Berlex Laboratories), Ferucarbotran (Resovist®, Bayer Healthcare), Ferumoxtran-10 (AMI-227 or Code-7227, Combidex®, AMAG Pharma; Sinerem®, Guerbet), NC100150 (Clariscan®, Nycomed,) and (VSOP C184, Ferropharm) have been designed and clinically tested as magnetic resonance contrast agents. However, until now Resovist® is current available in only a few countries. The other four agents have been stopped for further development or withdrawn from the market. Another SPIO agent Ferumoxytol (Feraheme®) is approved for the treatment of iron deficiency in adult chronic kidney disease patients. Ferumoxytol is comprised of iron oxide particles surrounded by a carbohydrate coat, and it is being explored as a potential imaging approach for evaluating lymph nodes and certain liver tumors. PMID:26715826

  16. Current status of superparamagnetic iron oxide contrast agents for liver magnetic resonance imaging.

    PubMed

    Wang, Yi-Xiang J

    2015-12-21

    Five types of superparamagnetic iron oxide (SPIO), i.e. Ferumoxides (Feridex(®) IV, Berlex Laboratories), Ferucarbotran (Resovist(®), Bayer Healthcare), Ferumoxtran-10 (AMI-227 or Code-7227, Combidex(®), AMAG Pharma; Sinerem(®), Guerbet), NC100150 (Clariscan(®), Nycomed,) and (VSOP C184, Ferropharm) have been designed and clinically tested as magnetic resonance contrast agents. However, until now Resovist(®) is current available in only a few countries. The other four agents have been stopped for further development or withdrawn from the market. Another SPIO agent Ferumoxytol (Feraheme(®)) is approved for the treatment of iron deficiency in adult chronic kidney disease patients. Ferumoxytol is comprised of iron oxide particles surrounded by a carbohydrate coat, and it is being explored as a potential imaging approach for evaluating lymph nodes and certain liver tumors.

  17. Effect of polychlorinated biphenyls on oxidation stress in the liver of juvenile GIFT, Oreochromis niloticus.

    PubMed

    Zheng, Y; Qiu, L P; Meng, S L; Fan, L M; Song, C; Li, D D; Zhang, C; Chen, J Z

    2016-09-02

    The present study clearly showed that chronic exposure to polychlorinated biphenyls (PCBs) at environmentally relevant concentrations can damage juvenile tilapia livers by modulating antioxidant enzyme activities and gene transcription, which affects toxic bioaccumulation and histological congestion. The results suggest that PCBs caused a decrease in the activity of some hepatic antioxidative and biotransformation enzymes (SOD, CAT, GST, T-GSH, and MDA) in tilapia at 7 days, as well as transcriptional changes (sod, cat, and gst). Except for some antioxidant parameters (T-GSH, GSH/GSSG, T-AOC, and MDA), significant declines and increases occurred at 14 and 21 days, respectively. Most of the antioxidant enzymatic signatures and genotoxicity significantly increased at 14 and 21 days. This study presented evidence that PCBs could result in hepatic toxicity through oxidative stress in the early growth stages of tilapia, and we speculated that oxidative stress plays an important role in embryonic developmental toxicity induced by PCBs.

  18. Resveratrol Protects Sepsis-Induced Oxidative DNA Damage in Liver and Kidney of Rats

    PubMed Central

    Aydın, Sevtap; Şahin, Tevfik Tolga; Bacanlı, Merve; Taner, Gökçe; Başaran, Arif Ahmet; Aydın, Mehtap; Başaran, Nurşen

    2016-01-01

    Background The increases of free radicals have been proposed to be involved in the pathogenesis of sepsis, which leads to multiple-organ dysfunction syndromes. The uses of antioxidants as a complementary tool in the medical care of oxidative stress-related diseases have attracted attention of researchers. Resveratrol (RV) has suggested being antioxidant, anti-proliferative, and anti-inflammatory effects in various experimental models and clinical settings. Aims This study was undertaken to evaluate the protective effects of RV on oxidative DNA damage induced by sepsis in the liver and kidney tissues of Wistar albino rats. Study Design Animal experimentation. Methods Four experimental groups consisting of eight animals for each was created using a total of thirty-two male Wistar albino rats. Sham group was given 0.5 mL of saline intra-peritoneal (ip) only following laparatomy. Sepsis group was given 0.5 mL saline ip only following the induction of sepsis. RV-treated group was given a dose of 100 mg/kg ip RV in 0.5 mL saline following laparatomy. RV-treated sepsis group was given 100 mg/kg ip RV in 0.5 mL saline following the induction of sepsis. A model of sepsis was created by cecal ligation and puncture technique. In the liver and kidney tissues, oxidative stress parameters (malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPX)) and a proinflammatory cytokine (tumor necrosis factor alpha (TNF-alpha)), were evaluated spectrophotometrically and DNA damage was determined by the alkaline single cell gel electrophoresis (comet assay) technique using formamidopyrimidine DNA glycosylase protein. Results In the RV-treated sepsis group, the levels of MDA and TNF-alpha were lower and GSH levels, SOD and GPX activities were higher than in the septic rats (p<0.05). RV treatment significantly reduced the sepsis-induced oxidative DNA damage in the liver and kidney cells (p<0.05). Conclusion It is suggested that RV treatment

  19. Oxidative stress-related liver dysfunction by sodium arsenite: Alleviation by Pistacia lentiscus oil.

    PubMed

    Klibet, Fahima; Boumendjel, Amel; Khiari, Mohamed; El Feki, Abdelfattah; Abdennour, Cherif; Messarah, Mahfoud

    2016-01-01

    Pistacia lentiscus L. (Anacardiaceae) is an evergreen shrub widely distributed throughout the Mediterranean region. Pistacia lentiscus oil (PLo) was particularly known in North African traditional medicine. Thus, people of these regions have used it externally to treat sore throats, burns and wounds, as well as they employed it internally for respiratory allergies. PLo is rich in essential fatty acids, vitamin E and polyphenols. As a very active site of metabolism, liver is reported to be susceptible to arsenic (As) intoxication. The present study evaluates the protective effect of PLo against sodium arsenite-induced hepatic dysfunction and oxidative stress in experimental Wistar rats. Twenty-eight rats were equally divided into four groups; the first served as a control, the remaining groups were respectively treated with PLo (3.3 mL/kg body weight), sodium arsenite (5.55 mg/kg body weight) and a combination of sodium arsenite and PLo. After 21 consecutive days, cellular functions were evaluated by hematological, biochemical and oxidative stress markers. A significant decrease in the levels of red blood cells, haemoglobin (p ≤ 0.001), hematocrit (p ≤ 0.001), reduced glutathione and metallothionein (p ≤ 0.05) associated with a significant increase of malondialdehyde (p ≤ 0.001) were noticed in the arsenic-exposed group when compared to the control. The As-treated group also exhibited an increase in hepatic antioxidant enzymes namely superoxide dismutase, glutathione peroxidase (p ≤ 0.01) and catalase (p ≤ 0.05). However, the co-administration of PLo has relatively reduced arsenic effect. The results showed that arsenic intoxication disturbed the liver pro-oxidant/antioxidant status. PLo co-administration mitigates arsenic-induced oxidative damage in rat.

  20. Zidovudine and isoniazid induced liver toxicity and oxidative stress: Evaluation of mitigating properties of silibinin.

    PubMed

    Raghu, Ramanathan; Karthikeyan, Sivanesan

    2016-09-01

    HIV/AIDS patients are more prone for opportunistic TB infections and they are administered the combined regimen of anti-retroviral drug zidovudine (AZT) and isoniazid (INH) for therapy. However, AZT+INH treatment has been documented to induce injury and remedial measures to prevent this adversity are not clearly defined. Silibinin (SBN) is a natural hepatoprotective principle isolated from medicinal plant Silybum marianum and is currently used for therapy of various liver diseases. This study investigate the hepatotoxic potentials of AZT alone, INH alone and AZT+INH treatments and the mitigating potentials of SBN against these drugs induced toxic insults of liver in rats. Separate groups of rats (n=6 in each group) were administered AZT alone (50mg/kg b.w.), INH alone (25mg/kg, b.w.), AZT+INH (50mg/kg, b.w. and 25mg/kg, b.w.), SBN alone (100mg/kg, b.w.) and SBN+AZT+INH daily for sub-chronic period of 45days orally. The control rats received saline/propylene glycol. INH alone and AZT+INH-induced parenchymal cell injury and cholestasis of liver was evidenced by highly significant increase in the activities of marker enzymes (aspartate and alanine transaminase, alkaline phosphatase, argino succinic acid lyase), bilirubin, protein, oxidative stress parameters (lipid peroxidation, superoxide dismutase, catalase, reduced glutathione, vitamins C and E) and membrane bound ATPases were evaluated in serum/liver tissue homogenates. Histopathological studies show ballooning degradation, inflammatory lesions, lipid deposition and hydropic changes in the liver tissue. All the above biochemical and pathological changes induced by AZT+INH treatments were mitigated in rats receiving SBN simultaneously with these hepatotoxins, indicating its hepatoprotective and antioxidant potentials against AZT+INH-induced hepatotoxicity. The moderate hepatoprotective and oxidant potentials of SBN could be due to its low bioavailability and this deficiency could be prevented by supplementation of

  1. Salvianolic acid A preconditioning confers protection against concanavalin A-induced liver injury through SIRT1-mediated repression of p66shc in mice.

    PubMed

    Xu, Xiaomei; Hu, Yan; Zhai, Xiaohan; Lin, Musen; Chen, Zhao; Tian, Xiaofeng; Zhang, Feng; Gao, Dongyan; Ma, Xiaochi; Lv, Li; Yao, Jihong

    2013-11-15

    Salvianolic acid A (SalA) is a phenolic carboxylic acid derivative extracted from Salvia miltiorrhiza. It has many biological and pharmaceutical activities. The purpose of this study was to investigate the effect of SalA on concanavalin A (ConA)-induced acute hepatic injury in Kunming mice and to explore the role of SIRT1 in such an effect. The results showed that in vivo pretreatment with SalA significantly reduced ConA-induced elevation in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and decreased levels of the hepatotoxic cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Moreover, the SalA pretreatment ameliorated the increases in NF-κB and in cleaved caspase-3 caused by ConA exposure. Whereas, the pretreatment completely reversed expression of the B-cell lymphoma-extra large (Bcl-xL). More importantly, the SalA pretreatment significantly increased the expression of SIRT1, a NAD(+)-dependent deacetylase, which was known to attenuate acute hypoxia damage and metabolic liver diseases. In our study, the increase in SIRT1 was closely associated with down-regulation of the p66 isoform (p66shc) of growth factor adapter Shc at both protein and mRNA levels. In HepG2 cell culture, SalA pretreatment increased SIRT1 expression in a time and dose-dependent manner and such an increase was abrogated by siRNA knockdown of SIRT1. Additionally, inhibition of SIRT1 significantly reversed the decreased expression of p66shc, and attenuated SalA-induced p66shc down-regulation. Collectively, the present study indicated that SalA may be a potent activator of SIRT and that SalA can alleviate ConA-induced hepatitis through SIRT1-mediated repression of the p66shc pathway.

  2. Differential Fmo3 Gene Expression in Various Liver Injury Models Involving Hepatic Oxidative Stress in Mice

    PubMed Central

    Rudraiah, Swetha; Moscovitz, Jamie E.; Donepudi, Ajay C.; Campion, Sarah N.; Slitt, Angela L.; Aleksunes, Lauren M.; Manautou, José E.

    2015-01-01

    Flavin-containing monooxygenase-3 (FMO3) catalyzes metabolic reactions similar to cytochrome P450 monooxygenase however, most metabolites of FMO3 are considered non-toxic. Recent findings in our laboratory demonstrated Fmo3gene induction following toxic acetaminophen (APAP) treatment in mice.The goal of this study was to evaluate Fmo3gene expression in diverseother mouse models of hepatic oxidative stress and injury. Fmo3 gene regulation by Nrf2 was also investigated using Nrf2 knockout (Nrf2 KO) mice. In our studies, male C57BL/6J mice were treated with toxic dosesof hepatotoxicants or underwent bile duct ligation (BDL, 10d). Hepatotoxicants included APAP (400 mg/kg, 24 to 72h), alpha-naphthylisothiocyanate (ANIT; 50 mg/kg, 2 to 48h), carbontetrachloride (CCl4;10 or 30 μL/kg, 24 and 48h) and allyl alcohol (AlOH; 30 or 60 mg/kg, 6 and 24h). Because oxidative stress activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2), additional studies investigated Fmo3 gene regulation by Nrf2 using Nrf2 knockout (Nrf2 KO) mice. At appropriate time-points, blood and liver samples were collected for assessment of plasma alanine aminotransferase (ALT) activity, plasma and hepatic bile acid levels, as well as liver Fmo3 mRNA and protein expression. Fmo3 mRNA expression increased significantly by 43-fold at 12h after ANIT treatment,and this increase translates to a 4-fold change in protein levels. BDL also increased Fmo3 mRNA expression by 1899-fold, but with no change in protein levels. Treatment of mice with CCl4decreased liver Fmo3gene expression, whileno change in expression was detected with AlOH treatment. Nrf2 KO mice are more susceptible to APAP (400 mg/kg, 72h) treatment compared to their wild-type (WT) counterparts, which is evidenced by greater plasma ALT activity. Fmo3 mRNA and protein expression increased in Nrf2 KO mice after APAP treatment. Collectively, not all hepatotoxicantsthat produce oxidative stress alter Fmo3gene expression. Along with APAP, toxic ANIT

  3. Effect of Light at Night on oxidative stress markers in Golden spiny mice (Acomys russatus) liver.

    PubMed

    Ashkenazi, Lilach; Haim, Abraham

    2013-07-01

    Light at Night (LAN) suppresses melatonin (MLT) production, and effects metabolism, hormone secretion, gene expression and enzyme activity. Changes in antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD), can be used as an indication for oxidative stress level. We assayed activity and expression of these enzymes in the liver of Acomys russatus exposed to LAN and treated with MLT. Short day (SD)-acclimated A. russatus, was exposed to 30min of LAN for two, seven or 21 nights. MLT impact was assessed simultaneously with two and seven nights of LAN exposure. GPx and SOD activities were measured. Gpx1 expression was evaluated by RT-PCR. There was a significant increase in GPx activity following LAN exposure for all acclimation durations, GPx activity was elevated after two nights of LAN and MLT treatment, Gpx1 expression was elevated by MLT after seven nights of LAN. SOD activity increased after two nights of LAN in MLT-treated A. russatus, GPx activity increased with the duration of LAN acclimation, indicating changes in liver redox status. Our results suggest that LAN is a stressor that influences oxidative stress. As in the other studies, MLT increases antioxidant activities, presumably attenuating stress response, in order to restore homeostasis.

  4. Burn after feeding. An old uncoupler of oxidative phosphorylation is redesigned for the treatment of nonalcoholic fatty liver disease.

    PubMed

    Fromenty, B

    2014-10-01

    Uncoupling of oxidative phosphorylation (OXPHOS) in brown adipose tissue can be used by hibernating animals to produce heat at the expense of their fat mass. In a recent work, Dr Shulman et al. generated a liver-targeted derivative of the prototypical OXPHOS uncoupler 2,4-dinitrophenol that alleviated steatosis, hypertriglyceridemia and insulin resistance in several models of nonalcoholic fatty liver disease and type 2 diabetes.

  5. The relationship between oxidative stress and nonalcoholic fatty liver disease: Its effects on the development of nonalcoholic steatohepatitis.

    PubMed

    Ucar, Fatma; Sezer, Sevilay; Erdogan, Serpil; Akyol, Sumeyya; Armutcu, Ferah; Akyol, Omer

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the most common underlying causes of chronic liver injury. They are associated with a wide spectrum of hepatic disorders including basic steatosis, steatohepatitis, and cirrhosis. The molecular and cellular mechanisms underlying hepatic injury in NAFLD and NASH are still unknown. This review describes the roles of oxidative stress and inflammatory responses in the pathogenesis of NAFLD and its progression to NASH.

  6. The role of microsomal oxidation in the regulation of monoamine oxidase activity in the brain and liver of rats.

    PubMed

    Kozochkin, Denis A; Manukhina, Eugenia B; Downey, H Fred; Tseilikman, Olga B; Komelkova, Maria V; Vasilyeva, Maria V; Lapshin, Maxim S; Sahabutdinov, Marat N; Lazuko, Svetlana S; Tseilikman, Vadim E

    2016-06-27

    It has been shown in previous data that monoamine oxidase (MAO) activity in different brain regions are correlated with a microsomal oxidation phenotype. The data obtained in this study, using the microsomal oxidation inhibitor SKF525, and using animals with different duration of hexobarbital sleep, has shown that increased intensity of microsomal oxidation might be associated with increased MAO activity. Since the rats with short hexobarbital sleep time had higher content of hepatic microsomal cytochrome P450 than did rats with long hexobarbital sleep time. In addition, the rats with higher hepatic content of CYP450 had higher activities of MAO-A and MAO-B. Moreover, the microsomal oxidation inhibitor SKF-525 reduced brain and liver activities of MAOA and MAO-B. Consequently, MAO activities in a brain and a liver depend on the microsomal oxidation process.

  7. Moderate hyperhomocysteinemia provokes dysfunction of cardiovascular autonomic system and liver oxidative stress in rats.

    PubMed

    Mendes, R H; Mostarda, C; Candido, G O; Moraes-Silva, I C; D'Almeida, V; Belló-Klein, A; Irigoyen, M C; Rigatto, K

    2014-02-01

    Hyperhomocysteinemia (HHcy) is associated with cardiovascular disease, atherosclerosis and reactive oxygen species generation. Thus, our aim was to investigate whether there was an association between HHcy, blood pressure, autonomic control and liver oxidative stress. Male Wistar rats were divided into 2 groups and treated for 8weeks: one group (control, CO) received tap water, while the other group (methionine, ME) was given a 100mg/kg of methionine in water by gavage. Two catheters were implanted into the femoral artery and vein to record arterial pressure (AP) and heart rate (HR) and drug administration. Signals were recorded by a data acquisition system. Baroreflex sensitivity was evaluated by HR responses to AP changes induced by vasoactive drugs. HR variability and AP variability were performed by spectral analysis in time and frequency domains to evaluate the contribution of the sympathetic and parasympathetic modulation. Lipid peroxidation and antioxidant enzyme activities were evaluated by measuring superoxide dismutase, catalase and glutathione peroxidase in liver homogenates. The ME group presented a significant increase in systolic arterial pressure (118±9 vs 135±6mmHg), diastolic arterial pressure (81±6 vs. 92±4) and mean arterial pressure (95±7 vs. 106±6). In addition, pulse interval variability presented a significant decrease (41%), while the low frequency component of AP was significantly increased (delta P=6.24mmHg(2)) in the ME group. We also found a positive association between lipid peroxidation and cardiac sympathetic modulation, sympathetic and vagal modulation ratio and systolic pressure variability. Collectively, these findings showed that HHcy induced dysfunction of cardiovascular autonomic system and liver oxidative stress. © 2013.

  8. Thymoquinone and curcumin prevent gentamicin-induced liver injury by attenuating oxidative stress, inflammation and apoptosis.

    PubMed

    Galaly, S R; Ahmed, O M; Mahmoud, A M

    2014-12-01

    This study was conducted to assess the preventive effect of two plant constituents, thymoquinone and curcumin, on gentamicin-induced deleterious effect on liver function, integrity and histological architecture. The gentamicin was intraperitoneally injected to rats at dose level of 100 mg/kg b.w. (every other day) for 21 days. The thymoquinone and curcumin were concurrently and orally administered at dose level of 20 mg/kg b.w. (every other day) to gentamicin-injected rats. The present data indicated that thymoquinone and curcumin significantly prevented the gentamicin-induced elevations of serum AST, ALT and LDH activities as well as tumor necrosis factor alpha (TNF-α) and total bilirubin levels. On the other hand, both agents markedly ameliorated the gentamicin-induced decrease in serum total protein, albumin and albumin/globulin ratio. In addition, the gentamicin-induced liver histological alterations including hydropic degeneration of hepatocytes, fatty changes, inflammatory cell infiltration and congestion of portal vein were successfully amended by thymoquinone and curcumin. The elevated proapoptotic proteins caspase 3 and Bax expression in cytoplasm and nucleus of hepatocytes of gentamicin-injected rats were reduced to normal value as a result of thymoquinone and curcumin administration while the lowered expression of antiapoptotic protein Bcl-2 was increased. Based on the previous findings, it can be concluded that thymoquinone and curcumin successfully prevents the deleterious effects on liver function and histological integrity to more or less the same degree by enhancing anti-oxidant defense system, suppression of oxidative stress and attenuation of inflammation and apoptosis.

  9. Role of the diet as a link between oxidative stress and liver diseases

    PubMed Central

    Arrigo, Teresa; Leonardi, Salvatore; Cuppari, Caterina; Manti, Sara; Lanzafame, Angela; D’Angelo, Gabriella; Gitto, Eloisa; Marseglia, Lucia; Salpietro, Carmelo

    2015-01-01

    Oxidative stress is caused by an imbalance between the production of reactive oxygen (free radicals) and the body’s ability (antioxidant capacity) to readily detoxify the reactive intermediates or easily repair the resulting damage. An adequate diet, characterized by daily intake of foods associated with improvements in the total antioxidant capacity of individuals and reduced incidence of diseases related to oxidation, can modulate the degree of oxidative stress. In fact, diet-derived micronutrients may be direct antioxidants, or are components of antioxidant enzymes, leading to improvement of some indicators of hepatic function. However, although their increased dietary intake might be beneficial, literature data are still controversial. This review summarizes what is known about the effects of diet nutrients on oxidative stress, inflammation and liver function. Moreover, we have analyzed: (1) the main nutritional components involved in the production and/or removal of free radicals; and (2) the role of free radicals in the pathogenesis of several hepatic diseases and related comorbidities. PMID:25593454

  10. The effect of iron overload on rat plasma and liver oxidant status in vivo.

    PubMed Central

    Dabbagh, A J; Mannion, T; Lynch, S M; Frei, B

    1994-01-01

    There is ample evidence implicating reactive oxygen species in a number of human degenerative diseases such as atherosclerosis and haemochromatosis. Although lipid peroxidation underlies many of the toxic effects of oxidative stress, there is a lack of a sensitive and reliable method for its assessment in vivo. To understand the implications of oxidative stress in vivo, we have used dietary iron overload (IO) in the rat. Oxidant status in these animals was determined by assessing depletion of endogenous antioxidants and formation of various lipid peroxidation products, including acylated F2-isoprostanes, a novel class of free-radical-derived prostaglandin-F2-like compounds. IO led to a significant decrease in the concentration of the antioxidants alpha-tocopherol and ascorbic acid in plasma, and alpha-tocopherol, beta-carotene and ubiquinol-10 in liver. Whereas there was no significant lipid peroxidation in plasma, hepatic F2-isoprostane levels were moderately but significantly increased in IO. In addition, IO caused a significant increase in plasma total and high-density lipoprotein cholesterol levels, an effect that was correlated with depletion of plasma ascorbic acid but not alpha-tocopherol. The data demonstrate that IO causes lipid metabolism disturbances and oxidative stress which is associated with substantial depletion of endogenous antioxidants and moderate lipid peroxidative damage. PMID:8010963

  11. Oxidative damage in gills and liver in Nile tilapia (Oreochromis niloticus) exposed to diazinon.

    PubMed

    Toledo-Ibarra, G A; Díaz Resendiz, K J G; Ventura-Ramón, G H; González-Jaime, F; Vega-López, A; Becerril-Villanueva, E; Pavón, L; Girón-Pérez, M I

    2016-10-01

    Agricultural activity demands the use of pesticides for plague control and extermination. In that matter, diazinon is one of the most widely used organophosphorus pesticides (OPs). Despite its benefits, the use of OPs in agricultural activities can also have negative effects since the excessive use of these substances can represent a major contamination problem for water bodies and organisms that inhabit them. The aim of this paper was to evaluate oxidative damage in lipids and proteins of Nile tilapia (Oreochromis niloticus) exposed acutely to diazinon (0.97, 1.95 and 3.95ppm) for 12 or 24h. The evaluation of oxidative damage was determined by quantifying lipid hydroperoxides (Fox method) and oxidized proteins (DNPH method). The data from this study suggest that diazinon induces a concentration-dependent oxidative damage in proteins, but not lipids, of the liver and gills of Nile tilapia. Furthermore, the treatment leads to a decrease in the concentration of total proteins, which can have serious consequences in cell physiology and fish development. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Preventive Effect of Carvacrol Against Oxidative Damage in Aged Rat Liver.

    PubMed

    Samarghandian, Saeed; Azimi-Nezhad, Mohsen; Farkhondeh, Tahereh

    2016-11-21

    The present study was designed to investigate the changes in activities of antioxidant enzymes and lipid peroxidation level in the liver of 2, 10 and 20 months old rats, and to see whether these changes are restored to those of the two month old rats after carvacrol treatment. Male rats of 2, 10, and 20 months (n = 10 for each group) were used for all the experiments. The aged rats (10 and 20 months old) were given carvacrol (15 mg/day per body weight) for 30 days. Control animals received an equal volume of vehicle. After the treatment, livers were removed for estimation of superoxide dismutase-SOD, glutathione-S-transferase-GST, catalase-CAT activities and lipid peroxidation level. The present findings determined that normal aging was associated with a significant decrease in the activities of antioxidant enzymes (SOD; 11.87 ± 0.6 (2 months old) vs 7.56 ± 0.1 (20 months old); P < 0.001) in liver, as well as an increase in lipid peroxidation level (MDA; 0.15 ± 0.01 (2 months old) vs 0.41 ± 0.01 (20 months old); P < 0.001) in aged rats. Also, the results of this study indicated that carvacrol treatment increased the activities of the antioxidant enzymes in 20 months old animals versus the aged matched control group (SOD; 9.87 ± 0.4; P < 0.01). Furthermore, carvacrol decreased lipid peroxidation content in 10 and 20 months old animals compared with the aged matched control (MDA; 9.87 ± 0.4; P < 0.001). Our data shows that carvacrol could be a candidate to inhibit the development of age-induced liver damage through inhibition of oxidative stress and also increasing antioxidant defenses.

  13. Effects of Apium graveolens Extract on the Oxidative Stress in the Liver of Adjuvant-Induced Arthritic Rats.

    PubMed

    Sukketsiri, Wanida; Chonpathompikunlert, Pennapa; Tanasawet, Supita; Choosri, Nutjanat; Wongtawatchai, Tulaporn

    2016-06-01

    Apium graveolens Linn. (Apiaceae) is an indigenous plant of the North and South Americas, Southern Europe, and Asia and has been widely used as a food or a traditional medicine for treatment of inflammation and arthritis. The purpose of this study was to investigate the antioxidant effects of a methanolic extract of A. graveolens (AGE) against liver oxidative stress in an adjuvant-induced arthritic rat model. The AGE (250, 500, and 1,000 mg/kg) was given orally for 24 consecutive days after induction by injecting complete Freund's adjuvant. Liver and spleen weights were recorded. The superoxide anion level, total peroxide (TP), glutathione peroxidase (GPx) activity, superoxide dismutase (SOD) activity, total antioxidant status, and oxidative stress index (OSI) were also measured. AGE treatment significantly decreased the levels of the superoxide anion, TP, and OSI whereas the GPx and SOD activities significantly increased in the liver of the arthritic rats. These results indicated that AGE showed an ameliorative effect against liver oxidative stress in adjuvant-induced arthritic rats by reducing the generation of liver free radicals and increasing the liver antioxidant enzyme activity.

  14. Quercetin protects against perfluorooctanoic acid-induced liver injury by attenuating oxidative stress and inflammatory response in mice.

    PubMed

    Zou, Weiying; Liu, Wenwen; Yang, Bei; Wu, Lei; Yang, Jianhua; Zou, Ting; Liu, Fangming; Xia, Liping; Zhang, Dalei

    2015-09-01

    The aim of the present study was to investigate the protective effect of quercetin (Que) against perfluorooctanoic acid (PFOA)-induced liver injury in mice and its possible mechanisms of action. Mice were intragastrically administered PFOA (10mg/kg/day) alone or in combination with Que (75 mg/kg/day) for 14 consecutive days. The hepatic injury was evaluated by measuring morphological changes, liver function, oxidative stress, inflammatory response and hepatocellular apoptosis. Compared with mice treated with PFOA alone, simultaneous supplementation of Que significantly decreased serum levels of liver injury indicators alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase and total bile acids. Moreover, Que treatment inhibited the production of oxidative stress biomarkers malondialdehyde, hydrogen peroxide and 8-hydroxy-2'-deoxyguanosine, reduced the levels of proinflammatory cytokines interleukin 6, cyclooxygenase-2 and C-reactive protein, and decreased the number of TUNEL-positive cells in the liver of PFOA-treated mice. These results combined with liver histopathology demonstrated that Que exhibited a potential protective effect against PFOA-induced liver damage via mechanisms involving the attenuation of oxidative stress, alleviation of inflammation and inhibition of hepatocellular apoptosis. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Protective Effect of Thalidomide on Liver Injury in Rats with Acute Pancreatitis via Inhibition of Oxidative Stress.

    PubMed

    Lv, Peng; Fan, Li-Juan; Li, Hong-Yun; Meng, Qing-Shun; Liu, Jie

    2015-01-01

    This study was designed to investigate the preventive effect of thalidomide on acute pancreatitis-associated liver injury in the rat and analyze its relationship with oxidative stress. The acute pancreatitis of rats was induced by the retrograde injection of 5% sodium taurocholate into the biliopancreatic duct. Thalidomide (100 mg/kg) was given daily via the intragastric route for 8 days before this injection. The levels of oxidative stress parameters including superoxide dismutase (SOD), glutathione peroxidase (GSHpx), and malondialdehyde (MDA) in the liver were detected by biochemical assay. Nuclear factor-κB p65 (NF-κBp65), tumor necrosis factor α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) protein and mRNA levels in the liver were detected using western blots and reverse transcriptase polymerase chain reaction, respectively. Compared with the untreated model group, liver histopathology, SOD, GSHpx, MDA levels, NF-κBp65, TNF-α, ICAM-1 protein, and mRNA levels in the liver of rats given thalidomide were improved significantly. Results demonstrate that thalidomide may exert its effects on oxidative stress to attenuate the progression of acute pancreatitis-associated liver injury in rats.

  16. Effects of Apium graveolens Extract on the Oxidative Stress in the Liver of Adjuvant-Induced Arthritic Rats

    PubMed Central

    Sukketsiri, Wanida; Chonpathompikunlert, Pennapa; Tanasawet, Supita; Choosri, Nutjanat; Wongtawatchai, Tulaporn

    2016-01-01

    Apium graveolens Linn. (Apiaceae) is an indigenous plant of the North and South Americas, Southern Europe, and Asia and has been widely used as a food or a traditional medicine for treatment of inflammation and arthritis. The purpose of this study was to investigate the antioxidant effects of a methanolic extract of A. graveolens (AGE) against liver oxidative stress in an adjuvant-induced arthritic rat model. The AGE (250, 500, and 1,000 mg/kg) was given orally for 24 consecutive days after induction by injecting complete Freund’s adjuvant. Liver and spleen weights were recorded. The superoxide anion level, total peroxide (TP), glutathione peroxidase (GPx) activity, superoxide dismutase (SOD) activity, total antioxidant status, and oxidative stress index (OSI) were also measured. AGE treatment significantly decreased the levels of the superoxide anion, TP, and OSI whereas the GPx and SOD activities significantly increased in the liver of the arthritic rats. These results indicated that AGE showed an ameliorative effect against liver oxidative stress in adjuvant-induced arthritic rats by reducing the generation of liver free radicals and increasing the liver antioxidant enzyme activity. PMID:27390722

  17. Oxidative stress response in gill and liver of Liza saliens, from the Esmoriz-Paramos coastal lagoon, Portugal.

    PubMed

    Fernandes, C; Fontaínhas-Fernandes, A; Ferreira, M; Salgado, M A

    2008-08-01

    Tissue-specific responses against oxidative stress and lipid peroxidation were analyzed in wild adult mullet (Liza saliens) caught in the Portuguese coastal lagoon Esmoriz-Paramos. Parameters measured were catalase (CAT), superoxide dismutase (SOD), and glutathione-S-transferase (GST) activities in liver and gill tissues and lipid peroxidation. The enzyme activities were related to gill histopathological alterations, as well as to heavy metals (Cu and Zn) concentrations in these tissues. Gill epithelium of L. saliens showed histological alterations, such as epithelial hyperplasia resulting in lamellar fusion, epithelial lifting, vasodilatation, and lamellar aneurisms, with a prevalence ranging from 62% to 92%. The highest Cu content was found in liver (379 mg x kg(-1)), while the highest Zn content was observed in gill (119 mg x kg(-1)). SOD and CAT activities showed differences between gill and liver. The highest activities found were SOD in gill (10.1 U/mg protein) and CAT in liver (39.2 mmol/min/mg protein). In gill, CAT activity was negatively related to both Cu levels and gill lifting, while a positive relationship was found between SOD activity and fish age. The positive relationship between Cu and CAT activity in liver suggests that an increase in metabolic level is related to Cu-induced oxidative stress. The decrease in gill CAT activity can be due to osmotic stress caused by damaged gill epithelium. CAT activity in liver is an appropriate biomarker of oxidative stress in the Esmoriz-Paramos lagoon.

  18. A high-fat and cholesterol diet causes fatty liver in guinea pigs. The role of iron and oxidative damage.

    PubMed

    Ye, P; Cheah, I K; Halliwell, B

    2013-08-01

    Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease. Iron, cholesterol, and oxidative damage are frequently suggested to be related to the progression of NAFLD, but the precise relationship between them remains unclear. Guinea pigs fed on a high cholesterol and fat diet (without oxidized lipids) generated a disease model of NAFLD with hallmark observations in liver histology and increased liver damage markers. Hepatic cholesterol and iron levels were found to be significantly elevated and directly correlated. Plasma hepcidin and transferrin levels were decreased. Plasma iron concentrations were found to be elevated, likely due to an increased intestinal iron absorption caused by the decrease in plasma hepcidin. However, hepatic transferrin receptor-2 levels were unchanged. No significant increase in hepatic lipid peroxidation was detected using F2-isoprostanes as a reliable biomarker, nor was there a rise in protein carbonyls, a general index of oxidative protein damage. Some increases in cholesterol oxidation products were observed, but largely negated after normalizing for the elevated hepatic cholesterol content. Indeed, increased hemosiderin deposition and unchanged ferritin levels in liver suggested that the excess iron mainly existed as hemosiderin, which is redox-inactive.

  19. Moderately oxidized oils and dietary zinc and α-tocopheryl acetate supplementation: effects on the oxidative stability of rabbit plasma, liver, and meat.

    PubMed

    Tres, Alba; Bou, Ricard; Codony, Rafael; Guardiola, Francesc

    2010-08-25

    The aim of this study was to assess the alterations in plasma, liver, and meat oxidative stability and α-tocopherol content when moderately oxidized sunflower oils were added to feeds and when feeds were supplemented with α-tocopheryl acetate (100 mg/kg) and Zn (200 mg/kg). The effects of cooking the meat and its subsequent refrigeration were also studied. When the content of primary oxidation compounds of the oil was high, rabbit plasma, liver, and meat α-tocopherol content was reduced and meat susceptibility to oxidation increased. The addition of oil with a high content of secondary oxidation compounds (oil heated at 140 °C, 31 h) to feed also led to an increase in meat susceptibility to oxidation, although it presented an α-tocopherol content similar to that of nonheated oil. Feed supplementation with α-tocopheryl acetate increased tissue α-tocopherol content and improved the oxidative stability of liver and meat. However, in the latter, it was less effective when oil heated at 55 °C was added.

  20. Saikokeishito Extract Exerts a Therapeutic Effect on α-Naphthylisothiocyanate-Induced Liver Injury in Rats through Attenuation of Enhanced Neutrophil Infiltration and Oxidative Stress in the Liver Tissue

    PubMed Central

    Ohta, Yoshiji; Kongo-Nishimura, Mutsumi; Hayashi, Takahiro; Kitagawa, Akira; Matsura, Tatsuya; Yamada, Kazuo

    2007-01-01

    We examined whether Saikokeishito extract (TJ-10), a traditional Japanese herbal medicine, exerts a therapeutic effect on α-naphthylisothiocyanate (ANIT)-induced liver injury in rats through attenuation of enhanced neutrophil infiltration and oxidative stress in the liver tissue. In rats treated once with ANIT (75 mg/kg, i.p.), liver injury with cholestasis occurred 24 h after treatment and progressed at 48 h. When ANIT-treated rats orally received TJ-10 (0.26, 1.3 or 2.6 g/kg) at 24 h after the treatment, progressive liver injury with cholestasis was significantly attenuated at 48 h after the treatment at the dose of 1.3 or 2.6 g/kg. At 24 h after ANIT treatment, increases in hepatic lipid peroxide and reduced glutathione contents and myeloperoxidase activity occurred with decreases in hepatic superoxide dismutase and glutathione reductase activities. At 48 h after ANIT treatment, these changes except for reduced glutathione were enhanced with decreases in catalase, Se-glutathione peroxidase, and glucose-6-phosphate dehydrogenase activities. TJ-10 (1.3 or 2.6 g/kg) post-administered to ANIT-treated rats attenuated these changes found at 48 h after the treatment significantly. These results indicate that TJ-10 exerts a therapeutic effect on ANIT-induced liver injury in rats possibly through attenuation of enhanced neutrophil infiltration and oxidative stress in the liver tissue. PMID:18437211

  1. Withaferin A Induces Oxidative Stress-Mediated Apoptosis and DNA Damage in Oral Cancer Cells.

    PubMed

    Chang, Hsueh-Wei; Li, Ruei-Nian; Wang, Hui-Ru; Liu, Jing-Ru; Tang, Jen-Yang; Huang, Hurng-Wern; Chan, Yu-Hsuan; Yen, Ching-Yu

    2017-01-01

    Withaferin A (WFA) is one of the most active steroidal lactones with reactive oxygen species (ROS) modulating effects against several types of cancer. ROS regulation involves selective killing. However, the anticancer and selective killing effects of WFA against oral cancer cells remain unclear. We evaluated whether the killing ability of WFA is selective, and we explored its mechanism against oral cancer cells. An MTS tetrazolium cell proliferation assay confirmed that WFA selectively killed two oral cancer cells (Ca9-22 and CAL 27) rather than normal oral cells (HGF-1). WFA also induced apoptosis of Ca9-22 cells, which was measured by flow cytometry for subG1 percentage, annexin V expression, and pan-caspase activity, as well as western blotting for caspases 1, 8, and 9 activations. Flow cytometry analysis shows that WFA-treated Ca9-22 oral cancer cells induced G2/M cell cycle arrest, ROS production, mitochondrial membrane depolarization, and phosphorylated histone H2A.X (γH2AX)-based DNA damage. Moreover, pretreating Ca9-22 cells with N-acetylcysteine (NAC) rescued WFA-induced selective killing, apoptosis, G2/M arrest, oxidative stress, and DNA damage. We conclude that WFA induced oxidative stress-mediated selective killing of oral cancer cells.

  2. Inhibition of neutral sphingomyelinase decreases elevated levels of nitrative and oxidative stress markers in liver ischemia-reperfusion injury.

    PubMed

    Unal, Betul; Ozcan, Filiz; Tuzcu, Hazal; Kırac, Ebru; Elpek, Gulsum O; Aslan, Mutay

    2017-07-01

    Oxidative stress and excessive nitric oxide production via induction of inducible nitric oxide synthase (NOS)-2 have been shown in the pathogenesis of liver ischemia-reperfusion (IR) injury. Neutral sphingomyelinase (N-SMase)/ceramide pathway can regulate NOS2 expression therefore this study determined the role of selective N-SMase inhibition on nitrative and oxidative stress markers following liver IR injury. Selective N-SMase inhibitor was administered via intraperitoneal injections. Liver IR injury was created by clamping blood vessels supplying the median and left lateral hepatic lobes for 60 min, followed by 60 min reperfusion. Nitrative and oxidative stress markers were determined by evaluating NOS2 expression, protein nitration, nitrite/nitrate levels, 4-hydroxynonenal (HNE) formation, protein carbonyl levels and xanthine oxidase/xanthine dehydrogenase (XO/XDH) activity. Levels of sphingmyelin and ceramide in liver tissue were determined by an optimized multiple reaction monitoring method using ultra-fast liquid chromatography coupled with tandem mass spectrometry (MS/MS). Spingomyelin levels were significantly increased in all IR groups compared to controls. Treatment with a specific N-SMase inhibitor significantly decreased all measured ceramides in IR injury. NOS2 expression, nitrite/nitrate levels and protein nitration were significantly greater in IR injury and decreased with N-SMase inhibition. Treatment with a selective N-SMase inhibitor significantly decreased HNE formation, protein carbonyl levels and the hepatic conversion of XO. Data confirm the role of nitrative and oxidative injury in IR and highlight the protective effect of selective N-SMase inhibition. Future studies evaluating agents blocking N-SMase activity can facilitate the development of treatment strategies to alleviate oxidative injury in liver I/R injury.

  3. Li-Gan-Shi-Liu-Ba-Wei-San improves non-alcoholic fatty liver disease through enhancing lipid oxidation and alleviating oxidation stress.

    PubMed

    Jiang, Youzhao; Chen, Liu; Wang, Hui; Narisi, Bao; Chen, Bing

    2015-12-24

    Mongolian medicine is an important constituent of traditional Chinese medicine. Its representative prescription, Li-Gan-Shi-Liu-Ba-Wei-San (LGSLBWS), is widely used for long-term treatment of chronic liver disease and nonalcoholic fatty liver disease (NAFLD). This study explored the effects and mechanism of LGSLBWS on NAFLD. NAFLD rat model was established with high-fat diet. The effects of LGSLBWS on lipid metabolism, liver function, and hepatic morphology were observed in NAFLD rats. Superoxide dismutase (SOD) and malondialdehyde (MDA) contents in the liver, as well as the expression levels of peroxisome proliferator-activated receptor (PPAR)α, PPARβ, inhibitor of nuclear factor κB α(IκBα), and inducible nitric oxide synthase (iNOS) were all detected. Finally, the effects of LGSLBWS on fatty acid oxidation, PPARα, PPARβ, IκBα, and iNOS were determined in HepG2 cells. LGSLBWS significantly reduced the fat deposition in the liver and the serum aspartate aminotransferase levels in NAFLD rats. Serum triglyceride and free fatty acid levels were reduced by LGSLBWS. Total cholesterol and triglyceride contents in the liver were also downregulated. SOD and MDA levels were increased and decreased by LGSLBWS, respectively. LGSLBWS can significantly promote fatty acid oxidation of HepG2 cells. Upregulation of PPARα, PPARβ, and IκBα and downregulation of iNOS by LGSLBWS were both observed in the NAFLD model and HepG2 cells. LGSLBWS can significantly improve NAFLD by enhancing fatty acid oxidation and alleviating oxidative stress. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Protective effect of rosuvastatin treatment by regulating oxidized low-density lipoprotein expression in a rat model of liver fibrosis.

    PubMed

    Yu, Shuiping; Zhou, Xueling; Hou, Bingzong; Tang, Bo; Li, Jian; Zhang, Baimeng

    2016-09-01

    The present study aimed to evaluate the protective effect of rosuvastatin treatment on the mechanism of oxidized low-density lipoprotein (Ox-LDL) in rats with liver fibrosis. In total, 72 male Sprague-Dawley rats were divided into 3 groups: 24 in the control group (A), 24 in the obstructive jaundice models group (B) and 24 in the rosuvastatin group (C). Each group was further divided into four subgroups for assessment at different time-points. The obstructive jaundice models were established and rosuvastatin was administered by gavage. Liver fibrosis indicators, Ox-LDL, malonaldehyde (MDA) and superoxide dismutase (SOD), were measured and liver pathological changes were observed at weeks 1, 2, 3 and 4 after model induction. In groups B and C, the rat models were successfully established, and there were significant changes in the expression of Ox-LDL and the three liver fibrosis indicators when compared to group A (P<0.01). However, the expression of Ox-LDL and the three liver fibrosis indicators in group C were decreased compared with group B (P<0.05), while SOD increased (P<0.05) and MDA decreased (P<0.05). The three liver fibrosis indicators were different in comparison to group B (P<0.05). Thus, there appeared to be an association between the expression of Ox-LDL and liver fibrosis. Treatment with rosuvastatin could regulate the expression of Ox-LDL and improve liver fibrosis in rat models with obstructive jaundice.

  5. Sympathetic Nervous System Control of Carbon Tetrachloride-Induced Oxidative Stress in Liver through α-Adrenergic Signaling.

    PubMed

    Lin, Jung-Chun; Peng, Yi-Jen; Wang, Shih-Yu; Lai, Mei-Ju; Young, Ton-Ho; Salter, Donald M; Lee, Herng-Sheng

    2016-01-01

    In addition to being the primary organ involved in redox cycling, the liver is one of the most highly innervated tissues in mammals. The interaction between hepatocytes and sympathetic, parasympathetic, and peptidergic nerve fibers through a variety of neurotransmitters and signaling pathways is recognized as being important in the regulation of hepatocyte function, liver regeneration, and hepatic fibrosis. However, less is known regarding the role of the sympathetic nervous system (SNS) in modulating the hepatic response to oxidative stress. Our aim was to investigate the role of the SNS in healthy and oxidatively stressed liver parenchyma. Mice treated with 6-hydroxydopamine hydrobromide were used to realize chemical sympathectomy. Carbon tetrachloride (CCl4) injection was used to induce oxidative liver injury. Sympathectomized animals were protected from CCl4 induced hepatic lipid peroxidation-mediated cytotoxicity and genotoxicity as assessed by 4-hydroxy-2-nonenal levels, morphological features of cell damage, and DNA oxidative damage. Furthermore, sympathectomy modulated hepatic inflammatory response induced by CCl4-mediated lipid peroxidation. CCl4 induced lipid peroxidation and hepatotoxicity were suppressed by administration of an α-adrenergic antagonist. We conclude that the SNS provides a permissive microenvironment for hepatic oxidative stress indicating the possibility that targeting the hepatic α-adrenergic signaling could be a viable strategy for improving outcomes in patients with acute hepatic injury.

  6. Sympathetic Nervous System Control of Carbon Tetrachloride-Induced Oxidative Stress in Liver through α-Adrenergic Signaling

    PubMed Central

    Lin, Jung-Chun; Peng, Yi-Jen; Wang, Shih-Yu; Young, Ton-Ho; Salter, Donald M.; Lee, Herng-Sheng

    2016-01-01

    In addition to being the primary organ involved in redox cycling, the liver is one of the most highly innervated tissues in mammals. The interaction between hepatocytes and sympathetic, parasympathetic, and peptidergic nerve fibers through a variety of neurotransmitters and signaling pathways is recognized as being important in the regulation of hepatocyte function, liver regeneration, and hepatic fibrosis. However, less is known regarding the role of the sympathetic nervous system (SNS) in modulating the hepatic response to oxidative stress. Our aim was to investigate the role of the SNS in healthy and oxidatively stressed liver parenchyma. Mice treated with 6-hydroxydopamine hydrobromide were used to realize chemical sympathectomy. Carbon tetrachloride (CCl4) injection was used to induce oxidative liver injury. Sympathectomized animals were protected from CCl4 induced hepatic lipid peroxidation-mediated cytotoxicity and genotoxicity as assessed by 4-hydroxy-2-nonenal levels, morphological features of cell damage, and DNA oxidative damage. Furthermore, sympathectomy modulated hepatic inflammatory response induced by CCl4-mediated lipid peroxidation. CCl4 induced lipid peroxidation and hepatotoxicity were suppressed by administration of an α-adrenergic antagonist. We conclude that the SNS provides a permissive microenvironment for hepatic oxidative stress indicating the possibility that targeting the hepatic α-adrenergic signaling could be a viable strategy for improving outcomes in patients with acute hepatic injury. PMID:26798417

  7. TNF-α dependent production of inducible nitric oxide is involved in PGE1 protection against acute liver injury

    PubMed Central

    Muntane, J; Rodriguez, F; Segado, O; Quintero, A; Lozano, J; Siendones, E; Pedraza, C; Delgado, M; O'Valle, F; Garcia, R; Montero, J; De la Mata, M; Mino, G

    2000-01-01

    BACKGROUND—Tumour necrosis factor α (TNF-α) and nitric oxide modulate damage in several experimental models of liver injury. We have previously shown that protection against D-galactosamine (D-GalN) induced liver injury by prostaglandin E1 (PGE1) was accompanied by an increase in TNF-α and nitrite/nitrate in serum.
AIMS—The aim of the present study was to evaluate the role of TNF-α and nitric oxide during protection by PGE1 of liver damage induced by D-GalN.
METHODS—Liver injury was induced in male Wistar rats by intraperitoneal injection of 1 g/kg of D-GalN. PGE1 was administered 30 minutes before D-GalN. Inducible nitric oxide synthase (iNOS) was inhibited by methylisothiourea (MT), and TNF-α concentration in serum was lowered by administration of anti-TNF-α antibodies. Liver injury was evaluated by alanine aminotransferase activity in serum, and histological examination and DNA fragmentation in liver. TNF-α and nitrite/nitrate concentrations were determined in serum. Expression of TNF-α and iNOS was also assessed in liver sections.
RESULTS—PGE1 decreased liver injury and increased TNF-α and nitrite/nitrate concentrations in serum of rats treated with D-GalN. PGE1 protection was related to enhanced expression of TNF-α and iNOS in hepatocytes. Administration of anti-TNF-α antibodies or MT blocked the protection by PGE1 of liver injury induced by D-GalN.
CONCLUSIONS—This study suggests that prior administration of PGE1 to D-GalN treated animals enhanced expression of TNF-α and iNOS in hepatocytes, and that this was causally related to protection by PGE1 against D-GalN induced liver injury.


Keywords: tumour necrosis factor α; nitric oxide; prostaglandin E1; methylisothiourea; D-galactosamine; liver injury PMID:10986217

  8. Maternal ethanol consumption during pregnancy enhances bile acid-induced oxidative stress and apoptosis in fetal rat liver.

    PubMed

    Perez, Maria J; Velasco, Elena; Monte, Maria J; Gonzalez-Buitrago, Jose M; Marin, Jose J G

    2006-08-15

    Ethanol is able to cross the placenta, which may cause teratogenicity. Here we investigated whether ethanol consumption during pregnancy (ECDP), even at doses unable to cause malformation, might increase the susceptibility of fetal rat liver to oxidative insults. Since cholestasis is a common condition in alcoholic liver disease and pregnancy, exposure to glycochenodeoxycholic acid (GCDCA) has been used here as the oxidative insult. The mothers received drinking water without or with ethanol from 4 weeks before mating until term, when placenta, maternal liver, and fetal liver were used. Ethanol induced a decreased GSH/GSSG ratio in these organs, together with enhanced gamma-glutamylcysteine synthetase and glutathione reductase activities in both placenta and fetal liver. Lipid peroxidation in placenta and fetal liver was enhanced by ethanol, although it had no effect on caspase-3 activity. Although the basal production of reactive oxygen species (ROS) was higher by fetal (FHs) than by maternal (AHs) hepatocytes in short-term cultures, the production of ROS in response to the presence of varying GCDCA concentrations was higher in AHs and was further increased by ECDP, which was associated to a more marked impairment in mitochondrial function. Moreover, GCDCA-induced apoptosis was increased by ECDP, as revealed by enhanced Bax-alpha/Bcl-2 ratio (both in AHs and FHs) and the activity of caspase-8 (only in AHs) and caspase-3. In sum, our results indicate that although AHs are more prone than FHs to producing ROS, at doses unable to cause maternal liver damage ethanol consumption causes oxidative stress and apoptosis in fetal liver.

  9. Aldehyde oxidase-catalysed oxidation of methotrexate in the liver of guinea-pig, rabbit and man.

    PubMed

    Jordan, C G; Rashidi, M R; Laljee, H; Clarke, S E; Brown, J E; Beedham, C

    1999-04-01

    Although 7-hydroxymethotrexate is a major metabolite of methotrexate during high-dose therapy, negligible methotrexate-oxidizing activity has been found in-vitro in the liver in man. The goals of this study were to determine the role of aldehyde oxidase in the metabolism of methotrexate to 7-hydroxymethotrexate in the liver and to study the effects of inhibitors and other substrates on the metabolism of methotrexate. Methotrexate, (+/-)-methotrexate and (-)-methotrexate were incubated with partially purified aldehyde oxidase from the liver of rabbit, guinea-pig and man and the products analysed by HPLC. Rabbit liver aldehyde oxidase was used for purposes of comparison. In-vitro aldehyde oxidase from the liver of man catalyses the oxidation of methotrexate to 7-hydroxymethotrexate, but the turnover is low. However, formation of 7-hydroxy-methotrexate from all forms of methotrexate by the liver in guinea-pig and man was significantly inhibited in the presence of 100 microM menadione and chlorpromazine, potent inhibitors of aldehyde oxidase. Allopurinol (100 microM) had a negligible inhibitory effect on liver aldehyde oxidase from guinea-pig and man. Allopurinol is a xanthine oxidase inhibitor. The production of 7-hydroxymethotrexate was enhanced in the presence of allopurinol. Although aldehyde oxidase is also responsible for some of this conversion, it is also possible that the closely related xanthine oxidase is responsible for the formation of 7-hydroxymethotrexate. By employing potent selective inhibitors of aldehyde oxidase, menadione and chlorpromazine, we have demonstrated for the first time that liver aldehyde oxidase from man is minimally involved in methotrexate oxidation.

  10. Salvianolic acid A preconditioning confers protection against concanavalin A-induced liver injury through SIRT1-mediated repression of p66shc in mice

    SciTech Connect

    Xu, Xiaomei; Hu, Yan; Zhai, Xiaohan; Lin, Musen; Chen, Zhao; Tian, Xiaofeng; Zhang, Feng; Gao, Dongyan; Ma, Xiaochi; Lv, Li; Yao, Jihong

    2013-11-15

    Salvianolic acid A (SalA) is a phenolic carboxylic acid derivative extracted from Salvia miltiorrhiza. It has many biological and pharmaceutical activities. The purpose of this study was to investigate the effect of SalA on concanavalin A (ConA)-induced acute hepatic injury in Kunming mice and to explore the role of SIRT1 in such an effect. The results showed that in vivo pretreatment with SalA significantly reduced ConA-induced elevation in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and decreased levels of the hepatotoxic cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Moreover, the SalA pretreatment ameliorated the increases in NF-κB and in cleaved caspase-3 caused by ConA exposure. Whereas, the pretreatment completely reversed expression of the B-cell lymphoma-extra large (Bcl-xL). More importantly, the SalA pretreatment significantly increased the expression of SIRT1, a NAD{sup +}-dependent deacetylase, which was known to attenuate acute hypoxia damage and metabolic liver diseases. In our study, the increase in SIRT1 was closely associated with down-regulation of the p66 isoform (p66shc) of growth factor adapter Shc at both protein and mRNA levels. In HepG2 cell culture, SalA pretreatment increased SIRT1 expression in a time and dose-dependent manner and such an increase was abrogated by siRNA knockdown of SIRT1. Additionally, inhibition of SIRT1 significantly reversed the decreased expression of p66shc, and attenuated SalA-induced p66shc down-regulation. Collectively, the present study indicated that SalA may be a potent activator of SIRT and that SalA can alleviate ConA-induced hepatitis through SIRT1-mediated repression of the p66shc pathway. - Highlights: • We report for the first time that SalA protects against ConA-induced hepatitis. • We find that SalA is a potential activator of SIRT1. • SalA's protection against hepatitis involves SIRT1-mediated repression of p66shc.

  11. Swimming Training Induces Liver Mitochondrial Adaptations to Oxidative Stress in Rats Submitted to Repeated Exhaustive Swimming Bouts

    PubMed Central

    Lima, Frederico D.; Stamm, Daniel N.; Della-Pace, Iuri D.; Dobrachinski, Fernando; de Carvalho, Nélson R.; Royes, Luiz Fernando F.; Soares, Félix A.; Rocha, João B.; González-Gallego, Javier; Bresciani, Guilherme

    2013-01-01

    Background and Aims Although acute exhaustive exercise is known to increase liver reactive oxygen species (ROS) production and aerobic training has shown to improve the antioxidant status in the liver, little is known about mitochondria adaptations to aerobic training. The main objective of this study was to investigate the effects of the aerobic training on oxidative stress markers and antioxidant defense in liver mitochondria both after training and in response to three repeated exhaustive swimming bouts. Methods Wistar rats were divided into training (n = 14) and control (n = 14) groups. Training group performed a 6-week swimming training protocol. Subsets of training (n = 7) and control (n = 7) rats performed 3 repeated exhaustive swimming bouts with 72 h rest in between. Oxidative stress biomarkers, antioxidant activity, and mitochondria functionality were assessed. Results Trained group showed increased reduced glutathione (GSH) content and reduced/oxidized (GSH/GSSG) ratio, higher superoxide dismutase (MnSOD) activity, and decreased lipid peroxidation in liver mitochondria. Aerobic training protected against exhaustive swimming ROS production herein characterized by decreased oxidative stress markers, higher antioxidant defenses, and increases in methyl-tetrazolium reduction and membrane potential. Trained group also presented higher time to exhaustion compared to control group. Conclusions Swimming training induced positive adaptations in liver mitochondria of rats. Increased antioxidant defense after training coped well with exercise-produced ROS and liver mitochondria were less affected by exhaustive exercise. Therefore, liver mitochondria also adapt to exercise-induced ROS and may play an important role in exercise performance. PMID:23405192

  12. Control of the effective P/O ratio of oxidative phosphorylation in liver mitochondria and hepatocytes.

    PubMed

    Brand, M D; Harper, M E; Taylor, H C

    1993-05-01

    The control exerted by substrate oxidation reactions, by ATP turnover and by the proton leak over the oxygen consumption rate, the phosphorylation rate, the proton leak rate and the protonmotive force (delta p) in isolated rat liver mitochondria under a range of conditions between non-phosphorylating (State 4) and maximum phosphorylation (State 3) was investigated by using the top-down approach of metabolic control analysis. The experiments were carried out with saturating concentrations of the substrates succinate, glutamate with malate, or pyruvate with malate. The distribution of control was very similar with each of the three substrates. The effective P/O ratio (i.e. not corrected for leak reactions) was also measured; it varied from zero in State 4 to 80-90% of the maximum theoretical P/O ratio in State 3. Under most conditions control over the effective P/O ratio was shared between proton leak (which had negative control) and the phosphorylating subsystem (which had roughly equal positive control); near State 4, substrate oxidation reactions also acquired some control over this ratio. In resting hepatocytes the effective P/O ratio was only 50% of its maximum theoretical value, corresponding to an effective P/O ratio of only 1.3 for complete oxidation of glucose. The effective P/O ratio for intracellular mitochondrial oxygen consumption was 64% of the maximum value. The control coefficient of the mitochondrial proton leak over the effective P/O ratio in cells was -0.34; the control coefficient of phosphorylation reactions over this ratio was 0.31 and the control coefficient of substrate oxidation reactions over the ratio was 0.03, showing how the coupling efficiency in cells can respond sensitively to agents that change the proton leak or the ATP demand, but not to those that change substrate oxidation.

  13. [Effect of ronggan mixture on immunoregulation and hepatocyte apoptosis-related factors in concanavalin A induced acute immunological liver injury mice].

    PubMed

    Zhang, Yin-qiang; Tang, Xu-dong; Wang, Feng-yun; Yang, Bin; Liu, Yan-ling; Guo, Peng; Wang, Ping; Bian, Li-qun; Zhao, Ying-pan

    2013-11-01

    To explore the effect of Ronggan Mixture (RM) on immunoregulation and hepatocyte apoptosis-related factors in concanavalin A (Con A) induced acute immunological liver injury mice. Totally 60 hepatitis B virus (HBV) transgenic mice were randomly divided into 6 groups, i.e., the blank control group, the model group, the RM group, the Herba Artemisiae Scopariae (HAS) group, the Yinchenhao Decoction (YD) group, and the Bifendate group, 10 mice in each group. The acute immunological liver injury model was established by tail vein injection of ConA. Fourteen days before modeling, normal saline was administered to mice in the blank control group and the model group. RM, YD, HAS decoction, and Bifendate solution was respectively given to mice in the RM group, the YD group, the HAS group, and the Bifendate group. The medication was performed once daily. One h after the last gastrogavage, phosphate buffer solution (PBS) was injected to mice in the blank control group from the tail vein. Modeling was conducted by injecting Con A at 3 microg/g body weight from the tail vein. Mice were sacrificed 8 h after modeling. Blood or tissue samples were collected to detect lab indicators such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), tumor necrosis factor alpha (TNF-alpha), interferon gamma (INF-gamma), IL-4, IL-10, Fas, FasL, Bax, and bcl-2. There was significant difference in all lab indicators between the normal group and the blank control group (P < 0.05, P < 0.01). Compared with the model group, ALT and AST levels were significantly lower in the RM group and the Bifendate group (P < 0.01); TBil significantly decreased in the RM group (P < 0.01). The expression level of TNF-alpha decreased in the RM group (P <0.05). The expression level of IFN-gamma decreased in the RM group and the YD group (P < 0.05). The expression level of IL-4 could be elevated in all medicated groups (P < 0.05). RM could elevate the expression level of IL-10

  14. Oxidatively damaged DNA and inflammation in the liver of dyslipidemic ApoE-/- mice exposed to diesel exhaust particles.

    PubMed

    Folkmann, Janne Kjaersgaard; Risom, Lotte; Hansen, Christian Stevns; Loft, Steffen; Møller, Peter

    2007-07-31

    Epidemiological studies have shown that exposure to air pollution particles is associated with cardiovascular diseases, whereas the role in the initiation of atherosclerosis is unresolved. Atherosclerosis is considered to be an inflammatory disease that also involves oxidative stress. Here we investigated effects of oxidative stress elicited by diesel exhaust particles (DEP) in the aorta, liver, and lung of dyslipidemic ApoE(-/-) mice at the age when visual plaques appear in the aorta (11-13 weeks). DEP was administrated by intraperitoneal injection (0, 50, 500 and 5,000 microg DEP/kg bodyweight) in order to omit vascular effects secondary to pulmonary inflammation. The mice were killed either 6 or 24h after the administration. Inflammation was measured as the expression of inducible nitric oxide synthase (iNOS) and serum nitric oxide and DNA damage was measured by the comet assay. The expression of iNOS mRNA was increased in the liver 6h after the administration. The level of oxidized purine bases, determined as formamidopyrimidine DNA glycosylase sites was increased by 67% (95% CI: 11-124%) in the liver after 24h in the mice administrated with only 50 microg/kg bodyweight. However, there was no indication of systemic inflammation determined as the serum concentration of nitric oxide and iNOS expression, and DNA damage was not increased in the aorta. These observations indicate that intraperitoneal DEP injection does not induce inflammation or oxidatively damaged DNA in the lung and aorta, whereas a direct effect in terms of inflammation and oxidized DNA was observed in the liver of dyslipidemic ApoE(-/-) mice.

  15. Connexin32 deficiency is associated with liver injury, inflammation and oxidative stress in experimental non-alcoholic steatohepatitis.

    PubMed

    Tiburcio, Taynã Cristina; Willebrords, Joost; da Silva, Tereza Cristina; Pereira, Isabel Veloso Alves; Nogueira, Marina Sayuri; Crespo Yanguas, Sara; Maes, Michaël; Silva, Elisangela Dos Anjos; Dagli, Maria Lucia Zaidan; de Castro, Inar Alves; Oliveira, Cláudia Pinto; Vinken, Mathieu; Cogliati, Bruno

    2017-02-01

    Non-alcoholic steatohepatitis is a highly prevalent liver pathology featured by hepatocellular fat deposition and inflammation. Connexin32, which is the major building block of hepatocellular gap junctions, has a protective role in hepatocarcinogenesis and is downregulated in chronic liver diseases. However, the role of connexin32 in non-alcoholic steatohepatitis remains unclear. Connexin32(-/-) mice and their wild-type littermates were fed a choline-deficient high-fat diet. The manifestation of non-alcoholic steatohepatitis was evaluated based on a battery of clinically relevant read-outs, including histopathological examination, diverse indicators of inflammation and liver damage, in-depth lipid analysis, assessment of oxidative stress, insulin and glucose tolerance, liver regeneration and lipid-related biomarkers. Overall, more pronounced liver damage, inflammation and oxidative stress were observed in connexin32(-/-) mice compared to wild-type animals. No differences were found in insulin and glucose tolerance measurements and liver regeneration. However, two lipid-related genes, srebf1 and fabp3, were upregulated in Cx32(-/-) mice in comparison with wild-type animals. These findings suggest that connexin32-based signalling is not directly involved in steatosis as such, but rather in the sequelae of this process, which underlie progression of non-alcoholic steatohepatitis.

  16. Energetic, oxidative and ionic exchange in rat brain and liver mitochondria at experimental audiogenic epilepsy (Krushinsky-Molodkina model).

    PubMed

    Venediktova, Natalya I; Gorbacheva, Olga S; Belosludtseva, Natalia V; Fedotova, Irina B; Surina, Natalia M; Poletaeva, Inga I; Kolomytkin, Oleg V; Mironova, Galina D

    2017-01-09

    The role of brain and liver mitochondria at epileptic seizure was studied on Krushinsky-Molodkina (KM) rats which respond to sound with an intensive epileptic seizure (audiogenic epilepsy). We didn't find significant changes in respiration rats of brain and liver mitochondria of KM and control rats; however the efficiency of АТР synthesis in the KM rat mitochondria was 10% lower. In rats with audiogenic epilepsy the concentration of oxidative stress marker malondialdehyde in mitochondria of the brain (but not liver) was 2-fold higher than that in the control rats. The rate of H2O2 generation in brain mitochondria of КМ rats was twofold higher than in the control animals when using NAD-dependent substrates. This difference was less pronounced in liver mitochondria. In KM rats, the activity of mitochondrial ATP-dependent potassium channel was lower than in liver mitochondria of control rats. The comparative study of the mitochondria ability to retain calcium ions revealed that in the case of using the complex I and complex II substrates, permeability transition pore is easier to trigger in brain and liver mitochondria of KM and КМs rats than in the control ones. The role of the changes in the energetic, oxidative, and ionic exchange in the mechanism of audiogenic epilepsy generation in rats and the possible correction of the epilepsy seizures are discussed.

  17. Protective effects of Spirulina maxima on hyperlipidemia and oxidative-stress induced by lead acetate in the liver and kidney.

    PubMed

    Ponce-Canchihuamán, Johny C; Pérez-Méndez, Oscar; Hernández-Muñoz, Rolando; Torres-Durán, Patricia V; Juárez-Oropeza, Marco A

    2010-03-31

    Oxidative damage has been proposed as a possible mechanism involved in lead toxicity, specially affecting the liver and kidney. Previous studies have shown the antioxidant effect of Spirulina maxima in several experimental models of oxidative stress. The current study was carried out to evaluate the antioxidant activity of Spirulina maxima against lead acetate-induced hyperlipidemia and oxidative damage in the liver and kidney of male rats. Control animals were fed on a standard diet and did not receive lead acetate (Control group). Experimental animals were fed on a standard laboratory diet with or without Spirulina maxima 5% in the standard laboratory diet and treated with three doses of lead acetate (25 mg each/weekly, intraperitoneal injection) (lead acetate with Spirulina, and lead acetate without Spirulina groups). The results showed that Spirulina maxima prevented the lead acetate-induced significant changes on plasma and liver lipid levels and on the antioxidant status of the liver and kidney. On the other hand, Spirulina maxima succeeded to improve the biochemical parameters of the liver and kidney towards the normal values of the Control group. It was concluded that Spirulina maxima has protective effects on lead acetate-induced damage, and that the effects are associated with the antioxidant effect of Spirulina.

  18. Protective effects of Spirulina maxima on hyperlipidemia and oxidative-stress induced by lead acetate in the liver and kidney

    PubMed Central

    2010-01-01

    Background Oxidative damage has been proposed as a possible mechanism involved in lead toxicity, specially affecting the liver and kidney. Previous studies have shown the antioxidant effect of Spirulina maxima in several experimental models of oxidative stress. The current study was carried out to evaluate the antioxidant activity of Spirulina maxima against lead acetate-induced hyperlipidemia and oxidative damage in the liver and kidney of male rats. Control animals were fed on a standard diet and did not receive lead acetate (Control group). Experimental animals were fed on a standard laboratory diet with or without Spirulina maxima 5% in the standard laboratory diet and treated with three doses of lead acetate (25 mg each/weekly, intraperitoneal injection) (lead acetate with Spirulina, and lead acetate without Spirulina groups). Results The results showed that Spirulina maxima prevented the lead acetate-induced significant changes on plasma and liver lipid levels and on the antioxidant status of the liver and kidney. On the other hand, Spirulina maxima succeeded to improve the biochemical parameters of the liver and kidney towards the normal values of the Control group. Conclusions It was concluded that Spirulina maxima has protective effects on lead acetate-induced damage, and that the effects are associated with the antioxidant effect of Spirulina. PMID:20353607

  19. Effects of carnosine, taurine, and betaine pretreatments on diethylnitrosamine-induced oxidative stress and tissue injury in rat liver.

    PubMed

    Başaran-Küçükgergin, C; Bingül, I; Tekkeşin, M Soluk; Olgaç, V; Doğru-Abbasoğlu, S; Uysal, M

    2016-08-01

    Several chemicals such as N-diethylnitrosamine (DEN) promote hepatocellular cancer in rodents and induce hepatocyte injury. DEN affects the initiation stage of carcinogenesis together with enhanced cell proliferation accompanied by hepatocellular necrosis. DEN-induced hepatocellular necrosis is reported to be related to enhanced generation of reactive oxygen species. Carnosine (CAR), taurine (TAU), and betaine (BET) are known to have powerful antioxidant properties. We aimed to investigate the effects of CAR, TAU, and BET pretreatments on DEN-induced oxidative stress and liver injury in male rats. Rats were given CAR (2 g L(-1) in drinking water), TAU (2.5% in chow), and BET (2.5% in chow) for 6 weeks and DEN (200 mg kg(-1) intraperitoneally) was given 2 days before the end of this period. Serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and γ-glutamyl transferase activities were determined and a histopathologic evaluation was performed on the liver tissue. Oxidative stress was detected in the liver by measuring malondialdehyde, diene conjugate, protein carbonyl and nitrotyrosine levels, glutathione and glutathione peroxidase levels, and superoxide dismutase and glutathione transferase activities. Pretreatments with CAR, TAU, and BET decreased liver prooxidant status without remarkable changes in antioxidant parameters in DEN-treated rats. Pretreatments with TAU and BET, but not CAR, were also found to be effective to reduce liver damage in DEN-treated rats. In conclusion, TAU, BET, and possibly CAR may have an ameliorating effect on DEN-induced hepatic injury by reducing oxidative stress in rats.

  20. Can garlic oil ameliorate diabetes-induced oxidative stress in a rat liver model? A correlated histological and biochemical study.

    PubMed

    Abdultawab, Hanem Saad; Ayuob, Nasra N

    2013-09-01

    This study aimed to characterise the structural changes in liver of an alloxan-induced diabetic rat and to explain such changes in terms of the biochemical changes in free radicals and antioxidants. In addition, it aimed to determine the potential ability of garlic oil to alter these changes. The study groups were: control (n=12), alloxan-induced diabetic rats (n=10) and alloxan-induced diabetic rats treated with garlic oil (10 mg/kg body weight (n=10)). Markers of oxidative stress were assessed. Small pieces of the liver were processed for transmission electron microscopic study. Garlic oil caused a significant decrease in levels of LPO in plasma (0.26 vs 0.53), erythrocyte lysate (14.4 vs 24.8) and liver tissue homogenate (1.04 vs 2.08), whereas those of thiols were significantly elevated (1.2 vs 0.46), (24 vs 15) in plasma and erythrocyte lysate respectively. SOD activity and G-S-T activity were significantly elevated in erythrocyte lysate (5.7 vs 3.3) (377 vs 179) and liver homogenate (1.4 vs 0.5) (752 vs 623) respectively after garlic oil administration. Ultrastructural study of the liver confirmed the ability of garlic to retard lipid peroxidation of cellular membranes induced by oxidative stress associated with diabetes. Therefore, garlic could normalise oxidative stress in alloxan-induced diabetic rats.

  1. Isorhamnetin attenuates liver fibrosis by inhibiting TGF-β/Smad signaling and relieving oxidative stress.

    PubMed

    Yang, Ji Hye; Kim, Sang Chan; Kim, Kyu Min; Jang, Chang Ho; Cho, Sam Seok; Kim, Seung Jung; Ku, Sae Kwang; Cho, Il Je; Ki, Sung Hwan

    2016-07-15

    Hepatic fibrosis is considered integral to the progression of chronic liver diseases, leading to the development of cirrhosis and hepatocellular carcinoma. Activation of hepatic stellate cells (HSCs) is the dominant event in hepatic fibrogenesis. We investigated the ability of isorhamnetin, the 3'-O-methylated metabolite of quercetin, to protect against hepatic fibrosis in vitro and in vivo. Isorhamnetin inhibited transforming growth factor (TGF)-β1-induced expression of α-smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), and collagen in primary murine HSCs and LX-2 cells. The TGF-β1- or Smad-induced luciferase reporter activity of Smad binding elements was significantly decreased by isorhamnetin with a concomitant decrease in Smad2/3 phosphorylation. Isorhamnetin increased the nuclear translocation of Nrf2 in HSCs and increased antioxidant response element reporter gene activity. Furthermore, isorhamnetin blocked TGF-β1-induced reactive oxygen species production. The specific role of Nrf2 in isorhamnetin-mediated suppression of PAI-1 and phosphorylated Smad3 was verified using a siRNA against Nrf2. To examine the anti-fibrotic effect of isorhamnetin in vivo, liver fibrosis was induced by CCl4 in mice. Isorhamnetin significantly prevented CCl4-induced increases in serum alanine transaminase and aspartate transaminase levels, and caused histopathological changes characterized by decreases in hepatic degeneration, inflammatory cell infiltration, and collagen accumulation. Moreover, isorhamnetin markedly decreased the expression of phosphorylated Smad3, TGF-β1, α-SMA, and PAI-1. Isorhamnetin attenuated the CCl4-induced increase in the number of 4-hydroxynonenal and nitrotyrosine-positive cells, and prevented glutathione depletion. We propose that isorhamnetin inhibits the TGF-β/Smad signaling pathway and relieves oxidative stress, thus inhibiting HSC activation and preventing liver fibrosis.

  2. Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants

    SciTech Connect

    Leone, Angelique; Nie, Alex; Brandon Parker, J.; Sawant, Sharmilee; Piechta, Leigh-Anne; Kelley, Michael F. Mark Kao, L.; Jim Proctor, S.; Verheyen, Geert; Johnson, Mark D.; Lord, Peter G.; McMillian, Michael K.

    2014-03-15

    Previously we reported a gene expression signature in rat liver for detecting a specific type of oxidative stress (OS) related to reactive metabolites (RM). High doses of the drugs disulfiram, ethinyl estradiol and nimesulide were used with another dozen paradigm OS/RM compounds, and three other drugs flutamide, phenacetin and sulindac were identified by this signature. In a second study, antiepileptic drugs were compared for covalent binding and their effects on OS/RM; felbamate, carbamazepine, and phenobarbital produced robust OS/RM gene expression. In the present study, liver RNA samples from drug-treated rats from more recent experiments were examined for statistical fit to the OS/RM signature. Of all 97 drugs examined, in addition to the nine drugs noted above, 19 more were identified as OS/RM-producing compounds—chlorpromazine, clozapine, cyproterone acetate, dantrolene, dipyridamole, glibenclamide, isoniazid, ketoconazole, methapyrilene, naltrexone, nifedipine, sulfamethoxazole, tamoxifen, coumarin, ritonavir, amitriptyline, valproic acid, enalapril, and chloramphenicol. Importantly, all of the OS/RM drugs listed above have been linked to idiosyncratic hepatotoxicity, excepting chloramphenicol, which does not have a package label for hepatotoxicity, but does have a black box warning for idiosyncratic bone marrow suppression. Most of these drugs are not acutely toxic in the rat. The OS/RM signature should be useful to avoid idiosyncratic hepatotoxicity of drug candidates. - Highlights: • 28 of 97 drugs gave a positive OS/RM gene expression signature in rat liver. • The specificity of the signature for human idiosyncratic hepatotoxicants was 98%. • The sensitivity of the signature for human idiosyncratic hepatotoxicants was 75%. • The signature can help eliminate hepatotoxicants from drug development.

  3. Effects of Obesity on Pro-Oxidative Conditions and DNA Damage in Liver of DMBA-Induced Mammary Carcinogenesis Models.

    PubMed

    Melnyk, Stepan; Korourian, Soheila; Levy, Joseph W; Pavliv, Oleksandra; Evans, Teresa; Hakkak, Reza

    2017-06-08

    The prevalence of the overweight and obesity is on the rise worldwide. Obesity can increase the risk of certain cancers and liver steatosis development. Previously, we reported that obesity increased liver steatosis in a mammary tumor model, but little is known about the effects of obesity in the liver in regard to global DNA methylation, DNA damage, and oxidative/nitrosative stress. Using a mammary tumor model, we investigated the effects of obesity on oxidative stress and DNA reaction. Five-week-old lean and obese female rats were used. At 50 days of age, all rats received 7,12-dimethylbenz(α)anthracene (DMBA) and were sacrificed 155 days later. HPLC with electrochemical and ultraviolet detection and LC-MS were used. Obesity caused higher (p < 0.0004) methionine levels, had no effect (p < 0.055) on SAM levels, caused lower (p < 0.0005) SAH levels, caused higher (p < 0.0005) SAM/SAH ratios, and increased (p < 0.02) global DNA methylation. Levels of free reduced GSH were not significantly lower (p < 0.08), but free oxidized GSSG was higher (p < 0.002) in obese rats. The GSH/GSSG ratio was lower (p < 0.0001), and oxidized guanosine was higher (p < 0.002) in DNA of obese rats compared to lean rats. Obesity caused significant oxidative/nitrosative stress, oxidative DNA damage, and change of DNA methylation pattern in the liver, and these changes may contribute to the development of liver steatosis in breast cancer models.

  4. [Interrupted alcohol treatment and liver: free radical homeostasis, nitric oxide, adaptive mechanisms].

    PubMed

    Miskevich, D A; Borodinskiĭ, A N; Petushok, N E; Konovalenko, O V; Lelevich, V V

    2006-01-01

    Alcohol administration can result in liver damage. Reactive oxygen species (ROS), nitric oxide (NO) and their interaction are crucial factors in this process. The aim of work was to investigate, free radical state and mechanisms of adaptation of the antioxidant system (AOS) to stress, caused by interrupted alcohol intake. Repeated cycles of alcoholization caused an imbalance between production and utilization of various ROS. This imbalance was due to impairments in the system superoxide dismutase/catalase. Nevertheless, in most experimental groups there was clear reduction of lipid peroxidation (LPO) products evaluated by thiobarbituric acid reactive substances. This might be attributed to the antioxidant effect of NO. However, there was an increased level of transaminases in blood plasma. After 28 days of this experimental scheme all the parameters studied normalized.

  5. Liver oxidation and inflammation in Fa/Fa rats fed glucomannan/spirulina-surimi.

    PubMed

    Vázquez-Velasco, Miguel; González-Torres, Laura; López-Gasco, Patricia; Bastida, Sara; Benedí, Juana; Sánchez-Reus, María Isabel; González-Muñoz, María José; Sánchez-Muniz, Francisco J

    2014-09-15

    The effect of high-fat squid-surimi diets enriched in glucomannan or glucomannan-spirulina on lipemia, liver glutathione status, antioxidant enzymes and inflammation biomarkers was determined in Zucker Fa/Fa rats. Groups of eight rats each received for 7weeks the squid-surimi control (C), glucomannan-enriched squid-surimi (G) and glucomannan-spirulina enriched squid-surimi (GS). Liver weight, cytochrome P450 7A1 expression and cholesterolemia were decreased in G and GS vs. C, improving glutathione red-ox index (p<0.05). G also showed increased glutathione reductase (GR) levels vs. C, but reduced the endothelial (eNOS) and increased the inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α) levels (p<0.05). The GS diet improved superoxide dismutase, catalase, glutathione peroxidase and GR activities and eNOS, iNOS and TNF-α levels (p<0.05). The glucomannan enriched surimi-diet induced hypocholesterolemic, antioxidant and proinflammatory effects, while the addition of 3g/kg spirulina kept those hypocholesterolemic and antioxidant effects but reduced the inflammation observed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Role of nitric oxide in liver transplantation: Should it be routinely used?

    PubMed Central

    Fukazawa, Kyota; Lang, John D

    2016-01-01

    Ischemia-reperfusion injury (IRI) continues to be a major contributor to graft dysfunction, thus supporting the need for therapeutic strategies focused on minimizing organ damage especially with growing numbers of extended criteria grafts being utilized which are more vulnerable to cold and warm ischemia. Nitric oxide (NO·) is highly reactive gaseous molecule found in air and regarded as a pollutant. Not surprising, it is extremely bioactive, and has been demonstrated to play major roles in vascular homeostasis, neurotransmission, and host defense inflammatory reactions. Under conditions of ischemia, NO· has consistently been demonstrated to enhance microcirculatory vasorelaxation and mitigate pro-inflammatory responses, making it an excellent strategy for patients undergoing organ transplantation. Clinical studies designed to test this hypothesis have yielded very promising results that includes reduced hepatocellular injury and enhanced graft recovery without any identifiable complications. By what means NO· facilitates extra-pulmonary actions is up for debate and speculation. The general premise is that they are NO· containing intermediates in the circulation, that ultimately mediate either direct or indirect effects. A plethora of data exists explaining how NO·-containing intermediate molecules form in the plasma as S-nitrosothiols (e.g., S-nitrosoalbumin), whereas other compelling data suggest nitrite to be a protective mediator. In this article, we discuss the use of inhaled NO· as a way to protect the donor liver graft against IRI in patients undergoing liver transplantation. PMID:28008339

  7. Caffeine protects against alcoholic liver injury by attenuating inflammatory response and oxidative stress.

    PubMed

    Lv, Xiongwen; Chen, Zhen; Li, Jun; Zhang, Lei; Liu, Hongfeng; Huang, Cheng; Zhu, Pengli

    2010-08-01

    The present investigation was designed to determine the effects of caffeine on alcohol-induced hepatic injury in mice. Five groups of mice (8 each) were used. The mice treated with different doses of caffeine (5, 10, and 20 mg/kg, respectively). The degree of alcoholic liver injury was evaluated biochemically by measuring serum markers and pathological examination. Real time PCR and ELISA methods were used to check the expression of cytokines and CYP 450. Treatment with caffeine significantly attenuated the elevated serum aminotransferase enzymes and reduced the severe extent of hepatic cell damage, steatosis and the immigration of inflammatory cells. Interestingly, caffeine decreased hepatic mRNA expression of lipogenic genes, while it had no effect on protein expression of hepatic CYP2E1. Furthermore, caffeine decreased serum and tissue inflammatory cytokines levels, tissue lipid peroxidation and inhibited the necrosis of hepatocytes. Kupffer cells isolated from ethanol-fed mice produced high amounts of reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-alpha), whereas Kupffer cells from caffeine treatment mice produced less ROS and TNF-alpha. These findings suggest that caffeine may represent a novel, protective strategy against alcoholic liver injury by attenuating oxidative stress and inflammatory response.

  8. Nitric Oxide and Redox Regulation in the Liver: Part I General Considerations and Redox biology in Hepatitis

    PubMed Central

    Diesen, Diana L.; Kuo, Paul C.

    2010-01-01

    Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are created in normal hepatocytes and are critical for normal physiological processes including oxidative respiration, growth, regeneration, apoptosis, and microsomal defense. When the levels of oxidation products exceed the capacity of normal antioxidant systems, oxidative stress occurs. This type of stress, in the form of ROS and RNS, can be damaging to all liver cells, including hepatocytes, Kupffer cells, stellate cells, and endothelial cells, through induction of inflammation, ischemia, fibrosis, necrosis, apoptosis, or through malignant transformation by damaging lipids, proteins, and/or DNA. In part I of this review, we will discuss basic redox biology in the liver, including a review of ROS, RNS, and antioxidants, with a focus on nitric oxide as a common source of RNS. We will then review the evidence for oxidative stress as a mechanism of liver injury in hepatitis (alcoholic, viral, non-alcoholic). In part II of this review, we will review oxidative stress in common pathophysiological conditions including ischemia/reperfusion injury, fibrosis, hepatocellular carcinoma, iron overload, Wilson's disease, sepsis and acetaminophen overdose. Finally, biomarkers, proteomic, and antioxidant therapies will be discussed as areas for future therapeutic interventions. PMID:20444470

  9. Protective effects of zinc on oxidative stress enzymes in liver of protein-deficient rats.

    PubMed

    Sidhu, Pardeep; Garg, M L; Dhawan, D K

    2005-01-01

    Persons afflicted with protein malnutrition are generally deficient in a variety of essential micronutrients like zinc, copper, iron, and selenium, which in turn affects number of metabolic processes in the body. To evaluate the protective effects of zinc on the enzymes involved in oxidative stress induced in liver of protein-deficient rats, the current study was designed. Zinc sulfate at a dose level of 227 mg/L zinc in drinking water was administered to female Sprague-Dawley normal control as well as protein-deficient rats for a total duration of 8 weeks. The effects of zinc treatment in conditions of protein deficiency were studied on rat liver antioxidant enzymes, which included catalase, glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), glutathione reduced (GSH), and glutathione-S-transferase (GST). Protein deficiency in normal rats resulted in a significant increase in hepatic activities of catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase and the levels of lipid peroxidation. A significant inhibition in the levels of reduced glutathione and the enzyme activity of superoxide dismutase has been observed after protein deficiency in normal rats. Interestingly, Zn treatment to protein-deficient animals lowered already raised activity catalase, glutathione peroxidase, and glutathione-S-transferase and levels of lipid peroxidation to significant levels when compared to protein-deficient animals. Also, Zn treatment to the protein-deficient animals resulted in a significant elevation in the levels of GSH and SOD activity as compared to their respective controls, thereby indicating its effectiveness in regulating their levels in adverse conditions. It has also been observed that concentrations of zinc, copper, iron, and selenium were found to be decreased significantly in protein-deficient animals. However, the levels of these elements came back to within normal limits when zinc was administrated

  10. Gossypetin ameliorates ionizing radiation-induced oxidative stress in mice liver--a molecular approach.

    PubMed

    Khan, Amitava; Manna, Krishnendu; Das, Dipesh Kr; Kesh, Swaraj Bandhu; Sinha, Mahuya; Das, Ujjal; Biswas, Sushobhan; Sengupta, Aaveri; Sikder, Kunal; Datta, Sanjukta; Ghosh, Mahua; Chakrabarty, Anindita; Banerji, Asoke; Dey, Sanjit

    2015-10-01

    Radioprotective action of gossypetin (GTIN) against gamma (γ)-radiation-induced oxidative stress in liver was explored in the present article. Our main aim was to evaluate the protective efficacy of GTIN against radiation-induced alteration of liver in murine system. To evaluate the effect of GTIN, it was orally administered to mice at a dose of 30 mg/kg body weight for three consecutive days prior to γ-radiation at a dose of 5 Gy. Radioprotective efficacy of GTIN were evaluated at physiological, cellular, and molecular level using biochemical analysis, comet assay, flow cytometry, histopathology, immunofluorescence, and immunoblotting techniques. Ionizing radiation was responsible for augmentation of hepatic oxidative stress in terms of lipid peroxidation and depletion of endogenous antioxidant enzymes. Immunoblotting and immunofluorescence studies showed that irradiation enhanced the nuclear translocation of nuclear factor kappa B (NF-κB) level, which leads to hepatic inflammation. To investigate further, we found that radiation induced the activation of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK)-mediated apoptotic pathway and deactivation of the NF-E2-related factor 2 (Nrf2)-mediated redox signaling pathway, whereas GTIN pretreatment ameliorated these radiation-mediated effects. This is the novel report where GTIN rationally validated the molecular mechanism in terms of the modulation of cellular signaling system' instead of ' This is the novel report where GTIN is rationally validated in molecular terms to establish it as promising radioprotective agents. This might be fruitful especially for nuclear workers and defense personnel assuming the possibility of radiation exposure.

  11. Cadmium Chloride Induces DNA Damage and Apoptosis of Human Liver Carcinoma Cells via Oxidative Stress.

    PubMed

    Skipper, Anthony; Sims, Jennifer N; Yedjou, Clement G; Tchounwou, Paul B

    2016-01-02

    Cadmium is a heavy metal that has been shown to cause its toxicity in humans and animals. Many documented studies have shown that cadmium produces various genotoxic effects such as DNA damage and chromosomal aberrations. Ailments such as bone disease, renal damage, and several forms of cancer are attributed to overexposure to cadmium. Although there have been numerous studies examining the effects of cadmium in animal models and a few case studies involving communities where cadmium contamination has occurred, its molecular mechanisms of action are not fully elucidated. In this research, we hypothesized that oxidative stress plays a key role in cadmium chloride-induced toxicity, DNA damage, and apoptosis of human liver carcinoma (HepG₂) cells. To test our hypothesis, cell viability was determined by MTT assay. Lipid hydroperoxide content stress was estimated by lipid peroxidation assay. Genotoxic damage was tested by the means of alkaline single cell gel electrophoresis (Comet) assay. Cell apoptosis was measured by flow cytometry assessment (Annexin-V/PI assay). The result of MTT assay indicated that cadmium chloride induces toxicity to HepG₂ cells in a concentration-dependent manner, showing a 48 hr-LD50 of 3.6 µg/mL. Data generated from lipid peroxidation assay resulted in a significant (p < 0.05) increase of hydroperoxide production, specifically at the highest concentration tested. Data obtained from the Comet assay indicated that cadmium chloride causes DNA damage in HepG₂ cells in a concentration-dependent manner. A strong concentration-response relationship (p < 0.05) was recorded between annexin V positive cells and cadmium chloride exposure. In summary, these in vitro studies provide clear evidence that cadmium chloride induces oxidative stress, DNA damage, and programmed cell death in human liver carcinoma (HepG₂) cells.

  12. Cranberry (Vaccinium macrocarpon) extract treatment improves triglyceridemia, liver cholesterol, liver steatosis, oxidative damage and corticosteronemia in rats rendered obese by high fat diet.

    PubMed

    Peixoto, Thamara C; Moura, Egberto G; de Oliveira, Elaine; Soares, Patrícia N; Guarda, Deysla S; Bernardino, Dayse N; Ai, Xu Xue; Rodrigues, Vanessa da S T; de Souza, Gabriela Rodrigues; da Silva, Antonio Jorge Ribeiro; Figueiredo, Mariana S; Manhães, Alex C; Lisboa, Patrícia C

    2017-05-13

    Obese individuals have higher production of reactive oxygen species, which leads to oxidative damage. We hypothesize that cranberry extract (CE) can improve this dysfunction in HFD-induced obesity in rats since it has an important antioxidant activity. Here, we evaluated the effects of CE in food intake, adiposity, biochemical and hormonal parameters, lipogenic and adipogenic factors, hepatic morphology and oxidative balance in a HFD model. At postnatal day 120 (PN120), male Wistar rats were assigned into two groups: (1) SD (n = 36) fed with a standard diet and (2) HFD (n = 36), fed with a diet containing 44.5% (35.2% from lard) energy from fat. At PN150, 12 animals from SD and HFD groups were killed while the others were subdivided into four groups (n = 12/group): animals that received 200 mg/kg cranberry extract (SD CE, HFD CE) gavage/daily/30 days or water (SD, HFD). At PN180, animals were killed. HFD group showed higher body mass and visceral fat, hypercorticosteronemia, higher liver glucocorticoid sensitivity, cholesterol and triglyceride contents and microsteatosis. Also, HFD group had higher lipid peroxidation (plasma and tissues) and higher protein carbonylation (liver and adipose tissue) compared to SD group. HFD CE group showed lower body mass gain, hypotrygliceridemia, hypocorticosteronemia, and lower hepatic cholesterol and fatty acid synthase contents. HFD CE group displayed lower lipid peroxidation, protein carbonylation (liver and adipose tissue) and accumulation of liver fat compared to HFD group. Although adiposity was not completely reversed, cranberry extract improved the metabolic profile and reduced oxidative damage and steatosis in HFD-fed rats, which suggests that it can help manage obesity-related disorders.

  13. OXPHOS-Mediated Induction of NAD+ Promotes Complete Oxidation of Fatty Acids and Interdicts Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Nam, Minwoo; Lei, Shi; Cooper, Marcus P.

    2015-01-01

    OXPHOS is believed to play an important role in non-alcoholic fatty liver disease (NAFLD), however, precise mechanisms whereby OXPHOS influences lipid homeostasis are incompletely understood. We previously reported that ectopic expression of LRPPRC, a protein that increases cristae density and OXPHOS, promoted fatty acid oxidation in cultured primary hepatocytes. To determine the biological significance of that observation and define underlying mechanisms, we have ectopically expressed LRPPRC in mouse liver in the setting of NAFLD. Interestingly, ectopic expression of LRPPRC in mouse liver completely interdicted NAFLD, including inflammation. Consistent with mitigation of NAFLD, two markers of hepatic insulin resistance—ROS and PKCε activity—were both modestly reduced. As reported by others, improvement of NAFLD was associated with improved whole-body insulin sensitivity. Regarding hepatic lipid homeostasis, the ratio of NAD+ to NADH was dramatically increased in mouse liver replete with LRPPRC. Pharmacological activators and inhibitors of the cellular respiration respectively increased and decreased the [NAD+]/[NADH] ratio, indicating respiration-mediated control of the [NAD+]/[NADH] ratio. Supporting a prominent role for NAD+, increasing the concentration of NAD+ stimulated complete oxidation of fatty acids. Importantly, NAD+ rescued impaired fatty acid oxidation in hepatocytes deficient for either OXPHOS or SIRT3. These data are consistent with a model whereby augmented hepatic OXPHOS increases NAD+, which in turn promotes complete oxidation of fatty acids and protects against NAFLD. PMID:25933096

  14. Swimming training induces liver adaptations to oxidative stress and insulin sensitivity in rats submitted to high-fat diet.

    PubMed

    Zacarias, Aline Cruz; Barbosa, Maria Andrea; Guerra-Sá, Renata; De Castro, Uberdan Guilherme Mendes; Bezerra, Frank Silva; de Lima, Wanderson Geraldo; Cardoso, Leonardo M; Santos, Robson Augusto Souza Dos; Campagnole-Santos, Maria José; Alzamora, Andréia Carvalho

    2017-11-01

    Oxidative stress, physical inactivity and high-fat (FAT) diets are associated with hepatic disorders such as metabolic syndrome (MS). The therapeutic effects of physical training (PT) were evaluated in rats with MS induced by FAT diet for 13 weeks, on oxidative stress and insulin signaling in the liver, during the last 6 weeks. FAT-sedentary (SED) rats increased body mass, retroperitoneal fat, mean arterial pressure (MAP) and heart rate (HR), and total cholesterol, serum alanine aminotransferase, glucose and insulin. Livers of FAT-SED rats increased superoxide dismutase activity, thiobarbituric acid-reactive substances, protein carbonyl and oxidized glutathione (GSSG); and decreased catalase activity, reduced glutathione/GSSG ratio, and the mRNA expression of insulin receptor substrate 1 (IRS-1) and serine/threonine kinase 2. FAT-PT rats improved in fitness and reduced their body mass, retroperitoneal fat, and glucose, insulin, total cholesterol, MAP and HR; and their livers increased superoxide dismutase and catalase activities, the reduced glutathione/GSSG ratio and the expression of peroxisome proliferator-activated receptor gamma and insulin receptor compared to FAT-SED rats. These findings indicated adaptive responses to PT by restoring the oxidative balance and insulin signaling in the liver and certain biometric and biochemical parameters as well as MAP in MS rats.

  15. Ion Channels and Oxidative Stress as a Potential Link for the Diagnosis or Treatment of Liver Diseases

    PubMed Central

    Ramírez, Ana; Vázquez-Sánchez, Alma Yolanda; Carrión-Robalino, Natalia; Camacho, Javier

    2016-01-01

    Oxidative stress results from a disturbed balance between oxidation and antioxidant systems. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) may be either harmful or beneficial to the cells. Ion channels are transmembrane proteins that participate in a large variety of cellular functions and have been implicated in the development of a variety of diseases. A significant amount of the available drugs in the market targets ion channels. These proteins have sulfhydryl groups of cysteine and methionine residues in their structure that can be targeted by ROS and RNS altering channel function including gating and conducting properties, as well as the corresponding signaling pathways associated. The regulation of ion channels by ROS has been suggested to be associated with some pathological conditions including liver diseases. This review focuses on understanding the role and the potential association of ion channels and oxidative stress in liver diseases including fibrosis, alcoholic liver disease, and cancer. The potential association between ion channels and oxidative stress conditions could be used to develop new treatments for major liver diseases. PMID:26881024

  16. Ion Channels and Oxidative Stress as a Potential Link for the Diagnosis or Treatment of Liver Diseases.

    PubMed

    Ramírez, Ana; Vázquez-Sánchez, Alma Yolanda; Carrión-Robalino, Natalia; Camacho, Javier

    2016-01-01

    Oxidative stress results from a disturbed balance between oxidation and antioxidant systems. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) may be either harmful or beneficial to the cells. Ion channels are transmembrane proteins that participate in a large variety of cellular functions and have been implicated in the development of a variety of diseases. A significant amount of the available drugs in the market targets ion channels. These proteins have sulfhydryl groups of cysteine and methionine residues in their structure that can be targeted by ROS and RNS altering channel function including gating and conducting properties, as well as the corresponding signaling pathways associated. The regulation of ion channels by ROS has been suggested to be associated with some pathological conditions including liver diseases. This review focuses on understanding the role and the potential association of ion channels and oxidative stress in liver diseases including fibrosis, alcoholic liver disease, and cancer. The potential association between ion channels and oxidative stress conditions could be used to develop new treatments for major liver diseases.

  17. Effects of Propofol on the Liver Oxidative-Antioxidant Balance in a Rat Model of Parkinson's Disease.

    PubMed

    Romuk, Ewa B; Szczurek, Wioletta; Nowak, Przemysław G; Hudziec, Edyta; Chwalińska, Ewa; Birkner, Ewa

    2016-01-01

    Parkinson's disease is caused by the destruction of dopaminergic neurons in the substantia nigra of the midbrain. One of the possible factors involved in the pathogenesis of Parkinson's disease is impaired oxidativeantioxidative balance. The present study aimed to evaluate selected parameters of the liver oxidative-antioxidative system in a Wistar rat model with Parkinson's disease treated with propofol. Experiments were performed on 32 rats divided into 4 groups: 1 - control, 2 - Parkinson's disease, 3 - control with propofol, 4 - Parkinson's disease with propofol. The rats were decapitated at 8 weeks of age and their livers were collected. In the liver, the activities of catalase (CAT), glutathione peroxidase (GPx), glutathione transferase (GST), glutathione reductase (GR) and the concentrations of: Malondialdehyde (MDA), total antioxidant capacity (TAC), total oxidant status (TOS) were assessed. The study demonstrated a decrease in CAT activity and an increase in MDA, TOS concentrations in group 2 compared to that of group 1. Administration of propofol in rats of group 4 caused an increase in CAT activity and a decrease in MDA concentration compared to that of group 2 and an increase in TAC, CAT, GR levels, decrease in MDA levels compared to that of group 1. There was also an increase in GR and TAC in group 3 compared to that of group 1. Propofol in Parkinson's disease stimulates the production of antioxidant enzymes in the liver, simultaneously decreasing oxidative stress, which has a beneficial effect on the oxidative-antioxidative balance.

  18. Studies on essential fatty acid deficiency. Effect of the deficiency on the lipids in liver mitochondria and oxidative phosphorylation

    PubMed Central

    Biran, L. A.; Bartley, W.; Carter, C. W.; Renshaw, A.

    1965-01-01

    1. Dietary deficiency of essential fatty acids results in a twofold increase in the neutral lipid content of liver mitochondria as compared with the corresponding value for stock-fed rats. 2. Deficiency produces changes in the pattern of the constituent fatty acids of the main phospholipid fractions of liver mitochondria which are similar to those previously reported for the lipids of whole liver. There is a fall in the content of C18:2 acid and to a smaller extent of C20:4 acid associated with a rise of C16:1, C18:1 and C20:3 acids. 3. Deficiency results in small decreases in the phosphorylation quotients of liver mitochondria during oxidation of succinate and pyruvate, but the values lie within the range reported for normal mitochondria. Mitochondrial respiration with succinate is decreased as a result of deficiency but no change was observed with pyruvate as substrate. PMID:14342237

  19. Zn(II)-curcumin protects against hemorheological alterations, oxidative stress and liver injury in a rat model of acute alcoholism.

    PubMed

    Yu, Chuan; Mei, Xue-Ting; Zheng, Yan-Ping; Xu, Dong-Hui

    2014-03-01

    Curcumin can chelate metal ions, forming metallocomplexes. We compared the effects of Zn(II)-curcumin with curcumin against hemorheological alterations, oxidative stress and liver injury in a rat model of acute alcoholism. Oral administration of Zn(II)-curcumin dose-dependently prevented the ethanol-induced elevation of serum malondialdehyde (MDA) content and reductions in glutathione level and superoxide dismutase (SOD) activity. Zn(II)-curcumin also inhibited ethanol-induced liver injury. Additionally, Zn(II)-curcumin dose-dependently inhibited hemorheological abnormalities, including the ethanol-induced elevation of whole blood viscosity, plasma viscosity, blood viscosity at corrected hematocrit (45%), erythrocyte aggregation index, erythrocyte rigidity index and hematocrit. Compared to curcumin at the same dose, Zn(II)-curcumin more effectively elevated SOD activity, ameliorated liver injury and improved hemorheological variables. These results suggest that Zn(II)-curcumin protected the rats from ethanol-induced liver injury and hemorheological abnormalities via the synergistic effect of curcumin and zinc.

  20. Effects of green tea on iron accumulation and oxidative stress in livers of iron-challenged thalassemic mice.

    PubMed

    Saewong, T; Ounjaijean, S; Mundee, Y; Pattanapanyasat, K; Fucharoen, S; Porter, J B; Srichairatanakool, S

    2010-03-01

    Liver is affected by secondary iron overload in transfusions dependent b-thalassemia patients. The redox iron can generate reactive oxidants that damage biomolecules, leading to liver fibrosis and cirrhosis. Iron chelators are used to treat thalassemias to achieve negative iron balance and relieve oxidant-induced organ dysfunctions. Green tea (GT) (Camellia sinensis) catechins exhibit anti-oxidation, the inhibition of carcinogenesis, the detoxification of CYP2E1-catalyzed HepG2 cells and iron chelation. The purpose of this study was to investigate the effectiveness of GT in iron-challenged thalassemic mice. Heterozygous BKO type-thalassemia (BKO) mice (C57BL/6) experienced induced iron overload by being fed a ferrocene-supplemented diet (Fe diet) for 8 weeks, and by orally being given GT extract (300 mg/kg) and deferiprone (DFP) (50 mg/kg) for a further 8 weeks. Liver iron content (LIC) was analyzed by TPTZ colorimetric and Perl's staining techniques. Concentrations of liver reduced glutathione (GSH), collagen and malondialdehyde (MDA) were also measured. Dosages of the GT extract and DFP lowered LIC in the Fe diet-fed BKO mice effectively. The extract did not change any concentrations of liver glutathione, collagen and MDA in the BKO mice. Histochemical examination showed leukocyte infiltration in the near by hepatic portal vein and high iron accumulation in the livers of the iron-loaded BKO mice, however GT treatment lowered the elevated iron deposition. In conclusion, green tea inhibits or delays the deposition of hepatic iron in regularly iron-loaded thalassemic mice effectively. This will prevent the iron-induced generation of free radicals via Haber-Weiss and Fenton reactions, and consequently liver damage and fibrosis. Combined chelation with green tea would be investigated in beta-thalassemia patients with iron overload.

  1. Impaired sulfur-amino acid metabolism and oxidative stress in nonalcoholic fatty liver are alleviated by betaine supplementation in rats.

    PubMed

    Kwon, Do Y; Jung, Young S; Kim, Sun J; Park, Hee K; Park, Jae H; Kim, Young C

    2009-01-01

    Nonalcoholic fatty liver is involved in the development of nonalcoholic steatohepatitis and chronic liver injury. Impairment of hepatic transsulfuration reactions is suggested to be critically linked with alcoholic liver injury, but its role in nonalcoholic fatty liver remains unknown. We examined the early changes in sulfur-amino acid metabolism and their implication in nonalcoholic fatty liver disease (NAFLD). Male rats were provided with a standard liquid diet or a high-fat liquid diet (HF) for 3 wk. An additional group of rats received the HF diet supplemented with betaine (1%). HF diet intake elevated hepatic triglyceride and serum tumor necrosis factor-alpha (TNFalpha) concentrations. Antioxidant capacity of liver cytosol against hydroxyl and peroxyl radicals was reduced significantly. Hepatic S-adenosylmethionine (SAM) and glutathione (GSH) decreased, but hypotaurine and taurine concentrations increased. Methionine adenosyltransferase (MAT) activity, not its concentration, was depressed, whereas both activity and concentration of cysteine dioxygenase and GSH S-transferase were elevated. Betaine supplementation of the HF diet inhibited hepatic fat accumulation and serum TNFalpha elevation. The decrease in cytosolic antioxidant capacity was also prevented. MAT activity and its concentration were induced significantly. Hepatic SAM and GSH increased and elevation of hypotaurine and taurine was depressed. The results indicate that the metabolism of S-containing substances is significantly disturbed by the HF diet, suggesting a causal role of impairment of hepatic transsulfuration reactions in NAFLD. Betaine supplementation protects the liver from nonalcoholic steatosis and oxidative stress most probably via its effects on the transsulfuration reactions.

  2. Maize Purple Plant Pigment Protects Against Fluoride-Induced Oxidative Damage of Liver and Kidney in Rats

    PubMed Central

    Zhang, Zhuo; Zhou, Bo; Wang, Hiaohong; Wang, Fei; Song, Yingli; Liu, Shengnan; Xi, Shuhua

    2014-01-01

    Anthocyanins are polyphenols and well known for their biological antioxidative benefits. Maize purple plant pigment (MPPP) extracted and separated from maize purple plant is rich in anthocyanins. In the present study, MPPP was used to alleviate the adverse effects generated by fluoride on liver and kidney in rats. The results showed that the ultrastructure of the liver and kidney in fluoride treated rats displayed shrinkage of nuclear and cell volume, swollen mitochondria and endoplasmic reticulum and vacuols formation in the liver and kidney cells. MPPP significantly attenuated these fluoride-induced pathological changes. The MDA levels in serum and liver tissue of fluoride alone treated group were significantly higher than those of the control group (p < 0.05). The presence of 5 g/kg MPPP in the diet reduced the elevation of MDA levels in blood and liver, and increased the SOD and GSH-Px activities in kidney and GSH level in liver and kidney compared with the fluoride alone treated group (p < 0.05). In addition, MPPP alleviated the decrease of Bcl-2 protein expression and the increase of Bax protein expression induced by fluoride. This study demonstrated the protective role of MPPP against fluoride-induced oxidative stress in liver and kidney of rats. PMID:24419046

  3. Caffeine intake decreases oxidative stress and inflammatory biomarkers in experimental liver diseases induced by thioacetamide: Biochemical and histological study.

    PubMed

    Amer, Mona G; Mazen, Nehad F; Mohamed, Ahmed M

    2017-03-01

    Liver disease remains a significant global health problem. Increased caffeine consumption has been associated with a lower prevalence of chronic liver disease. This study aimed to investigate the modifying effects of caffeine on liver injury induced by thioacetamide (TAA) administration in male rats and the possible underlying mechanisms. Forty adult male rats were equally classified into four groups: control group, received only tap water; caffeine-treated group, received caffeine (37.5 mg/kg per day); TAA-treated group, received intraperitoneal (i.p.) TAA (200 mg/kg b.w.) twice a week; and caffeine + TAA-treated group, received combined TAA and caffeine in the same previous doses. After eight weeks of treatment, blood samples were collected for biochemical analysis and liver specimens were prepared for histological and immunohistochemical studies and for assessment of oxidative stress. TAA induced liver toxicity with elevated liver enzymes and histological alterations, fatty changes, apoptosis, and fibrosis evidenced by increased immunohistochemical reaction to matrix metalloproteinase-9 (MMP-9) and collagen type IV in hepatocytes. Also, the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in serum were significantly elevated. Co-treatment with caffeine and TAA restored normal liver structure and function. Caffeine provided an anti-fibrogenic, anti-inflammatory, and antioxidant effect that was associated with recovery of hepatic histological and functional alterations from TAA-induced hepatotoxicity.

  4. Protective Efficacy of Alpha-lipoic Acid against AflatoxinB1-induced Oxidative Damage in the Liver

    PubMed Central

    Li, Y.; Ma, Q. G.; Zhao, L. H.; Guo, Y. Q.; Duan, G. X.; Zhang, J. Y.; Ji, C.

    2014-01-01

    Alpha-lipoic acid (α-LA) is not only involved in energy metabolism, but is also a powerful antioxidant that can protect against hepatic oxidative stress induced by some drugs, toxins, or under various physiological and pathophysiological conditions. Here, we investigated the effect of α-LA against liver oxidative damage in broilers exposed to aflatoxin B1 (AFB1). Birds were randomly divided into four groups and assigned different diets: basal diet, 300 mg/kg α-LA supplementation in basal diet, diet containing 74 μg/kg AFB1, and 300 mg/kg α-LA supplementation in diet containing 74 μg/kg AFB1, for 3 weeks. The results revealed that the addition of 300 mg/kg α-LA protected against the liver function damage of broilers induced by chronic low dose of AFB1 as estimated by a significant (p<0.05) change in levels of plasma total protein, albumin, alkaline phosphatase and the activities of liver glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase. The histopathological analysis also showed that liver tissues were injured in the AFB1 diet, but this effect was alleviated by the addition of 300 mg/kg α-LA. Additionally, AFB1 induced a profound elevation of oxidative stress in birds, as indicated by an increase in malondialdehyde level, a decrease in glutathione peroxidase activity and a depletion of the glutathione content in the liver. All of these negative effects were inhibited by treatment with α-LA. Our results suggest that the inhibition of AFB1-induced excess production of lipid peroxides and the maintenance of intracellular antioxidant status may play important roles in the protective effects of α-LA against AFB1-induced oxidative damage in the liver. PMID:25050030

  5. Fluoride-induced oxidative stress is involved in the morphological damage and dysfunction of liver in female mice.

    PubMed

    Zhou, Bian-hua; Zhao, Jing; Liu, Jeffrey; Zhang, Ji-liang; Li, Jian; Wang, Hong-wei

    2015-11-01

    Fluoride (F), one of the most toxic environmental and industrial pollutants, is known to exert hepatotoxicity. The contribution of oxidative stress to the F tolerance of liver remains largely unknown. In this study, the morphological and ultrastructural characteristics of liver were observed using hematoxylin and eosin staining and transmission electron microscopy (TEM), respectively. Oxidative-stress participations was analysed and the mRNA expression levels of catalase (Cat), glutathione peroxidase 1 (GSH-Px1), nitric oxide synthase 2 (NOS2), and superoxide dismutase 1 (SOD1) were investigated by real-time PCR. Changes in liver-function parameters were also detected. Results showed that the reactive content of reactive oxygen species increased significantly, whereas SOD and GSH-Px activities, as well as total anti-oxidising capability (T-AOC), decreased significantly, with increased nitric oxide (NO) and malondialdehyde (MDA) contents in liver and serum after 70days of F treatment. The mRNA expression levels of Cat, GSH-Px1, and SOD were significantly downregulated, whereas NOS2 mRNA expression level was up upregulated, after F treatment for 70days. Light microscopy also revealed that hepatocytes were fused into pieces; cell boundaries were unclear, and nuclei were lightly stained. TEM further showed that hepatocytes were characterised by vague nuclear and mitochondrial membranes, dilated endoplasmic reticulum, and aggravated vacuolar degeneration. Activities of alanine transaminase, aspartate aminotransferase, alkaline phosphatase and lactate dehydrogenase, as well as the level of total bilirubin in serum increased. Overall, these results indicated that F interfered with the balance of antioxidase activity and morphological changes in liver, which were involved in mouse liver dysfunction.

  6. Ethacrynic-acid-induced glutathione depletion and oxidative stress in normal and Mrp2-deficient rat liver.

    PubMed

    Ji, Bin; Ito, Kousei; Sekine, Shuichi; Tajima, Ai; Horie, Toshiharu

    2004-12-01

    Oxidative stress in the liver is sometimes accompanied by cholestasis. We investigated the localization and role of multidrug-resistance-associated protein (Mrp) 2, a biliary transporter involved in bile-salt-independent bile flow, under ethacrynic acid (EA)-induced acute oxidative stress. Normal Sprague-Dawley rat (SDR) and Mrp2-deficient Eisai hyperbilirubinemic rat (EHBR) livers were perfused with 500 microM EA. The release of glutamic pyruvic transaminase (GPT) and thiobarbituric-acid-reactive substances (TBARS) from EHBR liver was markedly delayed compared with that from SDR liver. This is mainly due to the higher basal level of glutathione (GSH) in EHBR liver (59.1 +/- 0.3 nmol/mg protein) compared with SDR liver (39.7 +/- 1.5 nmol/mg protein). EA similarly induced a rapid reduction in GSH followed by mitochondrial permeability transition in the isolated mitochondria from both SDR and EHBR. Internalization of Mrp2 was detected before nonspecific disruption of the canalicular membrane and GPT release in SDR liver perfused with 100 microM EA. SDR liver preperfused with hyperosmolar buffer (405 mosmol/L) for 30 min induced internalization of Mrp2 without changing the basal GSH level, while elimination of hepatic GSH by 300 microM EA perfusion was significantly delayed thereafter. Concomitantly, hepatotoxicity assessed by the release of GPT and TBARS was also significantly attenuated under hyperosmolar conditions. In conclusion, preserved cytosolic and intramitochondrial GSH is the key factor involved in the acute hepatotoxicity induced by EA and its susceptibility could be altered by the presence of Mrp2.

  7. PCB126-Induced Disruption in Gluconeogenesis and Fatty Acid Oxidation Precedes Fatty Liver in Male Rats

    PubMed Central

    Gadupudi, Gopi S.; Klaren, William D.; Olivier, Alicia K.; Klingelhutz, Aloysius J.; Robertson, Larry W.

    2016-01-01

    3,3′,4,4′,5-Pentachlorobiphenyl (PCB126), a dioxin-like polychlorinated biphenyl (PCB) and a potent aryl hydrocarbon receptor (AhR) agonist, is implicated in the disruption of both carbohydrate and lipid metabolism which ultimately leads to wasting disorders, metabolic disease, and nonalcoholic fatty liver disease. However, the mechanisms are unclear. Because liver is the target organ for PCB toxicity and responsible for metabolic homeostasis, we hypothesized that early disruption of glucose and lipid homeostasis contributes to later manifestations such as hepatic steatosis. To test this hypothesis, groups of male Sprague Dawley rats, fed on AIN-93G diet, were injected (intraperitoneal.) with a single bolus of PCB126 (5 µmol/kg) at various time intervals between 9 h and 12 days prior to euthanasia. An early decrease in serum glucose and a gradual decrease in serum triglycerides were observed over time. Liver lipid accumulation was most severe at 6 and 12 days of exposure. Transcript levels of cytosolic phosphoenol-pyruvate carboxykinase (Pepck-c/Pck1) and glucose transporter (Glut2/Slc2a2) involved in gluconeogenesis and hepatic glucose transport were time-dependently downregulated between 9 h and 12 days of PCB126 exposure. Additionally, transcript levels of Pparα, and its targets acyl-CoA oxidase (Acox1) and hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2), were also downregulated, indicating changes in peroxisomal fatty acid oxidation and ketogenesis. In a separate animal study, we found that the measured changes in the transcript levels of Pepck-c, Glut2, Pparα, Acox1, and Hmgcs2 were also dose dependent. Furthermore, PCB126-induced effects on Pepck-c were demonstrated to be AhR dependent in rat H4IIE hepatocytes. These results indicate that PCB126-induced wasting and steatosis are preceded initially by (1) decreased serum glucose caused by decreased hepatic glucose production, followed by (2) decreased peroxisomal fatty acid oxidation. PMID

  8. Anti-oxidative responses of zebrafish (Danio rerio) gill, liver and brain tissues upon acute cold shock.

    PubMed

    Wu, Su Mei; Liu, Jia-Hao; Shu, Li-Hsin; Chen, Ching Hsein

    2015-09-01

    The present study seeks to detect oxidative damage and to compare anti-oxidative responses among liver, gills and brain of adult zebrafish that were cooled from 28 °C (control) to 12 °C (treatment) for 0-24 h. The lipid peroxidation of liver, gill and brain tissues significantly increased at 1h after transfer, but reactive oxygen species in the treatment group increased significantly after 24 h as compared to the control. The fish were found to develop a cascading anti-oxidative mechanism beginning with an increase in Cu/Zn-SOD levels, followed by increased CAT and GPx mRNA expressions in the three tissue types. Both smtB and mt2 mRNAs increased in the hepatic and brain tissues following 1h of cold stress, but only smtB exhibited a significant increase in the gills at 1 h and 6 h after transfer to 12 °C. Furthermore, cellular apoptosis in the brain was not evident after cold shock, but liver and gills showed cellular apoptosis at 1-3 h, with another peak in the liver at 6 h after cold shock. The results suggest that the cold shock induced oxidative stress, and the enzymatic (SOD, GPx and CAT) and non-enzymatic (mt-2 and smt-B) mRNA expressions all play a role in the resulting anti-oxidation within 1-6 h of cold shock. A functional comparison showed that the brain had the most powerful antioxidant defense system of the three tissue types since it had the highest smtB mRNA expression and a lower level of cell apoptosis than the liver and gills after exposure to cold stress.

  9. The liver fluke Opisthorchis viverrini expresses nitric oxide synthase but not gelatinases.

    PubMed

    Prakobwong, Suksanti; Pinlaor, Porntip; Charoensuk, Lakhanawan; Khoontawad, Jarinya; Yongvanit, Puangrat; Hiraku, Yusuke; Pinlaor, Somchai

    2012-03-01

    Host-parasite interaction during infection with the liver fluke Opisthorchis viverrini plays an important role in opisthorchiasis-associated cholangiocarcinoma via nitric oxide (NO) production. Host cells induce nitric oxide synthase (NOS)-dependent DNA damage and secrete Ras-related C3 botulinum toxin substrate (Rac)1, heme oxygenase (HO)-1, and gelatinases (matrix metalloproteinase (MMP)2 and MMP9). We evaluated whether these enzymes are expressed in O. viverrini. Colocalization of NOS and Rac1 was most prominently detected on day 30 post-infection (p.i.) in the gut, reproductive organ, eggs, acetabular and tegument. Expression of HO-1, an antioxidative enzyme, increased in a similar pattern to NOS, but was not present in the tegument. The levels of nitrate/nitrite, end products of NO, and ferric reducing antioxidant capacity, an indicator of antioxidant enzyme capacity, in parasite homogenates were highest on day 30 p.i. and then decreased on day 90 p.i. In contrast, zymography revealed that MMP2 and MMP9 were not present in parasite homogenates at all time points. In conclusion, O. viverrini induces NOS expression and NO production, but does not express gelatinases. The study may provide basic information and an insight into drug design for prevention and/or intervention approaches against O. viverrini infection. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  10. Kinetics and control of oxidative phosphorylation in rat liver mitochondria after chronic ethanol feeding.

    PubMed Central

    Marcinkeviciute, A; Mildaziene, V; Crumm, S; Demin, O; Hoek, J B; Kholodenko, B

    2000-01-01

    Changes in the kinetics and regulation of oxidative phosphorylation were characterized in isolated rat liver mitochondria after 2 months of ethanol consumption. Mitochondrial energy metabolism was conceptually divided into three groups of reactions, either producing protonmotive force (Deltap) (the respiratory subsystem) or consuming it (the phosphorylation subsystem and the proton leak). Manifestation of ethanol-induced mitochondrial malfunctioning of the respiratory subsystem was observed with various substrates; the respiration rate in State 3 was inhibited by 27+/-4% with succinate plus amytal, by 20+/-4% with glutamate plus malate, and by 17+/-2% with N,N,N',N'-tetramethyl-p-phenylenediamine/ascorbate. The inhibition of the respiratory activity correlated with the lower activities of cytochrome c oxidase, the bc(1) complex, and the ATP synthase in mitochondria of ethanol-fed rats. The block of reactions consuming the Deltap to produce ATP (the phosphorylating subsystem) was suppressed after 2 months of ethanol feeding, whereas the mitochondrial proton leak was not affected. The contributions of Deltap supply (the respiratory subsystem) and Deltap demand (the phosphorylation and the proton leak) to the control of the respiratory flux were quantified as the control coefficients of these subsystems. In State 3, the distribution of control exerted by different reaction blocks over respiratory flux was not significantly affected by ethanol diet, despite the marked changes in the kinetics of individual functional units of mitochondrial oxidative phosphorylation. This suggests the operation of compensatory mechanisms, when control redistributes among the different components within the same subsystem. PMID:10880351

  11. Oxyresveratrol abrogates oxidative stress by activating ERK-Nrf2 pathway in the liver.

    PubMed

    Choi, Hee Yoon; Lee, Ju-Hee; Jegal, Kyung Hwan; Cho, Il Je; Kim, Young Woo; Kim, Sang Chan

    2016-02-05

    Oxyresveratrol is a polyphenolic phytoalexin produced by plants as an antioxidant. This study investigated the hepatoprotective effects of oxyresveratrol as well as its underlying mechanism of action. Here, we evaluated the protective effects of oxyresveratrol against tert-butyl hydroperoxide (tBHP)-induced severe oxidative stress in HepG2 cells as well as acute liver injury caused by carbon tetrachloride (CCl4) in mice. tBHP-induced reactive oxygen species production and cell death in hepatocytes were blocked by oxyresveratrol, as indicated by MTT, TUNEL, and FACS analyses. Moreover, pretreatment with oxyresveratrol increased nuclear translocation and transactivation of NF-E2-related factor 2 (Nrf2), as assessed by antioxidant response element reporter gene expression and immunofluorescence staining, and transactivated expression of both hemeoxygenase-1 and glutamate-cysteine ligase catalytic subunit. More importantly, oxyresveratrol induced phosphorylation of Nrf2 mediated through activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Further, ERK inhibitors such as PD98059 and U0126 blocked phosphorylation of Nrf2 as well as the protective effect of oxyresveratrol in mitochondria. In mice, oral administration of oxyresveratrol significantly prevented hepatocyte degeneration, inflammatory cell infiltration, as well as elevation of plasma markers such as ALT and AST induced by CCl4 injection. In conclusion, this study confirmed that oxyresveratrol protected hepatocytes against oxidative stress and mitochondrial dysfunction, which might be associated with activation of Nrf2. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. Demethyleneberberine, a natural mitochondria-targeted antioxidant, inhibits mitochondrial dysfunction, oxidative stress, and steatosis in alcoholic liver disease mouse model.

    PubMed

    Zhang, Pengcheng; Qiang, Xiaoyan; Zhang, Miao; Ma, Dongshen; Zhao, Zheng; Zhou, Cuisong; Liu, Xie; Li, Ruiyan; Chen, Huan; Zhang, Yubin

    2015-01-01

    Excessive alcohol consumption induces oxidative stress and lipid accumulation in the liver. Mitochondria have long been recognized as the key target for alcoholic liver disease (ALD). Recently, the artificial mitochondria-targeted antioxidant MitoQ has been used to treat ALD effectively in mice. Here, we introduce the natural mitochondria-targeted antioxidant demethyleneberberine (DMB), which has been found in Chinese herb Cortex Phellodendri chinensis. The protective effect of DMB on ALD was evaluated with HepG2 cells and acutely/chronically ethanol-fed mice, mimicking two common patterns of drinking in human. The results showed that DMB, which is composed of a potential antioxidant structure, could penetrate the membrane of mitochondria and accumulate in mitochondria either in vitro or in vivo. Consequently, the acute drinking-caused oxidative stress and mitochondrial dysfunction were significantly ameliorated by DMB. Moreover, we also found that DMB suppressed CYP2E1, hypoxia inducible factor α, and inducible nitric oxide synthase, which contributed to oxidative stress and restored sirtuin 1/AMP-activated protein kinase/peroxisome proliferator-activated receptor-γ coactivator-1α pathway-associated fatty acid oxidation in chronic ethanol-fed mice, which in turn ameliorated lipid peroxidation and macrosteatosis in the liver. Taking these findings together, DMB could serve as a novel and potential therapy for ALD in human beings.

  13. Effects of grape seed polyphenols on oxidative damage in liver tissue of acutely and chronically exercised rats.

    PubMed

    Belviranlı, Muaz; Gökbel, Hakkı; Okudan, Nilsel; Büyükbaş, Sadık

    2013-05-01

    The objective of the present study was to investigate the effects of grape seed extract (GSE) supplementation on oxidative stress and antioxidant defense markers in liver tissue of acutely and chronically exercised rats. Rats were randomly assigned to six groups: Control (C), Control Chronic Exercise (CE), Control Acute Exercise (AE), GSE-supplemented Control (GC), GSE-supplemented Chronic Exercise(GCE) and GSE-supplemented Acute Exercise (GAE). Rats in the chronic exercise groups were subjected to a six-week treadmill running and in the acute exercise groups performed an exhaustive running. Rats in the GSE supplemented groups received GSE (100 mg.kg(-1) .day(-1) ) in drinking water for 6 weeks. Liver tissues of the rats were taken for the analysis of malondialdehyde (MDA), nitric oxide (NO) levels and total antioxidant activity (AOA) and xanthine oxidase (XO) activities. MDA levels decreased with GSE supplementation in control groups but increased in acute and chronic exercise groups compared to their non-supplemented control. NO levels increased with GSE supplementation. XO activities were higher in AE group compared to the CE group. AOA decreased with GSE supplementation. In conclusion, while acute exercise triggers oxidative stress, chronic exercise has protective role against oxidative stress. GSE has a limited antioxidant effect on exercise-induced oxidative stress in liver tissue.

  14. Metabolism of propionate by sheep liver. Oxidation of propionate by homogenates

    PubMed Central

    Smith, R. M.; Osborne-White, W. S.

    1965-01-01

    1. The rate and stability to aging of the metabolism of propionate by sheep-liver slices and sucrose homogenates were examined. Aging for up to 20min. at 37° in the absence of added substrate had little effect with slices, whole homogenates or homogenates without the nuclear fraction. 2. Metabolism of propionate by sucrose homogenates was confined to the mitochondrial fraction, but the mitochondrial supernatant (microsomes plus cell sap) stimulated propionate removal. 3. The rate of propionate metabolism by liver slices was higher in a high potassium phosphate–bicarbonate medium [0·88(±s.e.m. 0·16)μmole/mg. of N/hr.] than in Krebs–Ringer bicarbonate medium [0·44(±s.e.m. 0·13)μmole/mg. of N/hr.]. 4. Metabolism of propionate by sucrose homogenates freed from nuclei was dependent on the presence of oxygen, carbon dioxide and ATP. Propionate removal was stimulated 250% by Mg2+ ions and 670% by cytochrome c. 5. In the complete medium 2·39(±s.e.m. 0·15)μmoles of propionate were consumed/mg. of N/hr. 6. The ratio of oxygen consumption to propionate utilization was sufficient to account for the complete oxidation of half the propionate consumed. 7. The only products detected under these conditions were succinate, fumarate and malate. Propionate had no effect on the production of lactate from endogenous sources and did not itself give rise to lactate. 8. Methylmalonate did not accumulate when propionate was metabolized and was not oxidized. It was detected as an intermediate in the conversion of propionyl-CoA into succinate. The rate of this reaction sequence was adequate to account for the rate of propionate metabolism by sucrose homogenates or slices, provided that the rate of formation of propionyl-CoA was not limiting. 9. The methylmalonate pathway was predominantly a mitochondrial function. 10. The metabolism of propionate appeared to be dependent on active oxidative phosphorylation. PMID:14340092

  15. Metallothionein, oxidative stress and trace metals in gills and liver of demersal and pelagic fish species from Kuwaits' marine area.

    PubMed

    Beg, M U; Al-Jandal, N; Al-Subiai, S; Karam, Q; Husain, S; Butt, S A; Ali, A; Al-Hasan, E; Al-Dufaileej, S; Al-Husaini, M

    2015-11-30

    Two fish species yellowfin seabream (Acanthopagrus latus) and tonguesole (Cynoglossus arel) were collected from two locations in Kuwait's territorial waters in non-reproductive periods and used as bio-indicator organism for the assessment of metals in the marine environment. Species variation in fish was observed; seabream contained high metal content and metallothionein in liver and gill tissues compared to tonguesole, especially from Kuwait Bay area. Oxidative injury was registered in the gills of both species, but in tonguesole liver was also involved. Consequently, antioxidant enzyme catalase was elevated in tonguesole enabling bottom dwelling fish to combat oxidative assault. The study provided information about the current status of metals in marine sediment and levels of metals accumulated in representative species along with oxidative damage in exposed tissues and the range of biomarker protein metallothionein and enzymes of antioxidant defence mechanism enhancing our understanding about the biological response to the existing marine environment in Kuwait.

  16. Inhibition of nitric oxide production reverses diabetes-induced Kupffer cell activation and Klebsiella pneumonia liver translocation.

    PubMed

    Lin, Shu-Han; Chung, Pei-Hsuan; Wu, Ying-Ying; Fung, Chang-Phone; Hsu, Ching-Mei; Chen, Lee-Wei

    2017-01-01

    Klebsiella pneumoniae (KP) is the most common pathogen of pyogenic liver abscess in East and Southeast Asia and diabetes mellitus (DM) is a major risk factor. The effect and mechanism of diabetes on KP liver abscess was examined in streptozotocin-induced diabetic mice and Akita mice (C57BL/6J-Ins2Akita). KP translocation to liver and plasma alaine transaminase levels were increased and liver clearance of KP was decreased in DM mice. Diabetic mice exhibited overgrowth of Enterococcus as well as E.coli and decreased lactobacilli/bifidas growth in intestine, increased intestinal iNOS protein and nitrite levels in portal vein, and increased IL-1β and TNF-α expression of Kupffer cells. Fructooligosaccharides (FOS) or dead L. salivarius (dLac) supplementation reversed diabetes-induced enteric dysbiosis, NO levels in portal vein, and KP translocation to liver. L-NAME treatment decreased intestinal iNOS protein expression as well as Kupffer cell activation and increased liver clearance of KP in DM mice. Dead E.coli (2×108 CFU/ml) feeding for one week induced iNOS and TLR4 expression of intestine in germ-free (GF) mice. Dead bacteria feeding induced IL-1β and TNF-α expression of Kupffer cells in GF mice but not in GF TLR4-/- mice. In conclusion, balance of intestinal microflora is important for preventing intestinal iNOS expression, Kupffer cell activation, and KP liver translocation in diabetes. Reversal of diabetes-induced enteric dysbiosis with FOS or dead L. salivarius decreases diabetes-induced intestinal iNOS expression and KP liver translocation. Diabetes induces Kupffer cell activation and KP liver translocation through enteric dysbiosis and nitric oxide production.

  17. Inhibition of nitric oxide production reverses diabetes-induced Kupffer cell activation and Klebsiella pneumonia liver translocation

    PubMed Central

    Wu, Ying-Ying; Fung, Chang-Phone; Hsu, Ching-Mei

    2017-01-01

    Klebsiella pneumoniae (KP) is the most common pathogen of pyogenic liver abscess in East and Southeast Asia and diabetes mellitus (DM) is a major risk factor. The effect and mechanism of diabetes on KP liver abscess was examined in streptozotocin-induced diabetic mice and Akita mice (C57BL/6J-Ins2Akita). KP translocation to liver and plasma alaine transaminase levels were increased and liver clearance of KP was decreased in DM mice. Diabetic mice exhibited overgrowth of Enterococcus as well as E.coli and decreased lactobacilli/bifidas growth in intestine, increased intestinal iNOS protein and nitrite levels in portal vein, and increased IL-1β and TNF-α expression of Kupffer cells. Fructooligosaccharides (FOS) or dead L. salivarius (dLac) supplementation reversed diabetes-induced enteric dysbiosis, NO levels in portal vein, and KP translocation to liver. L-NAME treatment decreased intestinal iNOS protein expression as well as Kupffer cell activation and increased liver clearance of KP in DM mice. Dead E.coli (2×108 CFU/ml) feeding for one week induced iNOS and TLR4 expression of intestine in germ-free (GF) mice. Dead bacteria feeding induced IL-1β and TNF-α expression of Kupffer cells in GF mice but not in GF TLR4-/- mice. In conclusion, balance of intestinal microflora is important for preventing intestinal iNOS expression, Kupffer cell activation, and KP liver translocation in diabetes. Reversal of diabetes-induced enteric dysbiosis with FOS or dead L. salivarius decreases diabetes-induced intestinal iNOS expression and KP liver translocation. Diabetes induces Kupffer cell activation and KP liver translocation through enteric dysbiosis and nitric oxide production. PMID:28493939

  18. Featured Article: Oxidative stress status and liver tissue defenses in diabetic rats during intensive subcutaneous insulin therapy.

    PubMed

    Dal, Stéphanie; Jeandidier, Nathalie; Seyfritz, Elodie; Bietiger, William; Péronet, Claude; Moreau, François; Pinget, Michel; Maillard, Elisa; Sigrist, Séverine

    2016-01-01

    Long-term insulin delivery can reduce blood glucose variability in diabetic patients. In this study, its impact on oxidative stress status, inflammation, and liver injury was investigated. Diabetes was induced in Wistar rats with a single dose of streptozotocin (100 mg/kg). Untreated rats and rats administered Insuplant® (2 UI/200 g/day) through a subcutaneous osmotic pump for one or four weeks were compared with non-diabetic controls. Body weight, fructosamine level, total cholesterol, Insulin Growth Factor-1 (IGF-1) level, lipid peroxidation, and total antioxidant capacity were measured. Hepatic injury was determined through the measurement of glycogen content, reactive oxygen species (ROS) production, and macrophage infiltration. Liver oxidative stress status was evaluated through the measurement of superoxide dismutase (SOD), catalase (CAT), and nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) expression, and p38 mitogen-activated protein kinase (p38MAPK) activation. Induction of diabetes led to increased plasma oxidative stress and inflammation. Moreover, ROS production and macrophage infiltration increased in addition to SOD, CAT, and NADPH oxidase expression. Intensive insulin therapy improved metabolic control in diabetic animals as seen by a restoration of hepatic glycogen, plasma IGF-1 levels, and a decrease in plasma oxidative stress. However, insulin treatment did not result in a decrease in acute inflammation in diabetic rats as seen by continued ROS production and macrophage infiltration in the liver, and a decrease of p38MAPK activation. These results suggest that the onset of diabetes induces liver oxidative stress and inflammation, and that subcutaneous insulin administration cannot completely reverse these changes. Targeting oxidative stress and/or inflammation in diabetic patients could be an interesting strategy to improve therapeutic options.

  19. Toxic effects of hexaammine cobalt(III) chloride on liver and kidney in mice: Implication of oxidative stress.

    PubMed

    Naura, Amarjit S; Sharma, Rajeshwar

    2009-01-01

    Hexaammine cobalt (III) chloride is a trivalent complex cation of Co(III) and amine that has previously been shown to act as an inhibitor of insulin secretion, radiosensitizing agent, and an antiviral agent. We have recently reported the anticancer potential of the compound against diethylnitrosamine-induced carcinogenesis in mice. However, there is no report on the potential toxicity of the compound. The present study was conducted to evaluate the tissue distribution of the compound and its potential toxicity following acute administration of the compound through intraperitoneal route in Balb/c mice. Our results showed that cobalt accumulated maximally in kidney, followed by liver, spleen, blood, and lung in a decreasing order and in a dose-dependent manner. Evaluation of liver and kidney function tests revealed that the compound exerted a relatively higher toxicity in kidney, as compared to liver, as evidenced by the sharp enhancement in the serum levels of urea and creatinine in a dose-dependent manner. Examination of levels of lipid peroxidation and selected oxidative stress-related parameters in kidney, liver, and lung suggest that higher accumulation of cobalt in kidney may promote higher oxidative stress in the organ, as compared to liver and lung, which may eventually impair kidney function.

  20. Reversible mitochondrial uncoupling in the cold phase during liver preservation/reperfusion reduces oxidative injury in the rat model.

    PubMed

    Petrenko, Alexander Y; Cherkashina, Daria V; Somov, Alexander Y; Tkacheva, Elena N; Semenchenko, Olga A; Lebedinsky, Alexander S; Fuller, Barry J

    2010-06-01

    Reversible uncoupling of the mitochondrial electron-transport chain may be one strategy to prevent intracellular oxidative stress during liver cold preservation/warm reperfusion (CP/WR) injury. 2,4-Dinitrophenol (DNP) is a potent water-soluble uncoupling agent for supplementation of the hepatic CP solution. The aim of this work was to investigate the possible influence of DNP in the CP solution on the isolated rat liver state during CP/WR. Livers were subjected to CP at 4 degrees C in sucrose-phosphate based solution (SPS) for 18 h, followed by WR for 60 min in vitro. The final concentration of DNP was 100 microM. DNP presence during the CP stage led to partial ATP level decrease accompanied by a significant diminution in liver TBARS and a prevention of antioxidant enzyme activity decrease (catalase, GSH-PO, GSH-Red) when compared with livers stored without DNP. After DNP wash-out during WR, an improvement in the mitochondrial functional state (higher respiratory control indices and ATP levels, and a decrease in V(4) respiration rates) were observed. This was concurrent with lower TBARS levels, higher antioxidant enzyme activities and significant increase of bile production. The results suggest that reversible uncoupling may be one way to influence oxidative stress associated with hepatic cold preservation. Copyright 2010 Elsevier Inc. All rights reserved.

  1. Ameliorative effects of 5-hydroxymethyl-2-furfural (5-HMF) from Schisandra chinensis on alcoholic liver oxidative injury in mice.

    PubMed

    Li, Wei; Qu, Xin-Nan; Han, Ye; Zheng, Si-Wen; Wang, Jia; Wang, Ying-Ping

    2015-01-22

    The aim of this paper is to evaluate the protective effect of 5-hydroxymethyl-2-furfural (5-HMF) on acute alcohol-induced liver oxidative injury in mice. 5-HMF, a maillard reaction product, was isolated from the fruits of Schisandra chinensis for animal experiments. Experimental ICR mice were pretreated with different doses of 5-HMF (7.5, 15, and 30 mg/kg) for seven days by gavage feeding. Biochemical markers and enzymatic antioxidants from serum and liver tissue were examined. Our results showed that the activities of ALT (alanine aminotransferase), AST (aspartate transaminase), TC (total cholesterol), TG (triglyceride), L-DLC (low density lipoprotein) in serum and the levels of MDA (malondialdehyde) in liver tissue, decreased significantly (p < 0.05) in the 5-HMF-treated group compared with the alcohol group. On the contrary, enzymatic antioxidants CAT (catalase), GSH-Px (glutathione peroxidase), and GSH SOD (superoxide dismutase) were markedly elevated in liver tissue treated with 5-HMF (p < 0.05). Furthermore, the hepatic levels of pro-inflammatory response marker tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) were significantly suppressed (p < 0.05). Histopathological examination revealed that 5-HMF (30 mg/kg) pretreatment noticeably prevented alcohol-induced hepatocyte apoptosis and fatty degeneration. It is suggested that the hepatoprotective effects exhibited by 5-HMF on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties.

  2. Ameliorative Effects of 5-Hydroxymethyl-2-furfural (5-HMF) from Schisandra chinensis on Alcoholic Liver Oxidative Injury in Mice

    PubMed Central

    Li, Wei; Qu, Xin-Nan; Han, Ye; Zheng, Si-Wen; Wang, Jia; Wang, Ying-Ping

    2015-01-01

    The aim of this paper is to evaluate the protective effect of 5-hydroxymethyl-2-furfural (5-HMF) on acute alcohol-induced liver oxidative injury in mice. 5-HMF, a maillard reaction product, was isolated from the fruits of Schisandra chinensis for animal experiments. Experimental ICR mice were pretreated with different doses of 5-HMF (7.5, 15, and 30 mg/kg) for seven days by gavage feeding. Biochemical markers and enzymatic antioxidants from serum and liver tissue were examined. Our results showed that the activities of ALT (alanine aminotransferase), AST (aspartate transaminase), TC (total cholesterol), TG (triglyceride), L-DLC (low density lipoprotein) in serum and the levels of MDA (malondialdehyde) in liver tissue, decreased significantly (p < 0.05) in the 5-HMF-treated group compared with the alcohol group. On the contrary, enzymatic antioxidants CAT (catalase), GSH-Px (glutathione peroxidase), and GSH SOD (superoxide dismutase) were markedly elevated in liver tissue treated with 5-HMF (p < 0.05). Furthermore, the hepatic levels of pro-inflammatory response marker tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) were significantly suppressed (p < 0.05). Histopathological examination revealed that 5-HMF (30 mg/kg) pretreatment noticeably prevented alcohol-induced hepatocyte apoptosis and fatty degeneration. It is suggested that the hepatoprotective effects exhibited by 5-HMF on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties. PMID:25622257

  3. Apple cider vinegar modulates serum lipid profile, erythrocyte, kidney, and liver membrane oxidative stress in ovariectomized mice fed high cholesterol.

    PubMed

    Nazıroğlu, Mustafa; Güler, Mustafa; Özgül, Cemil; Saydam, Gündüzalp; Küçükayaz, Mustafa; Sözbir, Ercan

    2014-08-01

    The purpose of this study was to investigate the potentially beneficial effects of apple cider vinegar (ACV) supplementation on serum triglycerides, total cholesterol, liver and kidney membrane lipid peroxidation, and antioxidant levels in ovariectomized (OVX) mice fed high cholesterol. Four groups of ten female mice were treated as follows: Group I received no treatment and was used as control. Group II was OVX mice. Group III received ACV intragastrically (0.6% of feed), and group IV was OVX and was treated with ACV as described for group III. The treatment was continued for 28 days, during which the mice were fed a high-cholesterol diet. The lipid peroxidation levels in erythrocyte, liver and kidney, triglycerides, total, and VLDL cholesterol levels in serum were higher in the OVX group than in groups III and IV. The levels of vitamin E in liver, the kidney and erythrocyte glutathione peroxidase (GSH-Px), and erythrocyte-reduced glutathione (GSH) were decreased in group II. The GSH-Px, vitamin C, E, and β-carotene, and the erythrocyte GSH and GSH-Px values were higher in kidney of groups III and IV, but in liver the vitamin E and β-carotene concentrations were decreased. In conclusion, ACV induced a protective effect against erythrocyte, kidney, and liver oxidative injury, and lowered the serum lipid levels in mice fed high cholesterol, suggesting that it possesses oxidative stress scavenging effects, inhibits lipid peroxidation, and increases the levels of antioxidant enzymes and vitamin.

  4. Trypanosoma cruzi infection and benznidazole therapy independently stimulate oxidative status and structural pathological remodeling of the liver tissue in mice.

    PubMed

    Novaes, Rômulo Dias; Santos, Eliziária C; Cupertino, Marli C; Bastos, Daniel S S; Oliveira, Jerusa M; Carvalho, Thaís V; Neves, Mariana M; Oliveira, Leandro L; Talvani, André

    2015-08-01

    This study used a murine model of Chagas disease to investigate the isolated and combined impact of Trypanosoma cruzi infection and benznidazole (BZ) therapy on liver structure and function. Male C57BL/6 mice were challenged with T. cruzi and BZ for 15 days. Serum levels of cytokines and hepatic enzymes, liver oxidative stress, morphology, collagen, and glycogen content were monitored. Separately, T. cruzi infection and BZ treatment resulted in a pro-oxidant status and hepatic reactive damage. Concurrently, both T. cruzi infection and BZ treatment induced upregulation of antioxidant enzymes and pathological reorganization of the liver parenchyma and stroma. T. cruzi infection increased serum levels of Th1 cytokines, which were reduced by BZ in both infected and non-infected animals. BZ also induced functional organ damage, increasing serum levels of liver enzymes. When combined, T. cruzi infection and BZ therapy elicited intense hepatic reactive damage that was not compensated by antioxidant enzymatic reaction, subsequently culminating in more severe morphofunctional hepatic injury. Taken together, these findings indicate that during specific treatment of Chagas disease, hepatic pathology may be a result of an interaction between BZ metabolism and specific mechanisms activated during the natural course of T. cruzi infection, rather than an isolated toxic effect of BZ on liver structure and function.

  5. Lipoic acid prevents fructose-induced changes in liver carbohydrate metabolism: role of oxidative stress.

    PubMed

    Castro, María C; Francini, Flavio; Gagliardino, Juan J; Massa, María L

    2014-03-01

    Fructose administration rapidly induces oxidative stress that triggers compensatory hepatic metabolic changes. We evaluated the effect of an antioxidant, R/S-α-lipoic acid on fructose-induced oxidative stress and carbohydrate metabolism changes. Wistar rats were fed a standard commercial diet, the same diet plus 10% fructose in drinking water, or injected with R/S-α-lipoic acid (35mg/kg, i.p.) (control+L and fructose+L). Three weeks thereafter, blood samples were drawn to measure glucose, triglycerides, insulin, and the homeostasis model assessment-insulin resistance (HOMA-IR) and Matsuda indices. In the liver, we measured gene expression, protein content and activity of several enzymes, and metabolite concentration. Comparable body weight changes and calorie intake were recorded in all groups after the treatments. Fructose fed rats had hyperinsulinemia, hypertriglyceridemia, higher HOMA-IR and lower Matsuda indices compared to control animals. Fructose fed rats showed increased fructokinase gene expression, protein content and activity, glucokinase and glucose-6-phosphatase gene expression and activity, glycogen storage, glucose-6-phosphate dehydrogenase mRNA and enzyme activity, NAD(P)H oxidase subunits (gp91(phox) and p22(phox)) gene expression and protein concentration and phosphofructokinase-2 protein content than control rats. All these changes were prevented by R/S-α-lipoic acid co-administration. Fructose induces hepatic metabolic changes that presumably begin with increased fructose phosphorylation by fructokinase, followed by adaptive changes that attempt to switch the substrate flow from mitochondrial metabolism to energy storage. These changes can be effectively prevented by R/S-α-lipoic acid co-administration. Control of oxidative stress could be a useful strategy to prevent the transition from impaired glucose tolerance to type 2 diabetes. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. High calcium diet improves the liver oxidative stress and microsteatosis in adult obese rats that were overfed during lactation.

    PubMed

    Conceição, E P S; Moura, E G; Soares, P N; Ai, X X; Figueiredo, M S; Oliveira, E; Lisboa, P C

    2016-06-01

    Obesity is related to diabetes, higher oxidative stress and nonalcoholic fatty liver disease, and dietetic therapies, for instance calcium-rich diet, can improve these dysfunctions. Rats raised in small litters (SL) had increased fat depots and insulin resistance at adulthood associated with higher liver oxidative stress and microsteatosis. Thus, we evaluated if dietary calcium can improve these changes. In PN3, litter size was adjusted to 3 pups (SL group) to induce overfeeding, while controls had 10 pups until weaning. At PN120, SL group was randomly divided into: rats fed with standard chow or fed with calcium supplementation (SL-Ca group, 10 g/kg chow) for 60 days. At PN180, dietary calcium normalized food consumption, visceral fat, plasma aspartate aminotransferase (AST) and glycaemia. Concerning oxidative balance, calcium restored both higher hepatic lipid peroxidation and protein carbonylation as well as higher plasma lipid peroxidation. Higher fatty acid synthase (FAS) content, steatosis and lower protein kinase B (Akt) in SL group were normalized by dietary calcium and SL-Ca rats had lower hepatic cholesterol. Thus, calcium supplementation improved the insulin sensitivity, redox balance and steatosis in the liver. Therefore, dietary calcium can be a promising therapy for liver disease in the metabolic syndrome. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis.

    PubMed

    Okada, Kosuke; Warabi, Eiji; Sugimoto, Hirokazu; Horie, Masaki; Tokushige, Katsutoshi; Ueda, Tetsuya; Harada, Nobuhiko; Taguchi, Keiko; Hashimoto, Etsuko; Itoh, Ken; Ishii, Tetsuro; Utsunomiya, Hirotoshi; Yamamoto, Masayuki; Shoda, Junichi

    2012-08-01

    The transcription factor nuclear factor-E2-related factor-2 (Nrf2) is a key regulator for induction of hepatic antioxidative stress systems. We aimed to investigate whether activation of Nrf2 protects against steatohepatitis. Wild-type mice (WT), Nrf2 gene-null mice (Nrf2-null) and Keap1 gene-knockdown mice (Keap1-kd), which represent the sustained activation of Nrf2, were fed a methionine- and choline-deficient diet (MCDD) for 13 weeks and analyzed. In Keap1-kd fed an MCDD, steatohepatitis did not develop over the observation periods; however, in Nrf2-null fed an MCDD, the pathological state of the steatohepatitis was aggravated in terms of fatty change, inflammation, fibrosis and iron accumulation. In WT mice fed an MCDD, Nrf2 and antioxidative stress genes regulated by Nrf2 were potently activated in the livers, and in Keap1-kd, their basal levels were potently activated. Oxidative stress was significantly increased in the livers of the Nrf2-null and suppressed in the livers of the Keap1-kd compared to that of WT, based on the levels of 4-hydroxy-2-nonenal and malondialdehyde. Iron accumulation was greater in the livers of the Nrf2-null mice compared to those of the WT mice, and it was not observed in Keap1-kd. Further, the iron release from the isolated hepatocyte of Nrf2-null mice was significantly decreased. Sulforaphane, an activator of Nrf2, suppressed the pathological states and oxidative stress in the livers. Nrf2 has protective roles against nutritional steatohepatitis through inhibition of hepatic iron accumulation and counteraction against oxidative stress-induced liver injury. Nrf2 activation by pharmaceutical intervention could be a new option for the prevention and treatment of steatohepatitis.

  8. Relationship between expression of HSP70 and metallothionein and oxidative stress during mercury chloride induced acute liver injury in rats.

    PubMed

    Reus, Isabel Sánchez; Bando, Inmaculada; Andrés, David; Cascales, María

    2003-01-01

    Mercury is a highly toxic metal which induces oxidative stress. Metallothionein and heat shock protein 70 (HSP70) are stress proteins involved in response to different stimuli. In the present study rats were administered per oral application by gavage, a single daily dose (0.1 mg/kg) of HgCl(2) for 3 consecutive days. To find a relation between these two stress proteins and mercury, parameters of liver injury, redox state of the cells, and the expression and protein levels of HSP70 and metallothionein by Northern and Western blot analysis were assayed either in blood or in liver. HgCl(2) at the doses of 0.1 mg/kg induced liver injury detected by a slight increase in serum aspartate aminotransferase and alkaline phosphatase activities and by the enhanced levels of bilirubin. Oxidative stress was detected by a significant decrease in protein-SH and an increase in thiobarbituric acid reactive substances in liver following one dose of mercury. mRNA and protein levels of both metallothionein and HSP70 increased progressively from first to third doses of mercury. We conclude that against low doses of mercury that produce a slight liver injury and oxidative stress, the liver rapidly responds by inducing the expression of metallothionein and HSP70. We suggest that metallothionein induction attenuates the decrease in protein-SH induced by the first dose of mercury, since metallothionein increases the pool of thiol groups in the cytosol eliminating oxygen radicals and inhibiting lipid peroxidation. From these results we can suggest that the changes observed in these stress proteins by the effect of mercury appear to be a response rapidly induced at transcriptional and at translational levels. Copyright 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:161-168, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10074

  9. Effects of binge ethanol on lipid homeostasis and oxidative stress in a rat model of nonalcoholic fatty liver disease.

    PubMed

    Grasselli, Elena; Voci, Adriana; Demori, Ilaria; De Matteis, Rita; Compalati, Andrea D; Gallo, Gabriella; Vergani, Laura

    2014-06-01

    Excess fat accumulation renders the liver more vulnerable to ethanol, but it is still unclear how alcohol enhances lipid dysmetabolism and oxidative stress in a pre-existing steatosis condition. The effects produced by binge ethanol consumption in the liver of male Wistar rats fed a standard (Ctrl) or a high-fat diet HFD were compared. The liver status was checked through tissue histology and standard serum parameters. Alteration of hepatic lipid homeostasis and consequent oxidative unbalance were assessed by quantifying the mRNA expression of the lipid-regulated peroxisome proliferator-activated receptors (PPARs), of the cytochromes CYP2E1 and CYP4A1, and of some antioxidant molecules such as the metallothionein isoforms MT1 and MT2 and the enzymes catalase and superoxide dismutase. The number of adipose differentiation-related protein (ADRP)-positive lipid droplets (LDs) was evaluated by immunohistochemical staining. As a response to the double insult of diet and ethanol the rat liver showed: (1) a larger increase in fat accumulation within ADRP-positive LDs; (2) stimulation of lipid oxidation in the attempt to limit excess fat accumulation; (3) induction of antioxidant proteins (MT2, in particular) to protect the liver from the ethanol-induced overproduction of oxygen radicals. The data indicate an increased susceptibility of fatty liver to ethanol and suggest that the synergistic effect of diet and ethanol on lipid dysmetabolism might be mediated, at least in part, by PPARs and cytochromes CYP4A1 and CYP2E1.

  10. Aldosterone induces fibrosis, oxidative stress and DNA damage in livers of male rats independent of blood pressure changes

    SciTech Connect

    Queisser, Nina; Happ, Kathrin; Link, Samuel; Jahn, Daniel; Zimnol, Anna; Geier, Andreas; Schupp, Nicole

    2014-11-01

    Mineralocorticoid receptor blockers show antifibrotic potential in hepatic fibrosis. The mechanism of this protective effect is not known yet, although reactive oxygen species seem to play an important role. Here, we investigated the effects of elevated levels of aldosterone (Ald), the primary ligand of the mineralocorticoid receptor, on livers of rats in a hyperaldosteronism model: aldosterone-induced hypertension. Male Sprague–Dawley rats were treated for 4 weeks with aldosterone. To distinguish if damage caused in the liver depended on increased blood pressure or on increased Ald levels, the mineralocorticoid receptor antagonist spironolactone was given in a subtherapeutic dose, not normalizing blood pressure. To investigate the impact of oxidative stress, the antioxidant tempol was administered. Aldosterone induced fibrosis, detected histopathologically, and by expression analysis of the fibrosis marker, α-smooth muscle actin. Further, the mRNA amount of the profibrotic cytokine TGF-β was increased significantly. Fibrosis could be reduced by scavenging reactive oxygen species, and also by blocking the mineralocorticoid receptor. Furthermore, aldosterone treatment caused oxidative stress and DNA double strand breaks in livers, as well as the elevation of DNA repair activity. An increase of the transcription factor Nrf2, the main regulator of the antioxidative response could be observed, and of its target genes heme oxygenase-1 and γ-glutamylcysteine synthetase. All these effects of aldosterone were prevented by spironolactone and tempol. Already after 4 weeks of treatment, aldosteroneinfusion induced fibrosis in the liver. This effect was independent of elevated blood pressure. DNA damage caused by aldosterone might contribute to fibrosis progression when aldosterone is chronically increased. - Highlights: • Aldosterone has direct profibrotic effects on the liver independent of blood pressure. • Fibrosis is mediated by the mineralocorticoid receptor and

  11. Time course and mechanism of oxidative stress and tissue damage in rat liver subjected to in vivo ischemia-reperfusion.

    PubMed Central

    González-Flecha, B; Cutrin, J C; Boveris, A

    1993-01-01

    The time course of oxidative stress and tissue damage in zonal liver ischemia-reperfusion in rat liver in vivo was evaluated. After 180 min of ischemia, surface chemiluminescence decreased to zero, state 3 mitochondrial respiration decreased by 70-80%, and xanthine oxidase activity increased by 26% without change in the water content and in the activities of superoxide dismutase, catalase, and glutathione peroxidase. After reperfusion, marked increases in oxyradical production and tissue damage were detected. Mitochondrial oxygen uptake in state 3 and respiratory control as well as the activities of superoxide dismutase, catalase, and glutathione peroxidase and the level of nonenzymatic antioxidants (evaluated by the hydroperoxide-initiated chemiluminescence) were decreased. The severity of the post-reperfusion changes correlated with the time of ischemia. Morphologically, hepatocytes appeared swollen with zonal cord disarrangement which ranged from mild to severe for the tissue reperfused after 60-180 min of ischemia. Neutrophil infiltration was observed after 180 min of ischemia and 30 min of reperfusion. Mitochondria appear as the major source of hydrogen peroxide in control and in reperfused liver, as indicated by the almost complete inhibition of hydrogen peroxide production exerted by the uncoupler carbonylcyanide p-(trifluoromethoxy) phenylhydrazone. Additionally, inhibition of mitochondrial electron transfer by antimycin in liver slices reproduced the inhibition of state 3 mitochondrial respiration and the increase in hydrogen peroxide steady-state concentration found in reperfused liver. Increased rates of oxyradical production by inhibited mitochondria appear as the initial cause of oxidative stress and liver damage during early reperfusion in rat liver. Images PMID:8432855

  12. Permethrin-induced oxidative damage in liver of rainbow trout (Oncorhynchus mykiss) and its attenuation by vitamin C

    PubMed Central

    Mozhdeganloo, Z.; Moghadam Jafari, A.; Koohi, M. K.; Heidarpour, M.

    2016-01-01

    The objective of this study was to investigate the propensity of permethrin (PTN) to induce oxidative stress and changes in enzyme activities in liver of rainbow trout and its possible attenuation by vitamin C. Forty-eight fish were randomly assigned to 1 of 6 treatment groups and their livers were used for liver perfusion method: control (0 µgL-1 permethrin and 0 mgL-1 vitamin C), PTN-0.16 (0.16 µgL-1 permethrin), PTN-0.32 (0.32 µgL-1 permethrin), PTN-0.64 (0.64 µgL-1 permethrin), Vit. C (17.2 mgL-1 vitamin C), and PTN-0.64 + Vit. C (0.64 µgL-1 permethrin and 17.2 mgL-1 vitamin C). Results obtained showed that permethrin significantly (P<0.05) increased ALT, AST and LDH activities in the liver perfusion medium and malondialdehyde (MDA) level in liver tissue. The values of reduced glutathione (GSH) and total antioxidant capacity (FRAP) in the liver tissue were significantly decreased due to permethrin administration. Pearson’s correlation analysis revealed a positive correlation between MDA concentration and ALT, AST and LDH activities in the permethrin groups, suggesting that the enhanced lipid peroxidation may be linked to hepatic damage caused by permethrin. On the other hand, treatment with vitamin C in the PTN-0.64 + Vit. C group increased the values of GSH and FRAP, and decreased the level of MDA and the activities of hepatic enzymes, when compared to the PTN-0.64 group. The present study revealed that vitamin C could ameliorate permethrin-induced oxidative damage by decreasing lipid peroxidation and altering antioxidant defense system in liver of rainbow trout. PMID:27656226

  13. Epigallocatechin 3-Gallate Ameliorates Bile Duct Ligation Induced Liver Injury in Mice by Modulation of Mitochondrial Oxidative Stress and Inflammation

    PubMed Central

    Su, Rong; Xie, Haiyang; Zhou, Lin; Zheng, Shusen

    2015-01-01

    Cholestatic liver fibrosis was achieved by bile duct ligation (BDL) in mice. Liver injury associated with BDL for 15 days included significant reactive oxygen/nitrogen species generation, liver inflammation, cell death and fibrosis. Administration of Epigallocatechin 3-Gallate (EGCG) in animals reduced liver fibrosis involving parenchymal cells in BDL model. EGCG attenuated BDL-induced gene expression of pro-fibrotic markers (Collagen, Fibronectin, alpha 2 smooth muscle actin or SMA and connective tissue growth factor or CTGF), mitochondrial oxidative stress, cell death marker (DNA fragmentation and PARP activity), NFκB activity and pro-inflammatory cytokines (TNFα, MIP1α, IL1β, and MIP2). EGCG also improved BDL induced damages of mitochondrial electron transport chain complexes and antioxidant defense enzymes such as glutathione peroxidase and manganese superoxide dismutase. EGCG also attenuated hydrogen peroxide induced cell death in hepatocytes in vitro and alleviate stellate cells mediated fibrosis through TIMP1, SMA, Collagen 1 and Fibronectin in vitro. In conclusion, the reactive oxygen/nitrogen species generated from mitochondria plays critical pathogenetic role in the progression of liver inflammation and fibrosis and this study indicate that EGCG might be beneficial for reducing liver inflammation and fibrosis. PMID:25955525

  14. Cobalt-induced oxidative stress in brain, liver and kidney of goldfish Carassius auratus.

    PubMed

    Kubrak, Olha I; Husak, Viktor V; Rovenko, Bohdana M; Storey, Janet M; Storey, Kenneth B; Lushchak, Volodymyr I

    2011-10-01

    Cobalt is an essential element, but at high concentrations it is toxic. In addition to its well-known function as an integral part of cobalamin (vitamin B₁₂), cobalt has recently been shown to be a mimetic of hypoxia and a stimulator of the production of reactive oxygen species. The present study investigated the responses of goldfish, Carassius auratus, to 96 h exposure to 50, 100 or 150 mg L⁻¹ Co²⁺ in aquarium water (administered as CoCl₂). The concentrations of cobalt in aquaria did not change during fish exposure. Exposure to cobalt resulted in increased levels of lipid peroxides in brain (a 111% increase after exposure to 150 mg L⁻¹ Co²⁺) and liver (30-66% increases after exposure to 50-150 mg L⁻¹ Co²⁺), whereas the content of protein carbonyls rose only in kidney (by 112%) after exposure to 150 mg L⁻¹ cobalt. Low molecular mass thiols were depleted by 24-41% in brain in response to cobalt treatment. The activities of primary antioxidant enzymes, superoxide dismutase (SOD) and catalase, were substantially suppressed in brain and liver as a result of Co²⁺ exposure, whereas in kidney catalase activity was unchanged and SOD activity increased. The activities of glutathione-related enzymes, glutathione peroxidase and glutathione-S-transferase, did not change as a result of cobalt exposure, but glutathione reductase activity increased by ∼40% and ∼70% in brain and kidney, respectively. Taken together, these data show that exposure of fish to Co²⁺ ions results in the development of oxidative stress and the activation of defense systems in different goldfish tissues.

  15. Glutamine is highly effective in preventing in vivo cobalt-induced oxidative stress in rat liver

    PubMed Central

    Gonzales, Soledad; Polizio, Ariel H.; Erario, María A.; Tomaro, María L.

    2005-01-01

    AIM: To evaluate the in vivo effect of glutamine on cobalt-generated oxidative stress and (HO-1) induction in rat liver. METHODS: Fasted female Wistar rats received a single injection of cobalt chloride (375 µmol/kg body weight) and then were killed at different times. Lipid peroxidation and soluble and enzymatic antioxidant defense system (reduced glutathione (GSH), catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD)) were measured in liver homogenates. Ferritin and ferritin iron contents as well as heme oxygenase-1 (HO-1) activity and expression were also determined. The antioxidant properties of glutamine (Gln) were also evaluated. RESULTS: Cobalt chloride increased lipid peroxidation (50% over control values) 1 h after treatment. GSH reached a minimum at 3 h (40%) increasing thereafter. Twelve hours after CoCl2 injection, the antioxidant enzymes CAT, GSH-Px and SOD also diminished by about 30%. Heme oxygenase-1 induction was observed 6 h after treatment reaching a maximum value of 14-fold over the controls, 12 h after cobalt treatment. A 1.7-fold increase in ferritin and ferritin-bound iron 24 h after treatment were also obtained. Administration of glutamine (300 mg/kg body weight) by gavage 24 h before CoCl2 treatment entirely prevented the increase in thiobarbituric acid reactive substances (TBARS) content, the decrease in GSH levels, and partially reverted heme oxygenase-1 induction. CONCLUSION: These results suggested that a natural product such as glutamine prevents glutathione depletion and consequently heme oxygenase induction. PMID:15962369

  16. p62/SQSTM1 Plays a Protective Role in Oxidative Injury of Steatotic Liver in a Mouse Hepatectomy Model

    PubMed Central

    Haga, Sanae; Ozawa, Takeaki; Yamada, Yuma; Morita, Naoki; Nagashima, Izuru; Inoue, Hiroshi; Inaba, Yuka; Noda, Natsumi; Abe, Riichiro; Umezawa, Kazuo

    2014-01-01

    Abstract Aims: Liver injury and regeneration involve complicated processes and are affected by various physio-pathological factors. We investigated the mechanisms of steatosis-associated liver injury and delayed regeneration in a mouse model of partial hepatectomy. Results: Initial regeneration of the steatotic liver was significantly delayed after hepatectomy. Although hepatocyte proliferation was not significantly suppressed, severe liver injury with oxidative stress (OS) occurred immediately after hepatectomy in the steatotic liver. Fas-ligand (FasL)/Fas expression was upregulated in the steatotic liver, whereas the expression of antioxidant and anti-apoptotic molecules (catalase/MnSOD/Ref-1 and Bcl-2/Bcl-xL/FLIP, respectively) and p62/SQSTM1, a steatosis-associated protein, was downregulated. Interestingly, pro-survival Akt was not activated in response to hepatectomy, although it was sufficiently expressed even before hepatectomy. Suppression of p62/SQSTM1 increased FasL/Fas expression and reduced nuclear factor erythroid 2-related factor-2 (Nrf-2)-dependent antioxidant response elements activity and antioxidant responses in steatotic and nonsteatotic hepatocytes. Exogenously added FasL induced severe cellular OS and necrosis/apoptosis in steatotic hepatocytes, with only the necrosis being inhibited by pretreatment with antioxidants, suggesting that FasL/Fas-induced OS mainly leads to necrosis. Furthermore, p62/SQSTM1 re-expression in the steatotic liver markedly reduced liver injury and improved liver regeneration. Innovation: This study is the first which demonstrates that reduced expression of p62/SQSTM1 plays a crucial role in posthepatectomy acute injury and delayed regeneration of steatotic liver, mainly via redox-dependent mechanisms. Conclusion: In the steatotic liver, reduced expression of p62/SQSTM1 induced FasL/Fas overexpression and suppressed antioxidant genes, mainly through Nrf-2 inactivation, which, along with the hypo-responsiveness of Akt

  17. Oxidation of the flavonoids galangin and kaempferide by human liver microsomes and CYP1A1, CYP1A2, and CYP2C9.

    PubMed

    Otake, Yoko; Walle, Thomas

    2002-02-01

    There is very limited information on cytochrome P450 (P450)-mediated oxidative metabolism of dietary flavonoids in humans. In this study, we used human liver microsomes and recombinant P450 isoforms to examine the metabolism of two flavonols, galangin and kaempferide, and one flavone, chrysin. Both galangin and kaempferide, but not chrysin, were oxidized by human liver microsomes to kaempferol, with K(m) values of 9.5 and 17.8 microM, respectively. These oxidations were catalyzed mainly by CYP1A2 but also by CYP2C9. Consistent with these observations, the human liver microsomal metabolism of galangin and kaempferide were inhibited by the P450 inhibitors furafylline and sulfaphenazole. In addition, CYP1A1, although less efficient, was also able to oxidize the two flavonols. Thus, dietary flavonols are likely to undergo oxidative metabolism mainly in the liver but also extrahepatically.

  18. Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity.

    PubMed

    Jaeschke, Hartmut; McGill, Mitchell R; Ramachandran, Anup

    2012-02-01

    Hepatotoxicity is a serious problem during drug development and for the use of many established drugs. For example, acetaminophen overdose is currently the most frequent cause of acute liver failure in the United States and Great Britain. Evaluation of the mechanisms of drug-induced liver injury indicates that mitochondria are critical targets for drug toxicity, either directly or indirectly through the formation of reactive metabolites. The consequence of these modifications is generally a mitochondrial oxidant stress and peroxynitrite formation, which leads to structural alterations of proteins and mitochondrial DNA and, eventually, to the opening of mitochondrial membrane permeability transition (MPT) pores. MPT pore formation results in a collapse of mitochondrial membrane potential and cessation of adenosine triphosphate synthesis. In addition, the release of intermembrane proteins, such as apoptosis-inducing factor and endonuclease G, and their translocation to the nucleus, leads to nuclear DNA fragmentation. Together, these events trigger necrotic cell death. Alternatively, the release of cytochrome c and other proapoptotic factors from mitochondria can promote caspase activation and apoptotic cell death. Drug toxicity can also induce an inflammatory response with the formation of reactive oxygen species by Kupffer cells and neutrophils. If not properly detoxified, these extracellularly generated oxidants can diffuse into hepatocytes and trigger mitochondrial dysfunction and oxidant stress, which then induces MPT and necrotic cell death. This review addresses the formation of oxidants and the defense mechanisms available for cells and applies this knowledge to better understand mechanisms of drug hepatotoxicity, especially acetaminophen-induced liver injury.

  19. Oxidative stress in rat brain but not in liver following oral administration of a low dose of nanoparticulate silver.

    PubMed

    Skalska, Joanna; Dąbrowska-Bouta, Beata; Strużyńska, Lidia

    2016-11-01

    While it is known that silver nanoparticles (AgNPs) can enter the brain, our knowledge of AgNP-induced neurotoxicity remains incomplete. We investigated the ability of 10 nm citrate-stabilized AgNPs to generate oxidative stress in brain and liver of adult male Wistar rats after repeated oral exposure for 14 days, using a low dose of 0.2 mg/kg b.w. as compared with the same dose of ionic silver (silver citrate). In AgNP-exposed animals, the level of reactive oxygen species (ROS), lipid peroxidation (MDA) and glutathione peroxidase (GPx) activity were found to be significantly higher in brain relative to the control group receiving saline. Administration of ionic silver (silver citrate) increased ROS and MDA levels in both tissues. Activities of GPx in brain so as superoxide dismutase (SOD) and catalase (CAT) in liver of exposed animals were also elevated. Besides, AgNPs and silver ions were both found to cause statistically significant decrease in the reduced-to-oxidized glutathione ratio (GSH/GSSG) in brain. The results show that exposure to a very low dose of particulate silver generates mild oxidative stress in the brain but not in the liver of rats, indicating a role of oxidative stress in AgNP-induced neurotoxicity.

  20. OXIDANT STRESS, MITOCHONDRIA AND CELL DEATH MECHANISMS IN DRUG-INDUCED LIVER INJURY: LESSONS LEARNED FROM ACETAMINOPHEN HEPATOTOXICITY

    PubMed Central

    Jaeschke, Hartmut; McGill, Mitchell R.; Ramachandran, Anup

    2017-01-01

    Hepatotoxicity is a serious problem during drug development and for the use of many established drugs. For example, acetaminophen overdose is currently the most frequent cause of acute liver failure in the United States and Great Britain. Evaluation of the mechanisms of drug-induced liver injury indicates that mitochondria are critical targets for drug toxicity, either directly or indirectly through formation of reactive metabolites. The consequence of these modifications is generally a mitochondrial oxidant stress and peroxynitrite formation, which leads to structural alterations of proteins and mitochondrial DNA and eventually to the opening of mitochondrial membrane permeability transition (MPT) pores. MPT pore formation results in collapse of the mitochondrial membrane potential and cessation of ATP synthesis. In addition, the release of intermembrane proteins such as apoptosis-inducing factor and endonuclease G and their translocation to the nucleus leads to nuclear DNA fragmentation. Together these events trigger necrotic cell death. Alternatively, release of cytochrome c and other pro-apoptotic factors from mitochondria can promote caspase activation and apoptotic cell death. Drug toxicity can also induce an inflammatory response with formation of reactive oxygen species by Kupffer cells and neutrophils. If not properly detoxified, these extracellularly generated oxidants can diffuse into hepatocytes and trigger mitochondrial dysfunction and oxidant stress, which then induces the MPT and necrotic cell death. This review addresses the formation of oxidants and the defense mechanisms available for the cells and applies this knowledge to better understand mechanisms of drug hepatotoxicity, especially acetaminophen-induced liver injury. PMID:22229890

  1. Radioprotective effects of Nigella sativa oil against oxidative stress in liver tissue of rats exposed to total head irradiation.

    PubMed

    Cikman, Oztekin; Ozkan, Adile; Aras, Adem Bozkurt; Soylemez, Omer; Alkis, Hilal; Taysi, Seyithan; Karaayvaz, Muammer

    2014-10-01

    Many cancer patients treated with radiotherapy suffer severe side effects during and after their treatment. The aim of this study was to investigate the effects of irradiation and the addition of Nigella sativa oil (NSO) on the oxidant/antioxidant system in the liver tissue of irradiated rats. A total of 24 Sprague-Dawley rats were randomly distributed into three groups of equal numbers. The control group received neither NSO nor irradiation but received 1-ml saline orally. The irradiation group (IR) received total head 5 gray (Gy) of gamma irradiation as a single dose, plus 1-ml saline orally. The IR plus NSO group received both total head 5 Gy of gamma irradiation as a single dose and 1 g/kg/day NSO orally through an orogastric tube starting one hour before irradiation and continuing for 10 days. While liver tissue total oxidant status (TOS), lipid hydroperoxide (LOOH) level, and oxidative stress index (OSI) were significantly increased in the IR group compared to the control group, total antioxidant status (TAS), sulfhydryl (-SH) levels, and PON activity were significantly decreased. Cp activity in the IR plus NSO and IR groups was higher than in the control group. ARYL activity in the IR plus NSO supplemented group was higher than that in other groups. NSO reduces oxidative stress markers and has antioxidant effects, which also augments the antioxidant capacity in the liver tissue of rats.

  2. Factors influencing palmitoyl-CoA oxidation by rat liver peroxisomal fractions. Substrate concentration, organelle integrity and ATP.

    PubMed Central

    Thomas, J; Debeer, L J; De Schepper, P J; Mannaerts, G P

    1980-01-01

    1. The first dehydrogenation step of peroxisomal beta-oxidation involves the reduction of O2 to H2O2. Production rates of H2O2 and acetyl units by purified rat liver peroxisomes oxidizing palmitoyl-CoA were equal, indicating that H2O2 production is a reliable index for the release of acetyl units during peroxisomal fatty-acid oxidation. 2. Measurements of H2O2 and acid-soluble oxidation products during [1-14C]palmitoyl-CoA oxidation by purified peroxisomes revealed that the number of acetyl units released per molecule of palmitoyl-CoA oxidized rapidly decreased with increasing unbound palmitoyl-CoA concentrations. Structural damage to the peroxisomes caused by detergents or other treatments also decreased the number of acetyl units released. Under conditions where oxidation proceeded linearly with time the theoretical maximum of 5 acetyl units released per molecule of palmitoyl-CoA oxidized [Lazarow (1978) J. Biol. Chem. 253, 1522--1528] was never reached. 3. Expressed in terms of acetyl units produced and measured at low unbound-palmitoyl-CoA concentrations, mitochondrial oxidation was 10--20-fold higher than peroxisomal oxidation. 4. ATP stimulated peroxisomal palmitoyl-CoA oxidation approx. 2-fold. The ATP effect required the presence of Mg2+ and was lost when peroxisomal membranes were disrupted by Triton X-100 or high concentrations of unbound palmitoyl-CoA. 5. Disruption of peroxisomes by detergents, freeze--thawing, osmotic or mechanical treatment did not stimulate palmitoyl-CoA oxidation in the presence of ATP, indicating that peroxisomal fatty-acid-CoA oxidation was not latent. In the absence of ATP, Triton X-100 stimulated peroxisomal palmitoyl-CoA oxidation approx. 2-fold. PMID:7470063

  3. The nitric oxide donor S-nitrosoglutathione reduces apoptotic primary liver cell loss in a three-dimensional perfusion bioreactor culture model developed for liver support.

    PubMed

    Prince, Jose M; Vodovotz, Yoram; Baun, Matthew J; Monga, Satdarshan Pal; Billiar, Timothy R; Gerlach, Jörg C

    2010-03-01

    Artificial extracorporeal support for hepatic failure has met with limited clinical success. In hepatocytes, nitric oxide (NO) functions as an antiapoptotic modulator in response to a variety of stresses. We hypothesized that NO administration would yield improved viability and hepatocellular restructuring in a four-compartment, hollow fiber-based bioreactor with integral oxygenation for dynamic three-dimensional perfusion of hepatic cells in bioartificial liver support systems. Isolated adult rat liver cells were placed in culture medium alone (control) or medium supplemented with various concentrations of an NO donor (S-nitrosoglutathione [GSNO]) in the bioreactors. Media samples were obtained from the cell perfusion circuit to monitor cellular response. After 24 and 72 h, histology biopsies were taken to investigate spontaneous restructuring of the cells. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to quantify apoptotic nuclei. Control bioreactors exhibited 47.9 +/- 2.9% (mean +/- standard error of the mean) apoptotic nuclei. In contrast, NO-treated bioreactors exhibited a biphasic response. Fewer apoptotic nuclei were seen in the 200 and 500 microM GSNO groups (14.4 +/- 0.4%). No effect was observed in the 10 microM GSNO group (47.3%), and increased TUNEL staining was observed in the 1000 microM GSNO group (82.6%). Media lactate dehydrogenase levels were lower in bioreactor groups treated with 200 or 500 microM GSNO (310 +/- 38 IU/L) compared with the control group (919 +/- 188 IU/L; p < 0.05). Protein synthesis was not affected, as measured by albumin levels in the media (115 +/- 19 microg/day/cell inoculum in GSNO-treated bioreactors at 24 h vs. 110 +/- 13 in controls; p = 0.851). Histologically, all of the bioreactor groups exhibited liver cell aggregates with some attached to the bioreactor capillaries. Increased numbers of cells in the aggregates and superior spontaneous restructuring of the cells were seen at

  4. The p66Shc protein controls redox signaling and oxidation-dependent DNA damage in human liver cells.

    PubMed

    Perrini, Sebastio; Tortosa, Federica; Natalicchio, Annalisa; Pacelli, Consiglia; Cignarelli, Angelo; Palmieri, Vincenzo O; Caccioppoli, Cristina; De Stefano, Francesca; Porro, Stefania; Leonardini, Anna; Ficarella, Romina; De Fazio, Michele; Cocco, Tiziana; Puglisi, Francesco; Laviola, Luigi; Palasciano, Giuseppe; Giorgino, Francesco

    2015-11-15

    The p66Shc protein mediates oxidative stress-related injury in multiple tissues. Steatohepatitis is characterized by enhanced oxidative stress-mediated cell damage. The role of p66Shc in redox signaling was investigated in human liver cells and alcoholic steatohepatitis. HepG2 cells with overexpression of wild-type or mutant p66Shc, with Ser36 replacement by Ala, were obtained through infection with recombinant adenoviruses. Reactive oxygen species and oxidation-dependent DNA damage were assessed by measuring dihydroethidium oxidation and 8-hydroxy-2'-deoxyguanosine accumulation into DNA, respectively. mRNA and protein levels of signaling intermediates were evaluated in HepG2 cells and liver biopsies from control and alcoholic steatohepatitis subjects. Exposure to H2O2 increased reactive oxygen species and phosphorylation of p66Shc on Ser36 in HepG2 cells. Overexpression of p66Shc promoted reactive oxygen species synthesis and oxidation-dependent DNA damage, which were further enhanced by H2O2. p66Shc activation also resulted in increased Erk-1/2, Akt, and FoxO3a phosphorylation. Blocking of Erk-1/2 activation inhibited p66Shc phosphorylation on Ser36. Increased p66Shc expression was associated with reduced mRNA levels of antioxidant molecules, such as NF-E2-related factor 2 and its target genes. In contrast, overexpression of the phosphorylation defective p66Shc Ala36 mutant inhibited p66Shc signaling, enhanced antioxidant genes, and suppressed reactive oxygen species and oxidation-dependent DNA damage. Increased p66Shc protein levels and Akt phosphorylation were observed in liver biopsies from alcoholic steatohepatitis compared with control subjects. In human alcoholic steatohepatitis, increased hepatocyte p66Shc protein levels may enhance susceptibility to DNA damage by oxidative stress by promoting reactive oxygen species synthesis and repressing antioxidant pathways. Copyright © 2015 the American Physiological Society.

  5. Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver.

    PubMed

    Yang, Lili; Wu, Defeng; Wang, Xiaodong; Cederbaum, Arthur I

    2012-09-01

    Binge alcohol drinking induces hepatic steatosis. Recent studies showed that chronic ethanol-induced fatty liver was, at least in part, CYP2E1 dependent. The mechanism of acute alcohol-induced steatosis and whether CYP2E1 plays any role are still unclear. Increasing oxidative stress by alcohol can activate the JNK MAP kinase signaling pathway, suggesting that JNK might be a target for prevention of alcohol-induced steatosis. We used CYP2E1 knockout (KO) mice, a JNK inhibitor, and JNK1 or JNK2 knockout mice to test the role of CYP2E1, JNK, and the individual role of JNK1 and JNK2 in acute alcohol-induced steatosis. In wild-type (WT) mice, acute alcohol activates CYP2E1 and increases oxidative stress, which reciprocally increases activation of the JNK signaling pathway. Acute alcohol-induced fatty liver and oxidative stress were blunted in CYP2E1 KO mice and by the JNK inhibitor in WT mice. The antioxidant N-acetylcysteine decreased the acute alcohol-induced oxidative stress, the activation of JNK, and the steatosis but not the activation of CYP2E1. Acute alcohol decreased autophagy and increased expression of SREBP, effects blocked by the JNK inhibitor. Acute alcohol-induced fatty liver was the same in JNK1 and JNK2 KO mice as in WT mice; thus either JNK1 or JNK2 per se is sufficient for induction of steatosis by acute alcohol. The results show that acute alcohol elevation of CYP2E1, oxidative stress, and activation of JNK interact to lower autophagy and increase lipogenic SREBP resulting in fatty liver.

  6. Contribution of Cyclooxygenase End Products and Oxidative Stress to Intrahepatic Endothelial Dysfunction in Early Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Morales Arraez, Dalia; Marcelino Reyes, Raquel; Abrante, Beatriz; Diaz-Flores, Felicitas; Salido, Eduardo; Quintero, Enrique; Hernández-Guerra, Manuel

    2016-01-01

    Introduction Metabolic syndrome induces endothelial dysfunction, a surrogate marker of cardiovascular disease. In parallel, metabolic syndrome is frequently associated with non-alcoholic fatty liver disease (NAFLD), which may progress to cirrhosis. The aim of the present study was to evaluate intrahepatic endothelial dysfunction related to cyclooxygenase end products and oxidative stress as possible mechanisms involved in the pathophysiology of NAFLD. Materials and Methods Sprague-Dawley rats were fed standard diet (control-diet, CD) or high-fat-diet (HFD) for 6 weeks. Metabolic syndrome was assessed by recording arterial pressure, lipids, glycemia and rat body weight. Splanchnic hemodynamics were measured, and endothelial dysfunction was evaluated using concentration-effect curves to acetylcholine. Response was assessed with either vehicle, L-NG-Nitroarginine (L-NNA), indomethacin, tempol, or a thromboxane receptor antagonist, SQ 29548. We quantified inflammation, fibrosis, oxidative stress, nitric oxide (NO) bioavailability and thromboxane B2 levels. Results HFD rats exhibited metabolic syndrome together with the presence of NAFLD. Compared to control-diet livers, HFD livers showed increased hepatic vascular resistance unrelated to inflammation or fibrosis, but with decreased NO activity and increased oxidative stress. Endothelial dysfunction was observed in HFD livers compared with CD rats and improved after cyclooxygenase inhibition or tempol pre-incubation. However, pre-incubation with SQ 29548 did not modify acetylcholine response. Conclusions Our study provides evidence that endothelial dysfunction at an early stage of NAFLD is associated with reduced NO bioavailability together with increased cyclooxygenase end products and oxidative stress, which suggests that both pathways are involved in the pathophysiology and may be worth exploring as therapeutic targets to prevent progression of the disease. PMID:27227672

  7. The Protective Effect of Selenium on Oxidative Stress Induced by Waterpipe (Narghile) Smoke in Lungs and Liver of Mice.

    PubMed

    Charab, Mohamad A; Abouzeinab, Noura S; Moustafa, Mohamed E

    2016-12-01

    Waterpipe smoking is common in the Middle East populations and results in health problems. In this study, we investigated the effects of exposure of mice to waterpipe smoke on oxidative stress in lungs and liver and the effects of selenium administration before smoke exposure on the oxidative stress. Twenty-four mice were divided equally into four groups: (i) the control mice received no exposure or treatment; (ii) mice exposed to waterpipe smoke; (iii) mice received intraperitoneal injection of 0.59 μg selenium/kg body weight as sodium selenite 15 min before the exposure to waterpipe smoke; and (iv) mice received intraperitoneal injection of 1.78 μg selenium/kg body weight as sodium selenite 15 min before the exposure to waterpipe smoke. Mice were exposed to waterpipe smoke every other day for four times within 8 successive days. Malondialdehyde and nitric oxide levels were significantly higher in the lungs and liver, while the activities of superoxide dismutase, glutathione peroxidase-1, and catalase were significantly lower in the waterpipe smoke group when compared to control mice. Treating mice with 1.78 μg selenium/kg body weight significantly restored the normal levels of these parameters. Histological examinations of lungs and liver confirmed the protective actions of selenium against the effects of exposure to waterpipe smoke. In conclusion, exposure of mice to waterpipe smoke-induced oxidative stress in lungs and liver. Administration of low level of selenium, 1.78 μg selenium/kg body weight as sodium selenite, exerted protective effects against oxidative stress induced by exposure to waterpipe smoke.

  8. Ob/ob Mouse Livers Show Decreased Oxidative Phosphorylation Efficiencies and Anaerobic Capacities after Cold Ischemia

    PubMed Central

    Tagaloa, Sherry; Zhang, Linda; Dare, Anna J.; MacDonald, Julia R.; Yeong, Mee-Ling; Bartlett, Adam S. J. R.; Phillips, Anthony R. J.

    2014-01-01

    Background Hepatic steatosis is a major risk factor for graft failure in liver transplantation. Hepatic steatosis shows a greater negative influence on graft function following prolonged cold ischaemia. As the impact of steatosis on hepatocyte metabolism during extended cold ischaemia is not well-described, we compared markers of metabolic capacity and mitochondrial function in steatotic and lean livers following clinically relevant durations of cold preservation. Methods Livers from 10-week old leptin-deficient obese (ob/ob, n = 9) and lean C57 mice (n = 9) were preserved in ice-cold University of Wisconsin solution. Liver mitochondrial function was then assessed using high resolution respirometry after 1.5, 3, 5, 8, 12, 16 and 24 hours of storage. Metabolic marker enzymes for anaerobiosis and mitochondrial mass were also measured in conjunction with non-bicarbonate tissue pH buffering capacity. Results Ob/ob and lean mice livers showed severe (>60%) macrovesicular and mild (<30%) microvesicular steatosis on Oil Red O staining, respectively. Ob/ob livers had lower baseline enzymatic complex I activity but similar adenosine triphosphate (ATP) levels compared to lean livers. During cold storage, the respiratory control ratio and complex I-fueled phosphorylation deteriorated approximately twice as fast in ob/ob livers compared to lean livers. Ob/ob livers also demonstrated decreased ATP production capacities at all time-points analyzed compared to lean livers. Ob/ob liver baseline lactate dehydrogenase activities and intrinsic non-bicarbonate buffering capacities were depressed by 60% and 40%, respectively compared to lean livers. Conclusions Steatotic livers have impaired baseline aerobic and anaerobic capacities compared to lean livers, and mitochondrial function indices decrease particularly from after 5 hours of cold preservation. These data provide a mechanistic basis for the clinical recommendation of shorter cold storage durations in steatotic donor

  9. Ob/ob mouse livers show decreased oxidative phosphorylation efficiencies and anaerobic capacities after cold ischemia.

    PubMed

    Chu, Michael J J; Hickey, Anthony J R; Tagaloa, Sherry; Zhang, Linda; Dare, Anna J; MacDonald, Julia R; Yeong, Mee-Ling; Bartlett, Adam S J R; Phillips, Anthony R J

    2014-01-01

    Hepatic steatosis is a major risk factor for graft failure in liver transplantation. Hepatic steatosis shows a greater negative influence on graft function following prolonged cold ischaemia. As the impact of steatosis on hepatocyte metabolism during extended cold ischaemia is not well-described, we compared markers of metabolic capacity and mitochondrial function in steatotic and lean livers following clinically relevant durations of cold preservation. Livers from 10-week old leptin-deficient obese (ob/ob, n = 9) and lean C57 mice (n = 9) were preserved in ice-cold University of Wisconsin solution. Liver mitochondrial function was then assessed using high resolution respirometry after 1.5, 3, 5, 8, 12, 16 and 24 hours of storage. Metabolic marker enzymes for anaerobiosis and mitochondrial mass were also measured in conjunction with non-bicarbonate tissue pH buffering capacity. Ob/ob and lean mice livers showed severe (>60%) macrovesicular and mild (<30%) microvesicular steatosis on Oil Red O staining, respectively. Ob/ob livers had lower baseline enzymatic complex I activity but similar adenosine triphosphate (ATP) levels compared to lean livers. During cold storage, the respiratory control ratio and complex I-fueled phosphorylation deteriorated approximately twice as fast in ob/ob livers compared to lean livers. Ob/ob livers also demonstrated decreased ATP production capacities at all time-points analyzed compared to lean livers. Ob/ob liver baseline lactate dehydrogenase activities and intrinsic non-bicarbonate buffering capacities were depressed by 60% and 40%, respectively compared to lean livers. Steatotic livers have impaired baseline aerobic and anaerobic capacities compared to lean livers, and mitochondrial function indices decrease particularly from after 5 hours of cold preservation. These data provide a mechanistic basis for the clinical recommendation of shorter cold storage durations in steatotic donor livers.

  10. Increased oxidative-modifications of cytosolic proteins in 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-exposed rat liver.

    PubMed

    Upreti, Vijay V; Moon, Kwan-Hoon; Yu, Li-Rong; Lee, Insong J; Eddington, Natalie D; Ye, Xiaoying; Veenstra, Timothy D; Song, Byoung-Joon

    2011-01-01

    It is well established that 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) causes acute liver damage in animals and humans. The aim of this study was to identify and characterize oxidative modification and inactivation of cytosolic proteins in MDMA-exposed rats. Markedly increased levels of oxidized and nitrated cytosolic proteins were detected 12 h after the second administration of two consecutive MDMA doses (10 mg/kg each). Comparative 2-DE analysis showed markedly increased levels of biotin-N-methylimide-labeled oxidized cytosolic proteins in MDMA-exposed rats compared to vehicle-treated rats. Proteins in the 22 gel spots of strong intensities were identified using MS/MS. The oxidatively modified proteins identified include anti-oxidant defensive enzymes, a calcium-binding protein, and proteins involved in metabolism of lipids, nitrogen, and carbohydrates (glycolysis). Cytosolic superoxide dismutase was oxidized and its activity significantly inhibited following MDMA exposure. Consistent with the oxidative inactivation of peroxiredoxin, MDMA activated c-Jun N-terminal protein kinase and p38 kinase. Since these protein kinases phosphorylate anti-apoptotic Bcl-2 protein, their activation may promote apoptosis in MDMA-exposed tissues. Our results show for the first time that MDMA induces oxidative-modification of many cytosolic proteins accompanied with increased oxidative stress and apoptosis, contributing to hepatic damage.

  11. Effects of Naringenin on Oxidative Stress and Histopathological Changes in the Liver of Lead Acetate Administered Rats.

    PubMed

    Ozkaya, Ahmet; Sahin, Zafer; Dag, Uzeyir; Ozkaraca, Mustafa

    2016-05-01

    Lead has several adverse effects on the body due to one of the environmental pollutants. We aimed to determine the effects of naringenin on the oxidative stress and the hepatic damage against lead acetate treatment in the liver of male rats. Naringenin was administered by orogastric gavage (50 mg/kg) and lead acetate was given as daily 500 parts per million in drinking water for 4 weeks. Lead and antioxidant activities were measured, and histopathological evaluation was performed in the liver. Lead concentrations, malondialdehyde, and antioxidant activity were restored by the naringenin. The grade of necrosis, hydropic degeneration, and hepatic cord disorganization was decreased by the naringenin. However, there were no differences in the degree of sinusoidal congestion, hepatic steatosis, and capsular fibrosis between lead acetate and naringenin + lead acetate groups. We can suggest that naringenin has antioxidant and chelating effects in the liver. Nevertheless, this effect is not enough against the lead acetate induced hepatic injury. © 2016 Wiley Periodicals, Inc.

  12. Green tea extract improves the oxidative state of the liver and brain in rats with adjuvant-induced arthritis.

    PubMed

    de Almeida Gonçalves, Geferson; de Sá-Nakanishi, Anacharis Babeto; Wendt, Mariana Marques Nogueira; Comar, Jurandir Fernando; Bersani Amado, Ciomar Aparecida; Bracht, Adelar; Peralta, Rosane Marina

    2015-08-01

    The purpose of the study was to evaluate the possible effects of the administration of a green tea extract on the oxidative state of the liver and brain of adjuvant-induced arthritic rats, a model for human rheumatoid arthritis. Daily doses of 250 mg kg(-1) (59.8 mg catechins per kg) for 23 days were administered. This treatment produced significant diminutions in protein and lipid damage in liver, brain and plasma. It also diminished the tissue ROS contents and increased the antioxidant capacity of the plasma. The antioxidant defenses, which are diminished by arthritis, were improved by the green tea treatment, as revealed by the restoration of the GSH and protein thiol levels and by the strong tendency for normalizing the activities of the antioxidant enzymes. The activity of glucose 6-phosphate dehydrogenase, which is increased by arthritis in the liver, was also almost normalized by the treatment. In conclusion, it can be said that green tea consumption is possibly beneficial for the liver and brain of patients suffering from rheumatoid arthritis because it attenuates the pronounced oxidative stress that accompanies the disease and, thus, diminishes the injury to lipids and proteins in both liver and brain. There are also indications that, in the liver, the green tea can contribute to normalize the metabolic functions that are substantially modified by arthritis. For example, the green tea normalized the activity of glucose 6-phosphate dehydrogenase, a key enzyme of an important metabolic route (pentose monophosphate pathway). It is expected that the green tea treatment is equally able to normalize the activity of other enzymes (e.g., glucokinase and glucose 6-phosphatase), a hypothesis to be tested by future work.

  13. Puerarin protects the rat liver against oxidative stress-mediated DNA damage and apoptosis induced by lead.

    PubMed

    Liu, Chan-Min; Ma, Jie-Qiong; Sun, Yun-Zhi

    2012-09-01

    Puerarin (PU), a natural flavonoid, has been reported to have many benefits and medicinal properties. In this study, we valuated the protective effect of puerarin against lead-induced oxidative DNA damage and apoptosis in rat liver. A total of forty male Wistar rats (8-week-old) was divided into 4 groups: control group; lead-treated group (500 mg Pb/l as the only drinking fluid); lead+puerarin treated group (500 mg Pb/l as the only drinking fluid plus 400 mg PU/kg bwt intra-gastrically once daily); and puerarin-treated group (400 mg PU/kg bwt intra-gastrically once daily). The experimental period was lasted for 75 successive days. Our data showed that puerarin significantly effectively improved the lead-induced histology changes in rat liver and decreased the serum ALT and AST activities in lead-treated rats. Puerarin markedly restored Cu/Zn-SOD, CAT and GPx activities and the GSH/GSSG ratio in the liver of lead-treated rat. Furthermore, the increase of 8-hydroxydeoxyguanosine induced by lead was effectively suppressed by puerarin. The enhanced caspase-3 activity in the rat liver induced by lead was also inhibited by puerarin. TUNEL assay showed that lead-induced apoptosis in rat liver was significantly inhibited by puerarin, which might be attributed to its antioxidant property. In conclusion, these results suggested that puerarin could protect the rat liver against lead-induced injury by reducing ROS production, renewing the activities of antioxidant enzymes and decreasing DNA oxidative damage.

  14. Silymarin Prevents Restraint Stress-Induced Acute Liver Injury by Ameliorating Oxidative Stress and Reducing Inflammatory Response.

    PubMed

    Kim, Sou Hyun; Oh, Dal-Seok; Oh, Ji Youn; Son, Tae Gen; Yuk, Dong Yeon; Jung, Young-Suk

    2016-04-01

    Silymarin is a flavonoid extracted from the milk thistle Silybum marianum. It has been reported to prevent liver injuries induced by various chemicals or toxins. Our recent study suggested that silymarin induces hepatic synthesis of glutathione by increasing cysteine availability, which may consequently contribute to increased antioxidant capacity of the liver. In the present study, we investigated the effects of silymarin on acute liver injury induced by restraint stress. Silymarin (100 mg/kg) was orally administered to BALB/c mice every 12 h (3 times in total). After the last dose, mice were subjected to restraint stress for 6 h, and serum levels of aspartate and alanine aminotransferases, and hepatic levels of lipid peroxidation were determined. Hepatic levels of sulfur-containing metabolites such as methionine, S-adenosylmethionine, cysteine, and glutathione were also measured. The level of pro-inflammatory mediators in both liver and serum was determined. To study the mechanism of the effects of silymarin, we assessed Jun N-terminal kinase (JNK) activation and apoptotic signaling. Restraint stress induced severe oxidative stress and increased mRNA levels of pro-inflammatory mediators; both effects of restraint stress were significantly inhibited by silymarin. Moreover, administration of silymarin significantly prevented acute liver injury induced by restraint stress by blocking JNK activation and subsequently apoptotic signaling. In conclusion, these results suggest that the inhibition of restraint stress-induced liver injury by silymarin is due at least in part to its anti-oxidant activity and its ability to suppress the inflammatory response.

  15. Effects of shock waves on oxidative stress and some trace element levels of rat liver and diaphragm muscles.

    PubMed

    Gecit, İlhan; Kavak, Servet; Meral, Ismail; Güneş, Mustafa; Pirinççi, Necip; Sayir, Fuat; Demir, Halit; Ceylan, Kadir

    2012-06-01

    This study was designed to investigate whether the short-term extracorporeal shockwave lithotripsy (ESWL) exposure to kidney produces an oxidative stress and a change in some trace element levels in liver and diaphragm muscles of rats. Twelve male Wistar albino rats were divided randomly into two groups, each consisting of six rats. The animals in the first group did not receive any treatment and served as control group. The right-side kidneys of animals in group 2 were treated with two-thousand 18 kV shock waves while anesthetized with 50 mg kg(-1) ketamine. The localization of the right kidney was achieved after contrast medium injection through a tail vein under fluoroscopy control. The animals were killed 72 h after the ESWL treatment, and liver and diaphragm muscles were harvested for the determination of tissue oxidative stress and trace element levels. Although the malondialdehyde level increased, superoxide dismutase and glutathione peroxidase enzyme activities decreased in the livers and diaphragm muscles of ESWL-treated rats. Although glutathione level increased in liver, it decreased in diaphragm muscles of ESWL-treated animals. Fe, Mg and Mn levels decreased, and Cu and Pb levels increased in the livers of ESWL-treated animals. Fe and Cu levels increased, and Mg, Pb, Mn and Zn levels decreased in the diaphragm muscles of ESWL-treated animals. It also causes a decrease or increase in many mineral levels in liver and diaphragm muscles, which is an undesirable condition for the normal physiological function of tissues. Copyright © 2012 John Wiley & Sons, Ltd.

  16. Oxidative stress and hepatic stellate cell activation are key events in arsenic induced liver fibrosis in mice

    SciTech Connect

    Ghatak, Subhadip; Biswas, Ayan; Dhali, Gopal Krishna; Chowdhury, Abhijit; Boyer, James L.; Santra, Amal

    2011-02-15

    Arsenic is an environmental toxicant and carcinogen. Exposure to arsenic is associated with development of liver fibrosis and portal hypertension through ill defined mechanisms. We evaluated hepatic fibrogenesis after long term arsenic exposure in a murine model. BALB/c mice were exposed to arsenic by daily gavages of 6 {mu}g/gm body weight for 1 year and were evaluated for markers of hepatic oxidative stress and fibrosis, as well as pro-inflammatory, pro-apoptotic and pro-fibrogenic factors at 9 and 12 months. Hepatic NADPH oxidase activity progressively increased in arsenic exposure with concomitant development of hepatic oxidative stress. Hepatic steatosis with occasional collection of mononuclear inflammatory cells and mild portal fibrosis were the predominant liver lesion observed after 9 months of arsenic exposure, while at 12 months, the changes included mild hepatic steatosis, inflammation, necrosis and significant fibrosis in periportal areas. The pathologic changes in the liver were associated with markers of hepatic stellate cells (HSCs) activation, matrix reorganization and fibrosis including {alpha}-smooth muscle actin, transforming growth factor-{beta}1, PDGF-R{beta}, pro-inflammatory cytokines and enhanced expression of tissue inhibitor of metalloproteinase-1 and pro({alpha}) collagen type I. Moreover, pro-apoptotic protein Bax was dominantly expressed and Bcl-2 was down-regulated along with increased number of TUNEL positive hepatocytes in liver of arsenic exposed mice. Furthermore, HSCs activation due to increased hepatic oxidative stress observed after in vivo arsenic exposure was recapitulated in co-culture model of isolated HSCs and hepatocytes exposed to arsenic. These findings have implications not only for the understanding of the pathology of arsenic related liver fibrosis but also for the design of preventive strategies in chronic arsenicosis.

  17. Serum Cytokeratin-18 Is Associated with NOX2-Generated Oxidative Stress in Patients with Nonalcoholic Fatty Liver.

    PubMed

    Del Ben, M; Polimeni, L; Baratta, F; Bartimoccia, S; Carnevale, R; Loffredo, L; Pignatelli, P; Violi, F; Angelico, F

    2014-01-01

    Background & Aims. Hepatocyte apoptosis may play a role in progression of nonalcoholic fatty liver and oxidative stress seems one of the key mechanisms responsible for liver damage. The aim was to determine the association of oxidative stress with cytokeratin-18 M30 fragment levels, a marker of hepatocyte apoptosis. Methods. Steatosis severity was defined according to Hamaguchi's echographic criteria in 209 patients with nonalcoholic fatty liver. Serum cytokeratin-18, urinary 8-iso-prostaglandin F2 α , soluble NOX2-derived peptide, and adiponectin were measured. Results. Serum cytokeratin-18 progressively increased with steatosis severity (from 169.5 (129.3/183.8) to 176 (140/190) and 180 (169.5/192.5) μ IU/mL in mild, moderate, and severe steatosis, respectively; P < 0.01). After stratification by cytokeratin-18 tertiles, a significant progression of body mass index, HOMA-IR, triglycerides, urinary 8-iso-PGF2 α , soluble NOX2-derived peptide, and of the prevalence of diabetes and severe steatosis was found, while HDL-cholesterol and adiponectin progressively decreased. A positive correlation between cytokeratin-18 and body mass index, HOMA-IR, Hamaguchi's score, urinary 8-iso-PGF2 α , and soluble NOX2-derived peptide and a negative correlation between cytokeratin-18 and HDL-cholesterol and adiponectin were found. Body mass index, adiponectin, and soluble NOX2-derived peptide were independent predictors of serum cytokeratin-18 levels (adjusted R (2) = 0.36). Conclusion. We support an association between oxidative stress and severity of liver damage in patients with nonalcoholic fatty liver.

  18. Serum Cytokeratin-18 Is Associated with NOX2-Generated Oxidative Stress in Patients with Nonalcoholic Fatty Liver

    PubMed Central

    Del Ben, M.; Polimeni, L.; Baratta, F.; Bartimoccia, S.; Carnevale, R.; Loffredo, L.; Pignatelli, P.; Violi, F.; Angelico, F.

    2014-01-01

    Background & Aims. Hepatocyte apoptosis may play a role in progression of nonalcoholic fatty liver and oxidative stress seems one of the key mechanisms responsible for liver damage. The aim was to determine the association of oxidative stress with cytokeratin-18 M30 fragment levels, a marker of hepatocyte apoptosis. Methods. Steatosis severity was defined according to Hamaguchi's echographic criteria in 209 patients with nonalcoholic fatty liver. Serum cytokeratin-18, urinary 8-iso-prostaglandin F2α, soluble NOX2-derived peptide, and adiponectin were measured. Results. Serum cytokeratin-18 progressively increased with steatosis severity (from 169.5 (129.3/183.8) to 176 (140/190) and 180 (169.5/192.5) μIU/mL in mild, moderate, and severe steatosis, respectively; P < 0.01). After stratification by cytokeratin-18 tertiles, a significant progression of body mass index, HOMA-IR, triglycerides, urinary 8-iso-PGF2α, soluble NOX2-derived peptide, and of the prevalence of diabetes and severe steatosis was found, while HDL-cholesterol and adiponectin progressively decreased. A positive correlation between cytokeratin-18 and body mass index, HOMA-IR, Hamaguchi's score, urinary 8-iso-PGF2α, and soluble NOX2-derived peptide and a negative correlation between cytokeratin-18 and HDL-cholesterol and adiponectin were found. Body mass index, adiponectin, and soluble NOX2-derived peptide were independent predictors of serum cytokeratin-18 levels (adjusted R2 = 0.36). Conclusion. We support an association between oxidative stress and severity of liver damage in patients with nonalcoholic fatty liver. PMID:24678423

  19. Effects of agmatine on chlorpromazine toxicity in the liver of Wistar rats: the possible role of oxidant/antioxidant imbalance.

    PubMed

    Bratislav, Dejanovic; Irena, Lavrnja; Milica, Ninkovic; Ivana, Stojanovic; Ana, Djuric; Sanda, Dilber; Ivana, Stevanovic

    2017-01-27

    Chlorpromazine (CPZ) is a member of a widely used class of antipsychotic agents. The metabolic pathways of CPZ toxicity were examined by monitoring oxidative/nitrosative stress markers. The aim of the study was to investigate the hypothesis that agmatine (AGM) prevents oxidative stress in the liver of Wistar rats 48 h after administration of CPZ. All tested compounds were administered intraperitoneally (i.p.) in one single dose. The animals were divided into control (C, 0.9% saline solution), CPZ (CPZ, 38.7 mg/kg b.w.), CPZ+AGM (AGM, 75 mg/kg b.w. immediately after CPZ, 38.7 mg/kg b.w. i.p.), and AGM (AGM, 75 mg/kg b.w.) groups. Rats were sacrificed by decapitation 48 h after treatment. The CPZ and CPZ+AGM treatments significantly increased thiobarbituric acid reactive substances (TBARS), the nitrite and nitrate (NO2+NO3) concentration, and superoxide anion (O2(•-)) production in rat liver homogenates compared with C values. CPZ injection decreased the capacity of the antioxidant defense system: superoxide dismutase (SOD) activity, catalase (CAT) activity, total glutathione (GSH) content, glutathione peroxidase (GPx) activity, and glutathione reductase (GR) activity compared with the values of the C group. However, treatment with AGM increased antioxidant capacity in the rat liver; it increased the CAT activity, GSH concentration, GPx activity, and GR activity compared with the values of the CPZ rats. Immunohistochemical staining of ED1 in rats showed an increase in the number of positive cells 48 h after acute CPZ administration compared with the C group. Our results showed that AGM has no protective effects on parameters of oxidative and/or nitrosative stress in the liver but that it absolutely protective effects on the antioxidant defense system and restores the antioxidant capacity in liver tissue after administration of CPZ.

  20. Effects of agmatine on chlorpromazine toxicity in the liver of Wistar rats: the possible role of oxidant/antioxidant imbalance

    PubMed Central

    Bratislav, Dejanovic; Irena, Lavrnja; Milica, Ninkovic; Ivana, Stojanovic; Ana, Djuric; Sanda, Dilber; Ivana, Stevanovic

    2016-01-01

    Chlorpromazine (CPZ) is a member of a widely used class of antipsychotic agents. The metabolic pathways of CPZ toxicity were examined by monitoring oxidative/nitrosative stress markers. The aim of the study was to investigate the hypothesis that agmatine (AGM) prevents oxidative stress in the liver of Wistar rats 48 h after administration of CPZ. All tested compounds were administered intraperitoneally (i.p.) in one single dose. The animals were divided into control (C, 0.9% saline solution), CPZ (CPZ, 38.7 mg/kg b.w.), CPZ+AGM (AGM, 75 mg/kg b.w. immediately after CPZ, 38.7 mg/kg b.w. i.p.), and AGM (AGM, 75 mg/kg b.w.) groups. Rats were sacrificed by decapitation 48 h after treatment. The CPZ and CPZ+AGM treatments significantly increased thiobarbituric acid reactive substances (TBARS), the nitrite and nitrate (NO2+NO3) concentration, and superoxide anion (O2•-) production in rat liver homogenates compared with C values. CPZ injection decreased the capacity of the antioxidant defense system: superoxide dismutase (SOD) activity, catalase (CAT) activity, total glutathione (GSH) content, glutathione peroxidase (GPx) activity, and glutathione reductase (GR) activity compared with the values of the C group. However, treatment with AGM increased antioxidant capacity in the rat liver; it increased the CAT activity, GSH concentration, GPx activity, and GR activity compared with the values of the CPZ rats. Immunohistochemical staining of ED1 in rats showed an increase in the number of positive cells 48 h after acute CPZ administration compared with the C group. Our results showed that AGM has no protective effects on parameters of oxidative and/or nitrosative stress in the liver but that it absolutely protective effects on the antioxidant defense system and restores the antioxidant capacity in liver tissue after administration of CPZ. PMID:27523096

  1. Induction of Inducible Nitric Oxide Synthase by Lipopolysaccharide and the Influences of Cell Volume Changes, Stress Hormones and Oxidative Stress on Nitric Oxide Efflux from the Perfused Liver of Air-Breathing Catfish, Heteropneustes fossilis

    PubMed Central

    Choudhury, Mahua G.; Saha, Nirmalendu

    2016-01-01

    The air-breathing singhi catfish (Heteropneustes fossilis) is frequently being challenged by bacterial contaminants, and different environmental insults like osmotic, hyper-ammonia, dehydration and oxidative stresses in its natural habitats throughout the year. The main objectives of the present investigation were to determine (a) the possible induction of inducible nitric oxide synthase (iNOS) gene with enhanced production of nitric oxide (NO) by intra-peritoneal injection of lipopolysaccharide (LPS) (a bacterial endotoxin), and (b) to determine the effects of hepatic cell volume changes due to anisotonicity or by infusion of certain metabolites, stress hormones and by induction of oxidative stress on production of NO from the iNOS-induced perfused liver of singhi catfish. Intra-peritoneal injection of LPS led to induction of iNOS gene and localized tissue specific expression of iNOS enzyme with more production and accumulation of NO in different tissues of singhi catfish. Further, changes of hydration status/cell volume, caused either by anisotonicity or by infusion of certain metabolites such as glutamine plus glycine and adenosine, affected the NO production from the perfused liver of iNOS-induced singhi catfish. In general, increase of hydration status/cell swelling due to hypotonicity caused decrease, and decrease of hydration status/cell shrinkage due to hypertonicity caused increase of NO efflux from the perfused liver, thus suggesting that changes in hydration status/cell volume of hepatic cells serve as a potent modulator for regulating the NO production. Significant increase of NO efflux from the perfused liver was also observed while infusing the liver with stress hormones like epinephrine and norepinephrine, accompanied with decrease of hydration status/cell volume of hepatic cells. Further, oxidative stress, caused due to infusion of t-butyl hydroperoxide and hydrogen peroxide separately, in the perfused liver of singhi catfish, resulted in

  2. Induction of Inducible Nitric Oxide Synthase by Lipopolysaccharide and the Influences of Cell Volume Changes, Stress Hormones and Oxidative Stress on Nitric Oxide Efflux from the Perfused Liver of Air-Breathing Catfish, Heteropneustes fossilis.

    PubMed

    Choudhury, Mahua G; Saha, Nirmalendu

    2016-01-01

    The air-breathing singhi catfish (Heteropneustes fossilis) is frequently being challenged by bacterial contaminants, and different environmental insults like osmotic, hyper-ammonia, dehydration and oxidative stresses in its natural habitats throughout the year. The main objectives of the present investigation were to determine (a) the possible induction of inducible nitric oxide synthase (iNOS) gene with enhanced production of nitric oxide (NO) by intra-peritoneal injection of lipopolysaccharide (LPS) (a bacterial endotoxin), and (b) to determine the effects of hepatic cell volume changes due to anisotonicity or by infusion of certain metabolites, stress hormones and by induction of oxidative stress on production of NO from the iNOS-induced perfused liver of singhi catfish. Intra-peritoneal injection of LPS led to induction of iNOS gene and localized tissue specific expression of iNOS enzyme with more production and accumulation of NO in different tissues of singhi catfish. Further, changes of hydration status/cell volume, caused either by anisotonicity or by infusion of certain metabolites such as glutamine plus glycine and adenosine, affected the NO production from the perfused liver of iNOS-induced singhi catfish. In general, increase of hydration status/cell swelling due to hypotonicity caused decrease, and decrease of hydration status/cell shrinkage due to hypertonicity caused increase of NO efflux from the perfused liver, thus suggesting that changes in hydration status/cell volume of hepatic cells serve as a potent modulator for regulating the NO production. Significant increase of NO efflux from the perfused liver was also observed while infusing the liver with stress hormones like epinephrine and norepinephrine, accompanied with decrease of hydration status/cell volume of hepatic cells. Further, oxidative stress, caused due to infusion of t-butyl hydroperoxide and hydrogen peroxide separately, in the perfused liver of singhi catfish, resulted in

  3. Protective effects of capillary artemisia polysaccharide on oxidative injury to the liver in rats with obstructive jaundice

    PubMed Central

    HE, CHANG-SHENG; YUE, HONG-YI; XU, JIAN; XUE, FENG; LIU, JIAN; LI, YUAN-YUAN; JING, HONG-EN

    2012-01-01

    Obstructive jaundice is a condition caused by blockage of the flow of bile out of the liver. This results in an overflow of bile and its by-products into the blood, and bile excretion from the body is incomplete. Untreated, obstructive jaundice can lead to serious infection that spreads to other parts of the body. We examined the protective effect of capillary artemisia polysaccharide on oxidative damage to the liver in growing rats with obstructive jaundice (OJ). Growing male Wistar rats (n=40, age 3–4 weeks) were randomly divided into four groups (n=10 in each group): normal control group, sham group, OJ group and OJ with capillary artimesia polysaccha-ride treatment group (study group). The rats of the OJ group and the study group were subjected to common bile dust ligation, while the sham group had the bile duct mobilized but not ligated. The rats of the study group recieved 5 ml/kg capillary artimesia polysaccharide (0.5 g/ml) by intraperitoneal (i.p.) injection once daily while the other groups were administered 5 ml/kg saline by i.p. injection. After 4 weeks, the rats were sacrificed to obtain liver weight and to compute the liver coefficient. Additional measures included liver homogenate malondialdehyde (MDA) and the activity levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT). The liver weight and liver coefficient of rats in the study group were lower than those in the OJ group and higher than those in the control and sham groups (P<0.05). Liver homogenate MDA content in the study group rats was lower than that in the OJ group and higher than that in the control and sham group (P<0.05). SOD, GSH-Px and CAT activities were higher in the study group rats than those in the OJ group and lower than those in other groups (P<0.05). Capillary artimesia capillary artemisia polysaccharide protects the liver from oxidative damage and improves antioxidant defense in growing rats with obstructive jaundice. PMID:23170119

  4. Propranolol oxidation by human liver microsomes--the use of cumene hydroperoxide to probe isoenzyme specificity and regio- and stereoselectivity.

    PubMed

    Otton, S V; Gillam, E M; Lennard, M S; Tucker, G T; Woods, H F

    1990-11-01

    1. Three oxidations of the enantiomers of propranolol were studied in human liver microsomes under two reaction conditions. Previous in vitro studies had established that two of the livers were from poor metaboliser (PM) phenotypes for the debrisoquine 4-hydroxylase (cytochrome P-450IID6) and the remaining seven were from extensive metaboliser (EM) phenotypes. 2. In the presence of NADPH and oxygen 4- and 5-hydroxylation of propranolol occurred in microsomes from all nine livers, as did propranolol N-desisopropylation. R(+)-propranolol was oxidized preferentially along the three pathways, although enantioselectivity observed for N-desisopropylation may have arisen not only from stereoselectivity in formation rates, but also from stereoselectivity in subsequent microsomal metabolism, possibly by monoamine oxidase. The involvement of monoamine oxidase in the further microsomal metabolism of N-desisopropylpropranolol was indicated by inhibition of the metabolism of this compound when incubated with phenelzine. 3. Cumene hydroperoxide has been proposed to support only the activity of cytochrome P450IID6. This is consistent with the observations that a) propranolol 4- and 5-hydroxylation occurred in microsomes from the EM livers only and b) side-chain oxidation was not observed under these conditions in either PM or EM livers. 4. Using cumene hydroperoxide to support the reactions, the 4-hydroxylation of propranolol showed little enantioselectivity, whereas S(-)-propranolol was 5-hydroxylated about twice as fast as the R(+)-enantiomer. There were highly significant correlations between the rates of 4- and 5-hydroxylation of R(+)-propranolol (r = 0.96, P less than 0.001, n = 7 livers) and of S(-)-propranolol (r = 0.98, P less than 0.001). Both oxidations were described by single-site Michaelis-Menten kinetics. 5. The findings suggest that P450IID6 is involved in both the 4- and 5-hydroxylations of propranolol, but that these metabolites can also be formed by other P450

  5. Monoascorbate free radical-dependent oxidation-reduction reactions of liver Golgi apparatus membranes.

    PubMed

    Navas, Placido; Sun, Iris; Crane, Frederick L; Morré, Dorothy M; Morré, D James

    2010-04-01

    Golgi apparatus from rat liver contain an ascorbate free radical oxidoreductase that oxidizes NADH at neutral pH with monodehydroascorbate as acceptor to generate a membrane potential. At pH 5.0, the reverse reaction occurs from NAD(+). The electron spin resonance signal of the ascorbate-free radical and its disappearance upon the addition of NADH (pH 7) or NAD(+) (pH 5.0) confirms monodehydroascorbate involvement. Location of monodehydroascorbate both external to and within Golgi apparatus compartments is suggested from energization provided by inward or outward flux of electrons across the Golgi apparatus membranes. The isolated membranes are sealed, oriented cytoplasmic side out and impermeable to NAD(+) and ascorbate. NAD(+) derived through the action of Golgi apparatus beta-NADP phosphohydrolase is simultaneously reduced to NADH with monodehydroascorbate present. The response of the NADH- (NAD(+)-) ascorbate free radical oxidoreductase system to pH in Golgi apparatus provides a simple regulatory mechanism to control vesicle acidification.

  6. Predictive value of exhaled nitric oxide and aerobic capacity for sepsis complications after liver transplantation.

    PubMed

    Neviere, Remi; Trinh-Duc, Pierre; Hulo, Sébastien; Edme, Jean Louis; Dehon, Aurélie; Boleslawski, Emmanuel; Dharancy, Sébastien; Lebuffe, Gilles

    2016-12-01

    Our objective was to investigate the predictive value of fractional nitric oxide (NO) concentration in exhaled breath (FeNO) and aerobic capacity (peak VO2 ) for postoperative sepsis in liver transplantation candidates. Patients were identified and charts of all consecutive patients were prospectively reviewed. Bacterial sepsis represented the commonest postoperative complications (30%), which was attributed to peritonitis, pneumonia, and catheter-related infections. Preoperative FeNO and peak VO2 values were lower in patients with postoperative sepsis. Patients with sepsis required higher needs for mechanical ventilation and ICU length of stay. Inverse correlation was found between logarithmically FeNO-transformed data and systolic pulmonary artery pressure (r = -0.348; P = 0.018). Multivariate analyses using bootstrap sampling method indicated that odds of sepsis were associated with lower values of peak exercise VO2 [OR = 0.790 (0.592; 0.925)] and reduced log(FeNo) [OR = 0.027 (0.001; 0.451)], but not with higher MELD scores [OR = 1.141 (0.970; 1.486)]. By evaluating the cutoff for the ROC curves in each bootstrap resampling, median and 95% confidence interval were calculated for peak VO2 : 17 [16.2; 22] ml/kg/min and FeNO: 17.2 [13.0; 33.9] ppb. We conclude that low peak exercise VO2 and reduced FeNO may help identify patients who are at risk to develop perioperative sepsis. © 2016 Steunstichting ESOT.

  7. Highly proliferative primitive fetal liver hematopoietic stem cells are fueled by oxidative metabolic pathways.

    PubMed

    Manesia, Javed K; Xu, Zhuofei; Broekaert, Dorien; Boon, Ruben; van Vliet, Alex; Eelen, Guy; Vanwelden, Thomas; Stegen, Steve; Van Gastel, Nick; Pascual-Montano, Alberto; Fendt, Sarah-Maria; Carmeliet, Geert; Carmeliet, Peter; Khurana, Satish; Verfaillie, Catherine M

    2015-11-01

    Hematopoietic stem cells (HSCs) in the fetal liver (FL) unlike adult bone marrow (BM) proliferate extensively, posing different metabolic demands. However, metabolic pathways responsible for the production of energy and cellular building blocks in FL HSCs have not been described. Here, we report that FL HSCs use oxygen dependent energy generating pathways significantly more than their BM counterparts. RNA-Seq analysis of E14.5 FL versus BM derived HSCs identified increased expression levels of genes involved in oxidative phosphorylation (OxPhos) and the citric acid cycle (TCA). We demonstrated that FL HSCs contain more mitochondria than BM HSCs, which resulted in increased levels of oxygen consumption and reactive oxygen species (ROS) production. Higher levels of DNA repair and antioxidant pathway gene expression may prevent ROS-mediated (geno)toxicity in FL HSCs. Thus, we here for the first time highlight the underestimated importance of oxygen dependent pathways for generating energy and building blocks in FL HSCs. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  8. Thiamethoxam induces oxidative stress and antioxidant response in zebrafish (Danio Rerio) livers.

    PubMed

    Yan, Sai H; Wang, Jin H; Zhu, Lu S; Chen, Ai M; Wang, Jun

    2015-10-04

    Thiamethoxam, a second-generation neonicotinoid insecticide, was found to be toxic to nontarget aquatic organisms. The purpose of this study was to investigate the toxicity of thiamethoxam (0.30, 1.25, and 5.00 mg/L) on zebrafish (Danio rerio) livers at the 7th, 14th, 21st, and 28th days. The reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), glutathione-s-transferase (GST), malondialdehyde (MDA) content, and DNA damage were used to evaluate the toxic effects of thiamethoxam on zebrafish. Compared to control groups, ROS levels were ascended in the exposure period; SOD and CAT activities were dramatically increased during early exposure and then inhibited. GST activity only increased on days 28. MDA content was slightly elevated on days 21 and 28. Additionally, a clear dose-response relationship was found for DNA damage. In conclusion, thiamethoxam could induce oxidative stress and DNA damage on the exposed zebrafish. © 2015 Wiley Periodicals, Inc. Environ Toxicol, 2015.

  9. SUBCHRONIC MANCOZEB TREATEMENT INDUCED LIVER TOXICITY VIA OXIDATIVE STRESS IN MALE WISTAR RATS.

    PubMed

    Yahia, E; Aiche, M A; Chouabbia, A; Boulakoud, M S

    2014-01-01

    Mancozeb is a manganese/zinc ethylene-bis-dithiocarbamate fungicide that is widely used in agriculture to control a broad variety of fungal infections of both vegetables and ornamental plants. The present study has been carried out to investigate the possible effect of mancozeb on animal the oxidative stress and some of the biochemical markers in male Wistar rats. In this experiment, adult male rats weighing between 200 and 250 g were treated per os for 4 weeks with two different doses of 800 and 1200 mg/kg per day. Reduced glutathione (GSH) levels were decreased in all treated groups compared to control ones. It has been observed a significant increase in the fresh weight of liver in individuals of both doses. Moreover, mancozeb exposure caused a significant (p < 0.05) fall in aspartic aminotransferase (AST) and alanine aminotransferase (ALT) in group treated with 1200 and 800 mg/kg/day. Similarly, alkaline phosphatase (ALP) activity underwent a significant (p < 0.05) increase in both groups. The obtained observations clearly reveal hepatotoxic effects of mancozeb in rats and constitute, therefore, an environmental health risks to living organisms.

  10. Energy status and oxidation reduction status in rat liver at high altitude /3.8 km/

    NASA Technical Reports Server (NTRS)

    Reed, R. D.; Pace, N.

    1980-01-01

    Adult male rats were exposed to 3.8-km altitude for intervals ranging from 1 h-60 d. Liver samples were taken under light ether anesthesia and were examined by enzymatic analyses. Within 1-6 h of hypoxic exposure, ATP levels decreased while ADP and AMP levels increased, producing a fall in calculated ATP/ADP and adenylate charge ratios. Concurrently, lactate/pyruvate and alpha-glycerophosphate/dihydroxyacetone phosphate ratios increased markedly. Direct measurements of cellular pyridine nucleotides indicated increased NADH/NAD and NADPH/NADP ratios. Levels of total adenosine phosphates and pyridine nucleotides decreased in a significant accompanying response. Many metabolite levels and calculated ratios returned to near-normal values within 1 week of exposure, indicating secondary intracellular adjustments to hypoxic stress; however, persistence of that stress is reflected in lactate concentrations and both substrate redox ratios. Results support and explore concepts that increased oxidation-reduction status and decreased energy status are primary events during hypoxia.

  11. Effects of Oxidized Frying Oil on Proteins Related to α-Tocopherol Metabolism in Rat Liver

    PubMed Central

    Huang, Wen-Chi; Kang, Zhi-Chyang; Li, Yi-Jen; Shaw, Huey-Mei

    2009-01-01

    An oxidized frying oil (OFO) diet has been reported to induce an increase in lipid peroxidation and a reduction in vitamin E status in animal tissues. This study was performed to investigate how vitamin E metabolism is influenced by OFO. Male Wistar rats were divided into three groups, a control group (CO) and two OFO-fed groups (OF and OFE). The diet of the OFE group was supplemented with an extra 50 mg/kg of α-tocopherol acetate and thus contained twice as much vitamin E as that of the OF group. After six weeks on these diets, liver α-tocopherol levels in the OF group were the significantly lowest among the three groups. Excretion of the α-tocopherol metabolite, α-carboxyethyl hydroxychroman (α-CEHC) in the urine was significantly lower in the OF group than in the other two groups. There were no significant differences in protein levels of α-tocopherol transfer protein (α-TTP) and multidrug resistance protein among the three groups. Protein levels of cytochrome P450 monooxygenase (CYP) 3A, CYP4A, and catalase were markedly increased in both groups on the OFO diet. This suggests that an OFO diet may interfere with medicine metabolism and needs further investigation. PMID:19590703

  12. Energy status and oxidation reduction status in rat liver at high altitude /3.8 km/

    NASA Technical Reports Server (NTRS)

    Reed, R. D.; Pace, N.

    1980-01-01

    Adult male rats were exposed to 3.8-km altitude for intervals ranging from 1 h-60 d. Liver samples were taken under light ether anesthesia and were examined by enzymatic analyses. Within 1-6 h of hypoxic exposure, ATP levels decreased while ADP and AMP levels increased, producing a fall in calculated ATP/ADP and adenylate charge ratios. Concurrently, lactate/pyruvate and alpha-glycerophosphate/dihydroxyacetone phosphate ratios increased markedly. Direct measurements of cellular pyridine nucleotides indicated increased NADH/NAD and NADPH/NADP ratios. Levels of total adenosine phosphates and pyridine nucleotides decreased in a significant accompanying response. Many metabolite levels and calculated ratios returned to near-normal values within 1 week of exposure, indicating secondary intracellular adjustments to hypoxic stress; however, persistence of that stress is reflected in lactate concentrations and both substrate redox ratios. Results support and explore concepts that increased oxidation-reduction status and decreased energy status are primary events during hypoxia.

  13. Energy Drink Induced Lipid Peroxidation and Oxidative Damage in Rat Liver and Brain When Used Alone or Combined with Alcohol.

    PubMed

    Reis, Rengin; Charehsaz, Mohammad; Sipahi, Hande; Ekici, Asiye Işın Doğan; Macit, Çağlar; Akkaya, Hatice; Aydın, Ahmet

    2017-04-01

    Energy drinks (ED) are containing large doses of metabolic stimulants and its use with ethanol has increased dramatically among young adults. In this study, we examined the effects of ED exposure either alone or in combination with ethanol on oxidative stress parameters including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and lipid peroxidation parameter malondialdehyde (MDA) in rat. Some histopathological findings were also evaluated. ED exposure led to a dose-dependent increase in liver MDA compared to the control indicating oxidative damage. Histopathological findings also revealed that ED alone may generate liver damage. Ethanol exposure increased MDA level and SOD, CAT, and GSH-Px activity in both the brain and the liver. The combination of ethanol and ED produced greater damage which is considered by further increases in SOD and GSH-Px activity in the brain. Similar results for MDA were observed in both the liver and brain as well. Our findings suggest that ED consumption alone or combination with ethanol may represent a significant public health concern. © 2017 Institute of Food Technologists®.

  14. Cissus quadrangularis stem alleviates insulin resistance, oxidative injury and fatty liver disease in rats fed high fat plus fructose diet.

    PubMed

    Chidambaram, Jaya; Carani Venkatraman, Anuradha

    2010-01-01

    The study evaluated the protective effects of Cissus quadrangularis stem extract (CQEt) on oxidant-antioxidant balance and insulin resistance (IR) in rats fed high fat-high fructose diet (HFFD) and also tested its free-radical scavenging property in vitro. Rats were fed either control diet or HFFD for 15 days, following which the diet was fortified with CQEt at a dose of 10 g/100g diet. After 60 days, HFFD caused deleterious metabolic effects, including hyperglycemia, IR and liver dysfunction. Rats fed HFFD alone showed increased activities of hepatocellular enzymes in plasma, lipid deposition, significant decline in antioxidants, and elevated lipid peroxidation indices and protein carbonyl in liver. CQEt addition significantly improved insulin sensitivity, reduced liver damage and oxidative changes, and brought back the antioxidants and lipids towards normal. Histopathology of the liver confirmed the changes induced by HFFD and the heptoprotective effect of CQEt. The effects of CQEtin vivo were comparable with that of standard drug, metformin. Through in vitro assays, CQEt was found to contain large quantities of polyphenols, vitamins C and E. CQEt exhibited radical scavenging ability in a dose-dependent manner. These data suggest that CQEt affords hepatoprotection by its antioxidant and insulin-sensitizing activities. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  15. Protective effect of rosmarinic acid against oxidative stress biomarkers in liver and kidney of strepotozotocin-induced diabetic rats.

    PubMed

    Mushtaq, Nadia; Schmatz, Roberta; Ahmed, Mushtaq; Pereira, Luciane Belmonte; da Costa, Pauline; Reichert, Karine Paula; Dalenogare, Diéssica; Pelinson, Luana Paula; Vieira, Juliano Marchi; Stefanello, Naiara; de Oliveira, Lizielle Souza; Mulinacci, Nadia; Bellumori, Maria; Morsch, Vera Maria; Schetinger, Maria Rosa

    2015-12-01

    In the present study, we investigated the efficiency of rosmarinic acid (RA) in preventing the alteration of oxidative parameters in the liver and kidney of diabetic rats induced by streptozotocin (STZ). The animals were divided into six groups (n = 8): control, ethanol, RA 10 mg/kg, diabetic, diabetic/ethanol, and diabetic/RA 10 mg/kg. After 3 weeks of treatment, we found that TBARS levels in liver and kidney were significantly increased in the diabetic/saline group and the administration of RA prevented this increase in the liver and kidney (P < 0.05). Diabetes caused a significant decrease in the activity of superoxide dismutase (SOD) and catalase (CAT) in the diabetes/saline group (P < 0.05). However, the treatment with 10 mg/kg RA (antioxidant) prevented this alteration in SOD and CAT activity in the diabetic RA group (P < 0.05). In addition, RA reverses the decrease in ascorbic acid and non-protein-thiol (NPSH) levels in diabetic rats. The treatment with RA also prevented the decrease in the Delta-aminolevulinic acid dehydratase (ALA-D) activity in the liver and kidney of diabetic rats. Furthermore, RA did not have any effect on glycemic levels. These results indicate that RA effectively reduced the oxidative stress induced by STZ, suggesting that RA is a potential candidate for the prevention and treatment of pathological conditions in diabetic models.

  16. Indole-3-carbinol enhances oxidative stress responses resulting in the induction of preneoplastic liver cell lesions in partially hepatectomized rats initiated with diethylnitrosamine.

    PubMed

    Shimamoto, Keisuke; Dewa, Yasuaki; Ishii, Yuji; Kemmochi, Sayaka; Taniai, Eriko; Hayashi, Hitomi; Imaoka, Masako; Morita, Reiko; Kuwata, Kazunori; Suzuki, Kazuhiko; Shibutani, Makoto; Mitsumori, Kunitoshi

    2011-05-10

    The liver tumor-promoting effects of indole-3-carbinol (I3C), a cytochrome P450 (CYP) 1A inducer found in cruciferous vegetables, were investigated using a medium-term hepatocarcinogenesis model in rats. Six-week-old male F344 rats received an intraperitoneal injection of N-diethylnitrosamine (DEN) and were fed a diet containing 0 (DEN-alone), 0.25, 0.50 or 1.0% of I3C for 8 weeks from 2 weeks after DEN-initiation. The number and area of liver cell foci positive for glutathione S-transferase placental form (GST-P) significantly increased in the livers of rats given 0.5% I3C or more, compared to those in the DEN-alone group. The number of GST-P positive foci also increased in the 0.25% I3C group. The number of liver cells positive for proliferating cell nuclear antigen (PCNA) significantly increased in all I3C groups compared to that in the DEN-alone group. Real-time RT-PCR analysis showed that I3C increased transcript levels of not only Cyp1a1 but also aryl hydrocarbon receptor (AhR) and/or nuclear factor (erythroid-derived 2)-like 2 (Nrf2) gene batteries, such as Cyp1a2, Cyp1b1, Ugt1a6, Nrf2, Nqo1, Gsta5, Gstm2, Ggt1and Gpx2. Reactive oxygen species (ROS) in the microsomal fraction significantly increased in all I3C-treated groups compared to the DEN-alone group, and thiobarbituric acid-reactive substances (TBARS) levels and 8-hydroxy-2'-deoxyguanosine (8-OHdG) content significantly increased in all of the I3C-treated groups and 1.0% I3C group, respectively. These results suggest that I3C is an AhR activator and enhances microsomal ROS production resulting in the upregulation of Nrf2 gene batteries, but the oxidative stress generated overcomes the antioxidant effect of Nrf2-related genes. Such 'a redox imbalance' subsequently induces liver tumor-promoting effects by enhancing cellular proliferation in rats.

  17. The role of intracellular high-mobility group box 1 in the early activation of Kupffer cells and the development of Con A-induced acute liver failure.

    PubMed

    Yang, Qiao; Liu, Yanning; Shi, Yu; Zheng, Min; He, Jiliang; Chen, Zhi

    2013-10-01

    Acute liver failure (ALF) is a highly complex syndrome characterized by devastating activation of early activation of Kupffer cells (KCs) has been implicated in the pathogenesis of ALF. However, the factors regulating KC early activation are virtually unexplored. The aim of present study was to determine the role of the intracellular high-mobility group box 1 (HMGB1) in modulating the early activation of KCs during ALF. The intravenous injection of Concanavalin A (Con A) was used to establish a mouse model of ALF. The dynamic pro-inflammatory properties and MHC II expression of KCs were measured by qRT-PCR and flow cytometry. HMGB1 expression in KCs was measured by qRT-PCR and Western blotting. The immunofluorescence was implemented to determine the relocation of HMGB1 in KCs, and the siRNA against HMGB1 was utilized to assess the impact of HMGB1 on KC pro-inflammatory properties. The peak of pro-inflammatory cytokines production and MHC II expression in KCs appeared at the early stage of ALF. The up-regulation of HMGB1 expression and the translocation of HMGB1 in KCs were in parallel with the early activation of KCs. The blockade of intracellular HMGB1 expression caused by siRNA significantly inhibited the production of KC-derived pro-inflammatory cytokines, and led to a down-regulation of MAP kinase activation in KCs. The self-derived HMGB1 is an "early alarmin" of KC activation during Con A-induced ALF. HMGB1 might be a potential target for cell-specific strategy in ALF. Copyright © 2013 Elsevier GmbH. All rights reserved.

  18. miR-706 inhibits the oxidative stress-induced activation of PKCα/TAOK1 in liver fibrogenesis

    PubMed Central

    Yin, Ruili; Guo, Duo; Zhang, Shuxian; Zhang, Xiuying

    2016-01-01

    Oxidative stress induces the activation of liver fibrogenic cells (myofibroblasts), thus promoting the expression of fibrosis-related genes, leading to hepatic fibrogenesis. MicroRNAs (miRNAs) are a new class of small RNAs ~18–25 nucleotides in length involved in post-transcriptional regulation of gene expression. Wound-healing and remodeling processes in liver fibrosis have been associated with changes in hepatic miRNA expression. However, the role of miR-706 in liver fibrogenesis is currently unknown. In the present study, we show that miR-706 is abundantly expressed in hepatocytes. Moreover, oxidative stress leads to a significant downregulation of miR-706, and the further reintroduction of miR-706 inhibits oxidative stress-induced expression of fibrosis-related markers such as α-SMA. Subsequent studies revealed that miR-706 directly inhibits PKCα and TAOK1 expression via binding to the 3′-untranslated region, preventing epithelial mesenchymal transition. In vivo studies showed that intravenous injection of miR-706 agomir successfully increases hepatic miR-706 and decreases α-SMA, PKCα, and TAOK1 protein levels in livers of carbon tetrachloride (CCl4)-treated mice. In summary, this study reveals a protective role for miR-706 by blocking the oxidative stress-induced activation of PKCα/TAOK1. Our results further identify a major implication for miR-706 in preventing hepatic fibrogenesis and suggest that miR-706 may be a suitable molecular target for anti-fibrosis therapy. PMID:27876854

  19. [Influence of hypokinezia of varying duration on the nitric oxide productions dynamics in rat's heart, spinal cord and liver].

    PubMed

    Zaripova, R I; Andrianov, V V; Iafarova, G G; Gaĭnutdinov, Kh L; Khabibrakhmanov, I I; Zefirov, T L

    2014-08-01

    By electron paramagnetic resonance method analyzed the production of nitric oxide (NO) in atrias and ventricles of the rat's heart, spinal cord and liver of rats after the contained in conditions of hypokinesia during 30, 60 and 90 days. It was discovered that the regime of hypokinesia leads to increase NO production in all the investigated tissues, and the largest increases were observed in 30-day hypokinesia.

  20. A fatty acyl-CoA oxidizing system in rat liver peroxisomes; enhancement by clofibrate, a hypolipidemic drug.

    PubMed Central

    Lazarow, P B; De Duve, C

    1976-01-01

    Purified rat liver peroxisomes contain a cyanide-insensitive fatty acyl-CoA oxidizing system that uses O2 and NAD as electron acceptors. The system was detected by the ability of added palmitoyl-CoA to elicit O2 consumption, H2O2 production, and O2-dependent NAD reduction. The activity of this system is increased approximately one order of magnitude in rats treated with clofibrate, a hypolipidemic drug known to cause peroxisomal proliferation. Images PMID:180535

  1. Curcumin Attenuates Iron Accumulation and Oxidative Stress in the Liver and Spleen of Chronic Iron-Overloaded Rats

    PubMed Central

    Badria, Farid A.; Ibrahim, Ahmed S.; Badria, Adel F.; Elmarakby, Ahmed A.

    2015-01-01

    Objectives Iron overload is now recognized as a health problem in industrialized countries, as excessive iron is highly toxic for liver and spleen. The potential use of curcumin as an iron chelator has not been clearly identified experimentally in iron overload condition. Here, we evaluate the efficacy of curcumin to alleviate iron overload-induced hepatic and splenic abnormalities and to gain insight into the underlying mechanisms. Design and Methods Three groups of male adult rats were treated as follows: control rats, rats treated with iron in a drinking water for 2 months followed by either vehicle or curcumin treatment for 2 more months. Thereafter, we studied the effects of curcumin on iron overload-induced lipid peroxidation and anti-oxidant depletion. Results Treatment of iron-overloaded rats with curcumin resulted in marked decreases in iron accumulation within liver and spleen. Iron-overloaded rats had significant increases in malonyldialdehyde (MDA), a marker of lipid peroxidation and nitric oxide (NO) in liver and spleen when compared to control group. The effects of iron overload on lipid peroxidation and NO levels were significantly reduced by the intervention treatment with curcumin (P<0.05). Furthermore, the endogenous anti-oxidant activities/levels in liver and spleen were also significantly decreased in chronic iron overload and administration of curcumin restored the decrease in the hepatic and splenic antioxidant activities/levels. Conclusion Our study suggests that curcumin may represent a new horizon in managing iron overload-induced toxicity as well as in pathological diseases characterized by hepatic iron accumulation such as thalassemia, sickle cell anemia, and myelodysplastic syndromes possibly via iron chelation, reduced oxidative stress derived lipid peroxidation and improving the body endogenous antioxidant defense mechanism. PMID:26230491

  2. Bile salt-induced pro-oxidant liver damage promotes transplanted cell proliferation for correcting Wilson disease in the Long-Evans Cinnamon rat model.

    PubMed

    Joseph, Brigid; Kapoor, Sorabh; Schilsky, Michael L; Gupta, Sanjeev

    2009-05-01

    Insights into disease-specific mechanisms for liver repopulation are needed for cell therapy. To understand the efficacy of pro-oxidant hepatic perturbations in Wilson disease, we studied Long-Evans Cinnamon (LEC) rats with copper toxicosis under several conditions. Hepatocytes from healthy Long-Evans Agouti (LEA) rats were transplanted intrasplenically into the liver. A cure was defined as lowering of copper to below 250 microg/g liver, presence of ATPase, Cu++ transporting, beta polypeptide (atp7b) messenger RNA (mRNA) in the liver and improvement in liver histology. Treatment of animals with the hydrophobic bile salt, cholic acid, or liver radiation before cell transplantation produced cure rates of 14% and 33%, respectively; whereas liver radiation plus partial hepatectomy followed by cell transplantation proved more effective, with cure in 55%, P < 0.01; and liver radiation plus cholic acid followed by cell transplantation was most effective, with cure in 75%, P < 0.001. As a group, cell therapy cures in rats preconditioned with liver radiation plus cholic acid resulted in less hepatic copper, indicating greater extent of liver repopulation. We observed increased hepatic catalase and superoxide dismutase activities in LEC rats, suggesting chronic oxidative stress. After liver radiation or cholic acid, hepatic lipid peroxidation levels increased, indicating further oxidative injury, although we did not observe overt additional cytotoxicity. This contrasted with healthy animals in which liver radiation and cholic acid produced hepatic steatosis and loss of injured hepatocytes. We concluded that pro-oxidant perturbations were uniquely effective for cell therapy in Wilson disease because of the nature of preexisting hepatic damage.

  3. Biomarkers of oxidative stress and tissue damage released by muscle and liver after a single bout of swimming exercise.

    PubMed

    Ramos, Dionizio; Martins, Eduarda Gabrielle; Viana-Gomes, Diego; Casimiro-Lopes, Gustavo; Salerno, Verônica P

    2013-05-01

    Both acute exercise and excessive training can cause oxidative stress. The resulting increase in free radicals and the inadequate response from antioxidant systems can lead to a framework of cellular damage. An association between affected tissue and the biomarkers of oxidative stress that appear in plasma has not been clearly established. The aim of this study was to evaluate the source of oxidative stress biomarkers found in the plasma of untrained rats after a single bout of swimming exercise at 2 different intensities: low intensity (SBLIE) or high intensity (SBHIE). Immediately after the exercise, aspartate transaminase (AST), alanine transaminase (ALT), γ-glutamyltransferase (GGT), and lactate dehydrogenase (LDH) were measured in plasma to characterize cell damage. Oxidative stress was assessed using protein carbonylation (PC), total antioxidant capacity (TAC), and thiobarbituric acid reactive substances (TBARS) quantified by malondialdehyde concentration. SBHIE raised levels of plasma AST (93%) and ALT (17%), and both exercise regimens produced an increase in GGT (7%) and LDH (∼55%). Plasma levels of PC and TBARS were greater in the SBHIE group; there were no changes in TAC. SBLIE caused only a modest increase in TBARS. In muscle, there were no changes in TAC, PC, or TBARS, regardless of exercise intensity, In the liver, TAC and TBARS increased significantly in both the SBLIE and SBHIE groups. This indicates that the oxidative stress biomarkers measured in the plasma immediately after a single bout of swimming exercise were generated primarily in the liver, not in muscle.

  4. Protective Effects of Carvacrol against Oxidative Stress Induced by Chronic Stress in Rat's Brain, Liver, and Kidney

    PubMed Central

    Samarghandian, Saeed; Farkhondeh, Tahereh; Samini, Fariborz; Borji, Abasalt

    2016-01-01

    Restraint stress may be associated with elevated free radicals, and thus, chronic exposure to oxidative stress may cause tissue damage. Several studies have reported that carvacrol (CAR) has a protective effect against oxidative stress. The present study was designed to investigate the protective effects of CAR on restraint stress induced oxidative stress damage in the brain, liver, and kidney. For chronic restraint stress, rats were kept in the restrainers for 6 h every day, for 21 consecutive days. The animals received systemic administrations of CAR daily for 21 days. To evaluate the changes of the oxidative stress parameters following restraint stress, the levels of malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (CAT) activities were measured in the brain, liver, and kidney. In the stressed animals that received vehicle, the MDA level was significantly higher (P < 0.001) and the levels of GSH and antioxidant enzymes were significantly lower than the nonstressed animals (P < 0.001). CAR ameliorated the changes in the stressed animals as compared with the control group (P < 0.001). This study indicates that CAR can prevent restraint stress induced oxidative damage. PMID:26904286

  5. Exenatide improves liver mitochondrial dysfunction and insulin resistance by reducing oxidative stress in high fat diet-induced obese mice.

    PubMed

    Wang, Zixuan; Hou, Lin; Huang, Lanhui; Guo, Jun; Zhou, Xinli

    2017-04-22

    Oxidative stress is associated with obesity and may be accompanied by liver insulin resistance and mitochondrial dysfunction. Decreased mitochondrial respiratory chain enzymatic activities and decreased insulin metabolic signaling may promote these maladaptive changes. In this context, exenatide has been reported to reduce hepatic lipid deposition, improve insulin sensitivity and improve mitochondrial dysfunction. We hypothesized that exenatide would attenuate mitochondrial dysfunction by reducing hepatic lipid deposition, blunting oxidant stress and promoting insulin metabolic signaling in a high fat diet-induced model of obesity and insulin resistance. Sixteen-week-old male C57BL/6 diet-induced obese (DIO) mices and age-matched standard diet (STD) mices were treated with exenatide (10 μg/kg twice a day) for 28 days. Compared with untreated STD mice, untreated DIO mice exhibited deposited excessive lipid in liver and produced the oxidative stress in conjunction with insulin resistance, abnormal hepatic cells and mitochondrial histoarchitecture, mitochondrial dysfunction and reduced organism metabolism. Exenatide reduced hepatic steatosis, decreased oxidative stress, and improved insulin resistance in DIO mice, in concert with improvements in the insulin metabolic signaling, mitochondrial respiratory chain enzymatic activation, adenine nucleotide production, organism metabolism and weight gain. Results support the hypothesis that exenatide reduces hepatic cells and mitochondrial structural anomaly and improves insulin resistance in concert with improvements in insulin sensitivity and mitochondrial function activation, concomitantly with reductions in oxidative stress.

  6. Comparison of rat liver and brain proteasomes for oxidative stress-induced inactivation: Influence of ageing and dietary restriction.

    PubMed

    Dasuri, Kalavathi; Nguyen, Anhthao; Zhang, Le; Fernandez-Kim, Ok Sun; Bruce-Keller, Annadora J; Blalock, Bradford A; Cabo, Rafael De; Keller, Jeffrey N

    2009-01-01

    The present study examined brain and liver derived proteasome complexes to elucidate if there is a differential susceptibility in proteasome complexes from these tissues to undergo inactivation following exposure to oxidative stressors. It then examined the influence of ageing and dietary restriction (DR) on the observed proteasome inactivation. Studies used a filtration based methodology that allows for enrichment of proteasome complexes with less tissue than is required for traditional chromatography procedures. The results indicate that the brain has much lower levels of overall proteasome activity and exhibits increased sensitivity to hydrogen peroxide mediated inactivation as compared to proteasome complexes derived from the liver. Interestingly, the brain proteasome complexes did not appear to have increased susceptibility to 4-hydroxynonenal (HNE)-induced inactivation. Surprisingly, ageing and DR induced minimal effects on oxidative stress mediated proteasome inhibition. These results indicate that the brain not only has lower levels of proteasome activity compared to the liver, but is also more susceptible to inactivation following exposure to some (but certainly not all) oxidative stressors. This data also suggest that ageing and DR may not significantly modulate the resistance of the proteasome to inactivation in some experimental settings.

  7. Therapeutic potential of morin against liver fibrosis in rats: modulation of oxidative stress, cytokine production and nuclear factor kappa B.

    PubMed

    Heeba, Gehan H; Mahmoud, Magda E

    2014-03-01

    Therapeutic potential of morin, a member of flavonoid family, against carbon tetrachloride (CCl4)-induced liver fibrosis in rats was investigated and compared with that of silymarin. Results show that treatment with morin (30 mg/kg/day) revealed attenuation in liver index and serum biomarkers of liver function that were enhanced by chronic CCl4 intoxication. Further, morin inhibited the elevated levels of malondialdehyde and nitric oxide and restored hepatic reduced glutathione to its normal level. The increased production of hepatic hydroxyproline content by CCl4 was markedly decreased by administration of morin. In addition, treatment with morin significantly attenuated the inflammatory responses caused by CCl4 as evident by the decreased hepatic tumor necrosis factor-alpha (TNF-α) level, immunohistochemical expressions of inducible nitric oxide synthase and nuclear factor kappa B. Collectively, this study indicates that morin possesses antifibrotic effect in the CCl4 model of fibrosis via reducing oxidative stress, inflammatory responses and fibrogenic markers. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Involvement of oxidative stress in tri-ortho-cresyl phosphate-induced liver injury in male mice.

    PubMed

    Xu, L L; Long, C Y; Wang, J L; Yu, M; Chen, J X

    2016-10-01

    Tri-ortho-cresyl phosphate (TOCP) has been widely used as plasticizers, plastic softeners, and flame retardants in industry and reported to have delayed neurotoxicity and reproductive toxicology in animals. However, it remains to be elusive whether TOCP induces liver injury. In this study, male mice were orally administered different concentrations of TOCP (100, 200, or 400 mg/kg/day) for 28 days. Histological examination showed that TOCP led to serious hepatocellular injury. In addition, administration of TOCP induced a marked elevation in the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in mice. The content of malondialdehyde (MDA) was increased significantly in the liver after the mice were treated with TOCP; while there was a dramatic decrease in the content of glutathione (GSH) and the activities of antioxidative enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX). TOCP inhibited viability of mouse liver cancer Hepa 1-6 cells in a dose-dependent manner. Meanwhile, TOCP significantly increased MDA content and inhibited GSH content and the activities of SOD and GSH-PX in the cells, respectively. Oxidative stress dramatically inhibited viability of Hepa 1-6 cells; while inhibition of oxidative stress by N-acetyl-l-cysteine could rescue the cell viability inhibited by TOCP to a certain extent. In summary, oxidative stress might be involved in TOCP-induced hepatocellular injury in male mice. © The Author(s) 2016.

  9. Polyunsaturated lipids and vitamin A oxidation during cod liver oil in vitro gastrointestinal digestion. Antioxidant effect of added BHT.

    PubMed

    Nieva-Echevarría, Bárbara; Goicoechea, Encarnación; Guillén, María D

    2017-10-01

    The extent of cod liver oil hydrolysis and oxidation during in vitro gastrointestinal digestion was investigated by Proton Nuclear Magnetic Resonance ((1)H NMR) and Solid Phase Microextraction-Gas Chromatography/Mass Spectrometry (SPME-GC/MS). These techniques evidenced the degradation of polyunsaturated ω-3 and ω-6 lipids and, for the first time, that of vitamin A, naturally present in cod liver oil. Cis,trans-conjugated dienes associated with hydroperoxides, as well as monoepoxides, cis,trans-2,4-alkadienals, 4-hydroperoxy- and 4-hydroxy-2-alkenals, and several vitamin A derived metabolites were generated. Moreover, the effect of the addition of the synthetic antioxidant 2,6-di-tert-butyl-hydroxytoluene (BHT) at 20 and 800ppm was tackled. Both techniques showed BHT to be efficient in limiting oxidation reactions during digestion, almost inhibiting them at 800ppm. Therefore, the simultaneous intake of antioxidants with cod liver oil should be considered, in order to increase polyunsaturated lipid and vitamin A bioaccessibility and avoid formation of toxic oxidation compounds like oxygenated alpha,beta-unsaturated aldehydes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Effect of chromium supplementation on the diabetes induced-oxidative stress in liver and brain of adult rats.

    PubMed

    Refaie, Fawzia M; Esmat, Amr Y; Mohamed, Aly F; Aboul Nour, Wael H

    2009-12-01

    This study was designed to investigate the susceptibility of liver and brain tissues, as insulinin-dependent tissues, of normal adult male rats to the oxidative challenge of subchronic supplementation with chromium picolinate (CrPic) at low (human equivalent) and high doses (2.90 and 13.20 μg Cr kg(-1) day(-1), respectively). Also, the modulative effect of CrPic administration on the enhanced oxidative stress in the liver and brain tissues of alloxan-diabetic rats was studied. Fasting serum glucose level was not modified in normal rats but significantly reduced in diabetic rats that had received CrPic supplement. A mild oxidative stress was observed in the liver and brain of CrPic-supplemented normal rats confirmed by the dose-dependent reductions in the levels of hepatic and cerebral free fatty acids, superoxide dismutase and glutathione peroxidase activities, and in contrast increased tissue malondialdehyde concentration. On the other hand, hepatic and cerebral catalase activity was reduced in the high dose group only. CrPic supplementation did not act as a peroxisome proliferator confirmed by the significant reductions in liver and brain peroxisomal palmitoyl CoA oxidase activity. The non significant alterations in liver protein/DNA and RNA/DNA ratios indicate that CrPic did not affect protein synthesis per cell, and that mild elevations in hepatic total protein and RNA concentrations might be due to block or decrease in the export rate of synthesized proteins from the liver to the plasma. In diabetic rats, elevated levels of hepatic and cerebral free fatty acids and malondialdehyde, and in contrast the overwhelmed antioxidant enzymes, were significantly modulated in the low dose group and near-normalized in the high dose group. The significant increases observed in liver total protein and RNA concentrations, as well as protein/DNA and RNA/ DNA ratios in diabetic rats supplemented with the high dose of Cr, compared to untreated diabetics, may be related to the

  11. Acute administration of 3,4-methylenedioxymethamphetamine (MDMA) induces oxidative stress, lipoperoxidation and TNFα-mediated apoptosis in rat liver.

    PubMed

    Cerretani, D; Bello, S; Cantatore, S; Fiaschi, A I; Montefrancesco, G; Neri, M; Pomara, C; Riezzo, I; Fiore, C; Bonsignore, A; Turillazzi, E; Fineschi, V

    2011-11-01

    Liver toxicity is one of the consequences of ecstasy (3,4-methylenedioxymethamphetamine MDMA) abuse and hepatocellular damage is reported after MDMA consumption. Various factors probably play a role in ecstasy-induced hepatotoxicity, namely its metabolism, the increased efflux of neurotransmitters, the oxidation of biogenic amines, and hyperthermia. MDMA undergoes extensive hepatic metabolism that involves the production of reactive metabolites which form adducts with intracellular nucleophilic sites. MDMA-induced-TNF-α can promote multiple mechanisms to initiate apoptosis in hepatocytes, activation of pro-apoptotic (BID, SMAC/DIABLO) and inhibition of anti-apoptotic (NF-κB, Bcl-2) proteins. The aim of the present study was to obtain evidence for the oxidative stress mechanism and apoptosis involved in ecstasy-induced hepatotoxicity in rat liver after a single 20 mg/kg, i.p. MDMA administration. Reduced and oxidized glutathione (GSH and GSSG), ascorbic acid (AA), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and malondialdehyde (MDA), an indicator of lipid peroxidation, were determined in rat liver after 3 and 6h after MDMA treatment. The effect of a single MDMA treatment included decrease of GR and GPx activities (29% and 25%, respectively) and GSH/GSSG ratio (32%) with an increase of MDA (119%) after 3h from ecstasy administration compared to control rats. Liver cytosolic level of AA was increased (32%) after 6 h MDMA treatment. Our results demonstrate a strong positive reaction for TNFα (p<0.001) in hepatocytes and a diffuse apoptotic process in the liver specimens (p<0.001). There was correlation between immunohistochemical results and Western blotting which were quantitatively measured by densitometry, confirming the strong positivity for TNF-α (p<0.001) and NF-κB (p<0.001); weak and intense positivity reactions was confirmed for Bcl-2, SMAC/DIABLO (p<0.001) and BID reactions (p<0.001). The results obtained in the

  12. 4,6-Dinitro-o-cresol uncouples oxidative phosphorylation and induces membrane permeability transition in rat liver mitochondria.

    PubMed

    Castilho, R F; Vicente, J A; Kowaltowski, A J; Vercesi, A E

    1997-07-01

    The effect of the herbicide 4,6-dinitro-o-cresol (DNOC), a structural analogue of the classical protonophore 2,4-dinitrophenol, on the bioenergetics and inner membrane permeability of isolated rat liver mitochondria was studied. We observed that DNOC (10-50 microM) acts as a classical uncoupler of oxidative phosphorylation in rat liver mitochondria, promoting both an increase in succinate-supported mitochondrial respiration in the presence or absence of ADP and a decrease in transmembrane potential. The protonophoric activity of DNOC was evidenced by the induction of mitochondrial swelling in hyposmotic K(+)-acetate medium, in the presence of valinomycin. At higher concentrations (> 50 microM), DNOC also induces an inhibition of succinate-supported respiration, and a decrease in the activity of the succinate dehydrogenase can be observed. The addition of uncoupling concentrations of DNOC to Ca(2+)-loaded mitochondria treated with Ruthenium Red results in non-specific membrane permeabilization, as evidenced by mitochondrial swelling in isosmotic sucrose medium. Cyclosporin A, which inhibits mitochondrial permeability transition, prevented DNOC-induced mitochondrial swelling in the presence of Ca2+, which was accompanied by a decrease in mitochondrial membrane protein thiol content, owing to protein thiol oxidation. Catalase partially inhibits mitochondrial swelling and protein thiol oxidation, indicating the participation of mitochondrial-generated reactive oxygen species in this process. It is concluded that DNOC is a potent potent protonophore acting as a classical uncoupler of oxidative phosphorylation in rat liver mitochondria by dissipating the proton electrochemical gradient. Treatment of Ca(2+)-loaded mitochondria with uncoupling concentrations of DNOC results in mitochondrial permeability transition, associated with membrane protein thiol oxidation by reactive oxygen species.

  13. Modulatory effects of cod liver oil on the antioxidant status and oxidative stress induced by acute exposure to carbon tetrachloride (CCL4) in experimental animal models.

    PubMed

    Omugba, Abam Esther; Ajiboye, Adebayo J; Oyagbemi, Ademola A; Agofure, Eze

    2015-05-01

    This work was designed to investigate the modulatory effects of cod liver oil on the acute exposure to carbon tetrachloride (CCL4) in experimental animal models. Markers of oxidative stress, enzymic and non-enzymic antioxidants were assessed in the liver and kidney. The results showed significant (p<0.05) increase in the total protein of the kidney of rats pretreated with cod liver oil compared to the control and CCL4-treated groups. Acute exposure to CCL4 also significantly (p<0.05) increased thiobarbituric acid reactive substances in the liver of rats treated with cod liver oil compared to the CCL4-treated rats. The reduced glutathione (GSH) content in the liver of the rats administered with CCL4 decreased significantly compared to that in all other treatment groups, whereas rats pretreated and co-administered with cod liver oil and CCl4 showed significant (p<0.05) improvement in the liver GSH content. The catalase (CAT) activity in the liver of rats exposed to CCL4 decreased (p<0.05) significantly, whereas the activity increased (p<0.05) significantly in the rats that were treated with cod liver oil compared to the CCl4 only-treated group. The percentage inhibition of superoxide dismutase (SOD) increased (p<0.05) significantly in the liver of rats administered cod liver oil compared to the CCL4-treated rats and the control. Taken together, cod liver oil attenuates CCL4-induced toxicity and oxidative stress in the liver but not in the kidney of rats acutely exposed to CCL4.

  14. Amiodarone pretreatment of organ donors exerts anti-oxidative protection but induces excretory dysfunction in liver preservation and reperfusion.

    PubMed

    Moussavian, Mohammed Reza; Kollmar, Otto; Schmidt, Michael; Scheuer, Claudia; Wagner, Matthias; Slotta, Jan Erik; Gronow, Gernot; Justinger, Christoph; Menger, Michael Dieter; Schilling, Martin Karl

    2009-07-01

    The continuous shortage of organs necessitates the use of marginal organs from donors with various diseases, including arrhythmia-associated cardiac failure. One of the most frequently used anti-arrhythmic drugs is amiodarone (AM), which is given in particular in emergency situations. Apart from its anti-arrhythmic actions, AM provides anti-oxidative properties in cardiomyocytes. Thus, we were interested in whether AM donor pretreatment affects the organ quality and function of livers procured for preservation and transplantation. Donor rats were pretreated with AM (5 mg/kg of body weight) 10 minutes before flush-out of the liver with a cold (4 degrees C) histidine-tryptophan-ketoglutarate solution (n = 8). Livers were then stored for 24 hours at 4 degrees C before ex situ reperfusion with a 37 degrees C Krebs-Henseleit solution for 60 minutes in a nonrecirculating system. At the end of reperfusion, tissue samples were taken for histology and Western blot analysis. Animals with vehicle only (0.9% NaCl) served as ischemia/reperfusion controls (n = 8). Additionally, livers of untreated animals (n = 8) not subjected to 24 hours of cold ischemia served as sham controls. AM pretreatment effectively attenuated lipid peroxidation, stress protein expression, and apoptotic cell death. This was indicated by an AM-mediated reduction of malondialdehyde, heme oxygenase-1, and caspase-3 activation. However, AM treatment also induced mitochondrial damage and hepatocellular excretory dysfunction, as indicated by a significantly increased glutamate dehydrogenase concentration in the effluate and decreased bile production. In conclusion, AM donor pretreatment exerts anti-oxidative actions in liver preservation and reperfusion. However, these protective AM actions are counteracted by an induction of mitochondrial damage and hepatocellular dysfunction. Accordingly, AM pretreatment of donors for anti-arrhythmic therapy should be performed with caution.

  15. Amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice

    SciTech Connect

    Fromenty, B.; Fisch, C.; Labbe, G.; Degott, C.; Deschamps, D.; Berson, A.; Letteron, P.; Pessayre, D. )

    1990-12-01

    Amiodarone has been shown to produce microvesicular steatosis of the liver in some recipients. We have determined the effects of amiodarone on the mitochondrial oxidation of fatty acids in mice. In vitro, the formation of 14C-acid-soluble beta-oxidation products from (U-14C)palmitic acid by mouse liver mitochondria was decreased by 92% in the presence of 125 microM amiodarone and by 94% in the presence of 125 microM N-desethylamiodarone. Inhibition due to 100 or 150 microM amiodarone persisted in the presence of 5 mM acetoacetate, whereas acetoacetate totally relieved inhibition due to 15 microM rotenone. In vivo, exhalation of (14C)CO2 from (U-14C)palmitic acid was decreased by 31, 40, 58 and 78%, respectively, in mice receiving 19, 25, 50 and 100 mg.kg-1 of amiodarone hydrochloride 1 hr before the administration of (U-14C)palmitic acid. One hour after 100 mg.kg-1, the exhalation of (14C)CO2 from (1-14C)palmitic acid, (1-14C)octanoic acid or (1-14C)butyric acid was decreased by 78, 72 and 53%, respectively. Exhalation of (14C)CO2 from (1-14C)palmitic acid was normal between 6 and 9 hr after administration of 100 mg.kg-1 of amiodarone hydrochloride, but was still inhibited by 71 and 37%, 24 and 48 hr after 600 mg.kg-1. Twenty four hours after the latter dose of amiodarone, hepatic triglycerides were increased by 150%, and there was microvesicular steatosis of the liver. We conclude that amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.

  16. Role of PTEN in Oxidative Stress and DNA Damage in the Liver of Whole-Body Pten Haplodeficient Mice

    PubMed Central

    Bankoglu, Ezgi Eyluel; Tschopp, Oliver; Schmitt, Johannes; Burkard, Philipp; Jahn, Daniel

    2016-01-01

    Type 2 diabetes (T2DM) and obesity are frequently associated with non-alcoholic fatty liver disease (NAFLD) and with an elevated cancer incidence. The molecular mechanisms of carcinogenesis in this context are only partially understood. High blood insulin levels are typical in early T2DM and excessive insulin can cause elevated reactive oxygen species (ROS) production and genomic instability. ROS are important for various cellular functions in signaling and host defense. However, elevated ROS formation is thought to be involved in cancer induction. In the molecular events from insulin receptor binding to genomic damage, some signaling steps have been identified, pointing at the PI3K/AKT pathway. For further elucidation Phosphatase and Tensin homolog (Pten), a tumour suppressor phosphatase that plays a role in insulin signaling by negative regulation of PI3K/AKT and its downstream targets, was investigated here. Dihydroethidium (DHE) staining was used to detect ROS formation in immortalized human hepatocytes. Comet assay and micronucleus test were performed to investigate genomic damage in vitro. In liver samples, DHE staining and western blot detection of HSP70 and HO-1 were performed to evaluate oxidative stress response. DNA double strand breaks (DSBs) were detected by immunohistostaining. Inhibition of PTEN with the pharmacologic inhibitor VO-OHpic resulted in increased ROS production and genomic damage in a liver cell line. Knockdown of Pten in a mouse model yielded increased oxidative stress levels, detected by ROS levels and expression of the two stress-proteins HSP70 and HO-1 and elevated genomic damage in the liver, which was significant in mice fed with a high fat diet. We conclude that PTEN is involved in oxidative stress and genomic damage induction in vitro and that this may also explain the in vivo observations. This further supports the hypothesis that the PI3K/AKT pathway is responsible for damaging effects of high levels of insulin. PMID:27893783

  17. Biodistribution of polyacrylic acid-coated iron oxide nanoparticles is associated with proinflammatory activation and liver toxicity.

    PubMed

    Couto, Diana; Freitas, Marisa; Costa, Vera Marisa; Chisté, Renan Campos; Almeida, Agostinho; Lopez-Quintela, M Arturo; Rivas, José; Freitas, Paulo; Silva, Paula; Carvalho, Félix; Fernandes, Eduarda

    2016-10-01

    Iron oxide nanoparticles (IONs) have physical and chemical properties that render them useful for several new biomedical applications. Still, so far, in vivo safety studies of IONs with coatings of biomedical interest are still scarce. The aim of this study, therefore, was to clarify the acute biological effects of polyacrylic acid (PAA)-coated IONs, by determining their biodistribution and their potential proinflammatory and toxic effects in CD-1 mice. The biodistribution of PAA-coated IONs in several organs (liver, spleen, kidneys, brain, heart, testes and lungs), the plasma cytokines, chemokine and aminotransferases levels, white blood cell count, oxidative stress parameters, adenosine triphosphate and histologic features of liver, spleen and kidneys were evaluated 24 h after a single acute (8, 20 or 50 mg kg(-1) ) intravenous administration of PAA-coated IONs in magnetite form. The obtained results showed that these IONs accumulate mainly in the liver and spleen and, to a lesser extent, in the lungs. Although our data showed that PAA-coated IONs do not cause severe organ damage, an inflammatory process was triggered in vivo, as evidenced by as evidenced by increased neutrophils and large lymphocytes in the differential blood count. Moreover, an accumulation of iron in macrophages of the liver and spleen was observed and hepatic lipid peroxidation was elicited, showing that the IONs are able to induce oxidative stress. The effects of these nanoparticles need to be further investigated regarding the mechanisms involved and the long-term consequences of intravenous administration of PAA-coated IONs. Copyright © 2016 John Wiley & Sons, Ltd.

  18. Molecular Mechanisms of Lipoic Acid Protection against Aflatoxin B1-Induced Liver Oxidative Damage and Inflammatory Responses in Broilers

    PubMed Central

    Ma, Qiugang; Li, Yan; Fan, Yu; Zhao, Lihong; Wei, Hua; Ji, Cheng; Zhang, Jianyun

    2015-01-01

    Alpha-lipoic acid (α-LA) was evaluated in this study for its molecular mechanisms against liver oxidative damage and inflammatory responses induced by aflatoxin B1 (AFB1). Birds were randomly allocated into four groups with different diets for three weeks: a basal diet, a 300 mg/kg α-LA supplementation in a basal diet, a diet containing 74 μg/kg AFB1, and 300 mg/kg α-LA supplementation in a diet containing 74 μg/kg AFB1. In the AFB1 group, the expression of GSH-PX mRNA was down-regulated (p < 0.05), and the levels of lipid peroxide and nitric oxide were increased (p < 0.05) in the chicken livers compared to those of the control group. Additionally, the mRNA level of the pro-inflammatory factor interleukin-6 was up-regulated significantly (p < 0.05), the protein expressions of both the nuclear factor kappa B (NF-κB) p65 and the inducible nitric oxide synthase were enhanced significantly (p < 0.05) in the AFB1 group. All of these negative effects were inhibited by α-LA. These results indicate that α-LA may be effective in preventing hepatic oxidative stress, down-regulating the expression of hepatic pro-inflammatory cytokines, as well as inhibiting NF-κB expression. PMID:26694462

  19. Prevention of H2O2-induced oxidative stress in Chang liver cells by 4-hydroxybenzyl-chitooligomers.

    PubMed

    Trinh, Mai Duy Luu; Ngo, Dai-Hung; Tran, Dang-Khoa; Tran, Quoc-Tuan; Vo, Thanh-Sang; Dinh, Minh-Hiep; Ngo, Dai-Nghiep

    2014-03-15

    In this study, a bioactive derivative of chitooligomers (1.0-3.0 kDa), 4-hydroxybenzyl-COS (HB-COS), was synthesized to enhance antioxidant activity. Hence, HB-COS was evaluated for its capabilities against H2O2-induced oxidative stress in human Chang liver cells. It was found that HB-COS possessed the free radical scavenging activity via decreasing the intracellular reactive oxygen species production. Furthermore, HB-COS significantly reduced the oxidation of DNA in a dose-dependent manner. Notably, HB-COS treatment upregulated the gene and protein expressions of antioxidative enzymes and thereby enhancing the intracellular antioxidant mechanisms. In addition, HB-COS treatment caused a remarkable blockade on degradation of inhibitory kappa B alpha (IκB-α) protein and translocation of nuclear factor kappa B (NF-κB). The current study demonstrated that HB-COS effectively attenuated hydrogen peroxide-induced oxidative stress in Chang liver cells by increasing levels of antioxidant enzymes and inhibiting reactive oxygen species generation, DNA oxidation and the NF-κB signaling pathway.

  20. Endothelial Nitric Oxide Synthase Gene Variation Associated With Chronic Kidney Disease After Liver Transplant

    PubMed Central

    Bambha, Kiran; Kim, W. Ray; Rosen, Charles B.; Pedersen, Rachel A.; Rys, Cynthia; Kolbert, Christopher P.; Cunningham, Julie M.; Therneau, Terry M.

    2010-01-01

    OBJECTIVE: To identify single nucleotide polymorphisms (SNPs) associated with risk of developing chronic kidney disease (CKD), a prevalent comorbidity, after liver transplant (LT). PATIENTS AND METHODS: This study consists of a cohort of adult (≥18 years) primary-LT recipients who had normal renal function before LT and who survived 1 year or more after LT at a high-volume US LT program between January 1, 1990, and December 31, 2000. Patients with adequate renal function (estimated glomerular filtration rate, ≥40 mL/min per 1.73 m2 during follow-up; n=308) and patients with incident CKD (estimated glomerular filtration rate, <40 mL/min per 1.73 m2 after LT; n=92) were identified. To investigate the association of 6 candidate genes with post-LT CKD, we selected SNPs that have been associated with renal function in the literature. Hazard ratios were estimated using Cox regression, adjusted for potential confounding variables. RESULTS: The variant allele (298Asp) of the Glu298Asp SNP in the endothelial nitric oxide synthase gene (NOS3) was significantly associated with CKD after LT (P=.05; adjusted for multiple comparisons). The 5-year incidence of CKD was 70% among patients homozygous for the NOS3 variant allele (298Asp) compared with 42% among those not homozygous for the NOS3 variant allele. Specifically, homozygosity for the NOS3 variant allele conferred a 2.5-fold increased risk of developing CKD after LT (P=.005, adjusted for confounding variables). CONCLUSION: Homozygosity for the variant allele of NOS3 (298Asp) is associated with CKD after LT and may be useful for identifying recipients at higher risk of post-LT CKD. PMID:20810793

  1. Upper and lower limits of the proton stoichiometry of cytochrome c oxidation in rat liver mitoplasts.

    PubMed

    Reynafarje, B; Costa, L E; Lehninger, A L

    1986-06-25

    The stoichiometry of vectorial H+ translocation coupled to oxidation of added ferrocytochrome c by O2 via cytochrome-c oxidase of rat liver mitoplasts was determined employing a fast-responding O2 electrode. Electron flow was initiated by addition of either ferrocytochrome c or O2. When the rates were extrapolated to level flow, the H+/O ratios in both cases were less than but closely approached 4; the directly observed H+/O ratios significantly exceeded 3.0. The mechanistic H+/O ratio was then more closely fixed by a kinetic approach that eliminates the necessity for measuring energy leaks and is independent of any particular model of the mechanism of energy transduction. From two sets of kinetic measurements, an overestimate and an underestimate and thus the upper and lower limits of the mechanistic H+/O ratio could be obtained. In the first set, the utilization of respiratory energy was systematically varied through changes in the concentrations of valinomycin or K+. From the slope of a plot of the initial rates of H+ ejection (JH) and O2 uptake (JO) obtained in such experiments, the upper limit of the H+/O ratio was in the range 4.12-4.19. In the second set of measurements, the rate of respiratory energy production was varied by inhibiting electron transport. From the slope of a plot of JH versus JO, the lower limit of the H+/O ratio, equivalent to that at level flow, was in the range 3.83-3.96. These data fix the mechanistic H+/O ratio for the cytochrome oxidase reaction of mitoplasts at 4.0, thus confirming our earlier measurements (Reynafarje, B., Alexandre, A., Davies, P., and Lehninger, A. L. (1982) Proc. Natl. Acad. Sci. U.S.A. 79, 7218-7222). Possible reasons for discrepancies in published reports on the H+/O ratio of cytochrome oxidase in various mitochondrial and reconstituted systems are discussed.

  2. Effects of trans-10,cis-12 CLA on liver size and fatty acid oxidation under energy restriction conditions in hamsters.

    PubMed

    Lasa, Arrate; Simón, Edurne; Churruca, Itziar; Fernández-Quintela, Alfredo; Macarulla, María Teresa; Martínez, J Alfredo; Portillo, María Puy

    2011-01-01

    Little evidence exists concerning the effects of trans-10,cis-12 conjugated linoleic acid (CLA) under energy restriction. Thus, the effects of this CLA isomer on adipose tissue size, liver composition, as well as on expression and activity of carnitine-palmitoyl transferase I (CPT-I) and acyl CoA oxidase (ACO), in hamsters fed an energy-restricted diet were analyzed. Hamsters were fed a high-fat diet for 7 wk and then subjected to 25% energy-restricted diets supplemented with 0.5% linoleic acid or 0.5% trans-10,cis-12 CLA for 3 wk. Serum insulin, free-triiodothyronine and non-esterified fatty acid levels, liver triacylglycerol, protein and water contents, and CPT-I, ACO, and Peroxisome proliferator-activated receptor alpha (PPARα) expressions and enzyme activities were assessed. Energy restriction reduced liver size, serum levels of insulin, free-triiodothyronine, and non-esterified fatty acid and increased CPT-I activity. Liver composition was not modified. No differences were found between both restricted groups, with the exception of CPT-I and ACO oxidative enzyme activities, which were greater in hamsters fed the CLA diet. Energy restriction does not cause trans-10,cis-12 CLA to induce liver hyperplasia. Although this CLA isomer increases liver CPT-I and ACO activities, this effect does not result in reduced hepatic triacylglyerol content or decreased adipose tissue size. Consequently, this CLA isomer seems not to be a useful tool for inclusion in body weight loss strategies followed during obesity treatment. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Protective effects of hydrogen enriched saline on liver ischemia reperfusion injury by reducing oxidative stress and HMGB1 release

    PubMed Central

    2014-01-01

    Background The nuclear protein high-mobility group box 1 (HMGB1) is a key trigger for the inflammatory reaction during liver ischemia reperfusion injury (IRI). Hydrogen treatment was recently associated with down-regulation of the expression of HMGB1 and pro-inflammatory cytokines during sepsis and myocardial IRI, but it is not known whether hydrogen has an effect on HMGB1 in liver IRI. Methods A rat model of 60 minutes 70% partial liver ischemia reperfusion injury was used. Hydrogen enriched saline (2.5, 5 or 10 ml/kg) was injected intraperitoneally 10 minutes before hepatic reperfusion. Liver injury was assessed by serum alanine aminotransferase (ALT) enzyme levels and histological changes. We also measured malondialdehyde (MDA), hydroxynonenal (HNE) and 8-hydroxy-guanosine (8-OH-G) levels as markers of the peroxidation injury induced by reactive oxygen species (ROS). In addition, pro-inflammatory cytokines including TNF-α and IL-6, and high mobility group box B1 protein (HMGB1) were measured as markers of post ischemia-reperfusion inflammation. Results Hydrogen enriched saline treatment significantly attenuated the severity of liver injury induced by ischemia-reperfusion. The treatment group showed reduced serum ALT activity and markers of lipid peroxidation and post ischemia reperfusion histological changes were reduced. Hydrogen enriched saline treatment inhibited HMGB1 expression and release, reflecting a reduced local and systemic inflammatory response to hepatic ischemia reperfusion. Conclusion These results suggest that, in our model, hydrogen enriched saline treatment is protective against liver ischemia-reperfusion injury. This effect may be mediated by both the anti-oxidative and anti-inflammatory effects of the solution. PMID:24410860

  4. Caffeine 7-N-demethylation and C-8-oxidation mediated by liver microsomal cytochrome P450 enzymes in common marmosets.

    PubMed

    Uehara, Shotaro; Uno, Yasuhiro; Inoue, Takashi; Suzuki, Takako; Utoh, Masahiro; Sasaki, Erika; Yamazaki, Hiroshi

    2015-10-27

    1. 3-N-Demethylation of caffeine (1,3,7-trimethylxanthine) is mediated by human cytochrome P450 1A2, whereas 7-N-demethylation and C-8-hydroxylation are reportedly catalyzed by monkey P450 2C9 and rat P450 1A2, respectively. 2. Roles of marmoset P450 enzymes in caffeine oxidation were investigated using nine marmoset liver microsomes and 14 recombinantly expressed marmoset P450 enzymes. 3. Predominant caffeine 7-N-demethylation and C-8-hydroxylation activities in marmoset liver microsomes were moderately (r = 0.78, p < 0.05) and highly (r = 0.82, p < 0.01) correlated with midazolam 1'-hydroxylation activities, respectively, while the former was not strongly affected by ketoconazole or α-naphthoflavone. 4. Caffeine C-8-hydroxylation in liver microsomes was inhibited by ketoconazole and activated by α-naphthoflavone, suggesting main involvements of P450 3As. 5. Recombinant marmoset P450 3As had high Vmax/Km values for C-8-hydroxylation, comparable to Km values for marmoset liver microsomes. Marmoset P450 1As efficiently mediated caffeine 3-N-demethylation and C-8-hydroxylation with apparently lower Km values than those of liver microsomes. 6. These results collectively suggest highly active marmoset P450 3A enzymes toward caffeine 8-hydorxylaiton and involvement of multiple P450 isoforms including P450 1A in caffeine 7-N- and 3-N-demethylations in marmoset livers. Marmoset P450s have slightly different properties to human or monkey P450s regarding caffeine metabolic pathways.

  5. An analysis of the effects of Mn{sup 2+} on oxidative phosphorylation in liver, brain, and heart mitochondria using state 3 oxidation rate assays

    SciTech Connect

    Gunter, Thomas E.; Gerstner, Brent; Lester, Tobias; Wojtovich, Andrew P.; Malecki, Jon; Swarts, Steven G.; Brookes, Paul S.; Gavin, Claire E. Gunter, Karlene K.

    2010-11-15

    Manganese (Mn) toxicity is partially mediated by reduced ATP production. We have used oxidation rate assays-a measure of ATP production-under rapid phosphorylation conditions to explore sites of Mn{sup 2+} inhibition of ATP production in isolated liver, brain, and heart mitochondria. This approach has several advantages. First, the target tissue for Mn toxicity in the basal ganglia is energetically active and should be studied under rapid phosphorylation conditions. Second, Mn may inhibit metabolic steps which do not affect ATP production rate. This approach allows identification of inhibitions that decrease this rate. Third, mitochondria from different tissues contain different amounts of the components of the metabolic pathways potentially resulting in different patterns of ATP inhibition. Our results indicate that Mn{sup 2+} inhibits ATP production with very different patterns in liver, brain, and heart mitochondria. The primary Mn{sup 2+} inhibition site in liver and heart mitochondria, but not in brain mitochondria, is the F{sub 1}F{sub 0} ATP synthase. In mitochondria fueled by either succinate or glutamate + malate, ATP production is much more strongly inhibited in brain than in liver or heart mitochondria; moreover, Mn{sup 2+} inhibits two independent sites in brain mitochondria. The primary site of Mn-induced inhibition of ATP production in brain mitochondria when succinate is substrate is either fumarase or complex II, while the likely site of the primary inhibition when glutamate plus malate are the substrates is either the glutamate/aspartate exchanger or aspartate aminotransferase.

  6. Effect of the nitric oxide donor and the nitric oxide synthase inhibitor on the liver of rats with chronic hepatitis induced by dimethylnitrosamine.

    PubMed

    Lukivskaya, O; Lis, R; Zwierz, K; Buko, V

    2004-01-01

    The present study was designed to examine the effects of the donor of nitric oxide (NO), NaNO(2) and the inhibitor of NO synthase, N(omega)-nitro-L-arginine (L-NNA), on the development of dimethylnitrosamine (DMNA)-induced chronic hepatitis in rats. L-NNA decreased rat survival and enhanced the severity of hepatic encephalopathy in the DMNA-treated animals. The aggravation of the morphological signs of hepatitis, the activation of serum alanine aminotransferase and cytosolic superoxide dismutase activities and the increase in the liver malondialdehyde content were observed in this group. The treatment with NaNO(2) improved liver morphology, decreased serum marker enzyme activities, lowered the activities of alpha-D-mannosidase and N-acetyl-beta-D-glucosaminidase compared to the DMNA-treated group. The results of the morphological and biochemical studies suggest that L-NNA increased DMNA-induced liver damage, whereas NaNO(2) partially prevented the development of chronic hepatitis. It is proposed that the opposite effects of L-NNA and NaNO(2) are partially explained by a modulation of the free radical-dependent processes in the liver.

  7. The effect of dietary tryptophan levels on oxidative stress of liver induced by diquat in weaned piglets.

    PubMed

    Mao, Xiangbing; Lv, Mei; Yu, Bing; He, Jun; Zheng, Ping; Yu, Jie; Wang, Quyuan; Chen, Daiwen

    2014-01-01

    Oxidative stress can induce abnormal tryptophan metabolism. The present study was mainly conducted to determine the effect of dietary tryptophan levels on oxidative stress in the liver of weaned pigs challenged by diquat. A total of 36 PIC piglets weaned at 21 days of age were randomly allotted to 1 of 3 diets containing dietary tryptophan levels of 0.18, 0.30, and 0.45% for 14 d. On day 8, the piglets were injected intraperitoneally with sterile 0.9% NaCl solution or diquat (10 mg/kg body weight). During the first 7 d of trial, increasing dietary tryptophan levels enhanced average daily gain (P = 0.09) and average daily feed intake (P = 0.08), and decreased the feed efficiency (P < 0.05) of piglets. The growth performance was decreased by diquat injection (P < 0.05). Diquat injection also decreased the activities of the superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the plasma and liver (P < 0.05), increased plasma malondialdehyde (MDA) (P < 0.05) and urea nitrogen (P < 0.05) concentrations, and enhanced MDA concentration (P = 0.09) and tryptophan 2,3-dioxygenase (TDO) activity (P = 0.07) in liver of piglets. Increasing dietary tryptophan levels could attenuate the effects of diquat injection on the MDA (P = 0.06) concentration and the activities of SOD (P = 0.09) and GPx (P = 0.05) of the liver, and plasma urea nitrogen (P = 0.06) concentration in the piglet. There was a synergistic role for increasing TDO activity in the liver between dietary tryptophan levels and diquat injection (P < 0.05). These results suggest that increasing dietary tryptophan levels could attenuate the oxidative stress of the liver in weaned piglets intraperitoneally injected with diquat via enhancing the antioxidant capacity.

  8. Oxidative stress of brain and liver is increased by Wi-Fi (2.45GHz) exposure of rats during pregnancy and the development of newborns.

    PubMed

    Çelik, Ömer; Kahya, Mehmet Cemal; Nazıroğlu, Mustafa

    2016-09-01

    An excessive production of reactive oxygen substances (ROS) and reduced antioxidant defence systems resulting from electromagnetic radiation (EMR) exposure may lead to oxidative brain and liver damage and degradation of membranes during pregnancy and development of rat pups. We aimed to investigate the effects of Wi-Fi-induced EMR on the brain and liver antioxidant redox systems in the rat during pregnancy and development. Sixteen pregnant rats and their 48 newborns were equally divided into control and EMR groups. The EMR groups were exposed to 2.45GHz EMR (1h/day for 5 days/week) from pregnancy to 3 weeks of age. Brain cortex and liver samples were taken from the newborns between the first and third weeks. In the EMR groups, lipid peroxidation levels in the brain and liver were increased following EMR exposure; however, the glutathione peroxidase (GSH-Px) activity, and vitamin A, vitamin E and β-carotene concentrations were decreased in the brain and liver. Glutathione (GSH) and vitamin C concentrations in the brain were also lower in the EMR groups than in the controls; however, their concentrations did not change in the liver. In conclusion, Wi-Fi-induced oxidative stress in the brain and liver of developing rats was the result of reduced GSH-Px, GSH and antioxidant vitamin concentrations. Moreover, the brain seemed to be more sensitive to oxidative injury compared to the liver in the development of newborns.

  9. Proanthocyanidins Attenuation of Chronic Lead-Induced Liver Oxidative Damage in Kunming Mice via the Nrf2/ARE Pathway.

    PubMed

    Long, Miao; Liu, Yi; Cao, Yu; Wang, Nan; Dang, Meng; He, Jianbin

    2016-10-21

    Lead is harmful for human health and animals. Proanthocyanidins (PCs), a natural antioxidant, possess a broad spectrum of pharmacological and medicinal properties. However, its protective effects against lead-induced liver damage have not been clarified. This study was aimed to evaluate the protective effect of PCs on the hepatotoxicity of male Kunming mice induced by chronic lead exposure. A total of 70 healthy male Kunming mice were averagely divided into four groups: control group, i.e., the group exposed to lead, the group treated with PCs, and the group co-treated with lead and PCs. The mice exposed to lead were given water containing 0.2% lead acetate. Mice treated in the PCs and PCs lead co-treated groups were given PC (100 mg/kg) in 0.9% saline by oral gavage. Lead exposure caused a significant elevation in the liver function parameters, lead level, lipid peroxidation, and inhibition of antioxidant enzyme activities. The induction of oxidative stress and histological alterations in the liver were minimized by co-treatment with PCs. Meanwhile, the number of Transferase-Mediated Deoxyuridine Triphosphate-Biotin Nick End Labeling (TUNEL)-positive cells was significantly reduced in the PCs/lead co-treated group compared to the lead group. In addition, the lead group showed an increase in the expression level of Bax, while the expression of Bcl-2 was decreased. Furthermore, the lead group showed an increase in the expression level of endoplasmic reticulum (ER) stress-related genes and protein (GRP78 and CHOP). Co-treated with PCs significantly reversed these expressions in the liver. PCs were, therefore, demonstrated to have protective, antioxidant, and anti-ER stress and anti-apoptotic activities in liver damage caused by chronic lead exposure in the Kunming mouse. This may be due to the ability of PCs to enhance the ability of liver tissue to protect against oxidative stress via the Nrf2/ARE signaling pathway, resulting in decreasing ER stress and apoptosis of

  10. Proanthocyanidins Attenuation of Chronic Lead-Induced Liver Oxidative Damage in Kunming Mice via the Nrf2/ARE Pathway

    PubMed Central

    Long, Miao; Liu, Yi; Cao, Yu; Wang, Nan; Dang, Meng; He, Jianbin

    2016-01-01

    Lead is harmful for human health and animals. Proanthocyanidins (PCs), a natural antioxidant, possess a broad spectrum of pharmacological and medicinal properties. However, its protective effects against lead-induced liver damage have not been clarified. This study was aimed to evaluate the protective effect of PCs on the hepatotoxicity of male Kunming mice induced by chronic lead exposure. A total of 70 healthy male Kunming mice were averagely divided into four groups: control group, i.e., the group exposed to lead, the group treated with PCs, and the group co-treated with lead and PCs. The mice exposed to lead were given water containing 0.2% lead acetate. Mice treated in the PCs and PCs lead co-treated groups were given PC (100 mg/kg) in 0.9% saline by oral gavage. Lead exposure caused a significant elevation in the liver function parameters, lead level, lipid peroxidation, and inhibition of antioxidant enzyme activities. The induction of oxidative stress and histological alterations in the liver were minimized by co-treatment with PCs. Meanwhile, the number of Transferase-Mediated Deoxyuridine Triphosphate-Biotin Nick End Labeling (TUNEL)-positive cells was significantly reduced in the PCs/lead co-treated group compared to the lead group. In addition, the lead group showed an increase in the expression level of Bax, while the expression of Bcl-2 was decreased. Furthermore, the lead group showed an increase in the expression level of endoplasmic reticulum (ER) stress-related genes and protein (GRP78 and CHOP). Co-treated with PCs significantly reversed these expressions in the liver. PCs were, therefore, demonstrated to have protective, antioxidant, and anti-ER stress and anti-apoptotic activities in liver damage caused by chronic lead exposure in the Kunming mouse. This may be due to the ability of PCs to enhance the ability of liver tissue to protect against oxidative stress via the Nrf2/ARE signaling pathway, resulting in decreasing ER stress and apoptosis of

  11. The effect of copper deficiency on fetal growth and liver anti-oxidant capacity in the Cohen diabetic rat model

    SciTech Connect

    Ergaz, Zivanit; Shoshani-Dror, Dana; Guillemin, Claire; Neeman-azulay, Meytal; Fudim, Liza; Weksler-Zangen, Sarah; Stodgell, Christopher J.; Miller, Richard K.; Ornoy, Asher

    2012-12-01

    High sucrose low copper diet induces fetal growth restriction in the three strains of the Cohen diabetic rats: an inbred copper deficient resistant (CDr), an inbred copper deficient sensitive (CDs that become diabetic on high sucrose low copper diet -HSD) and an outbred Wistar derived Sabra rats. Although those growth restricted fetuses also exhibit increased oxidative stress, antioxidants do not restore normal growth. In the present study, we evaluated the role of copper deficiency in the HSD induced fetal growth restriction by adding to the drinking water of the rats 1 ppm or 2 ppm of copper throughout their pregnancy. Fetal and placental growth in correlation with fetal liver copper content and anti-oxidant capacity was evaluated on day 21 of pregnancy. HSD compared to regular chow induced fetal growth restriction, which was most significant in the Cohen diabetic sensitive animals. The addition of 1 ppm and 2 ppm copper to the drinking water normalized fetal growth in a dose dependent manner and reduced the degree of hyperglycemia in the diabetes sensitive rats. The CDs fetuses responded to the HSD with lower catalase like activity, and less reduced superoxide dismutase levels compared to the Sabra strain, and had high malondialdehyde levels even when fed regular chow. Immunostaining was higher for nitrotyrosine among the CDr and higher for hypoxia factor 1 α among the CDs. We conclude that in our model of dietary-induced fetal growth restriction, copper deficiency plays a major etiologic role in the decrease of fetal growth and anti-oxidant capacity. -- Highlights: ► High sucrose low copper diet restricted fetal growth in the Cohen diabetic rat model ► Maternal copper blood levels directly correlated with fetal liver copper content ► Copper supplementation decreased embryonic resorption in the inbred strains ► Copper supplementation reduced hyperglycemia in the sucrose sensitive inbred strain ► Copper supplementation alleviated growth restriction and

  12. Leucine accelerates blood ethanol oxidation by enhancing the activity of ethanol metabolic enzymes in the livers of SHRSP rats.

    PubMed

    Murakami, Hitoshi; Ito, Michiko; Furukawa, Yuji; Komai, Michio

    2012-12-01

    Chronic ethanol consumption induces liver diseases, such as alcoholic hepatitis and cirrhosis. The enhancement of alcohol oxidation is important in the prevention of these liver diseases. Chronic supplementation with branched chain amino acids (BCAAs) prevents liver cirrhosis. Therefore, BCAAs may be associated with enhanced ethanol oxidation. To evaluate this hypothesis, we investigated the effect of the administration of individual BCAAs on ethanol oxidation and changes in alcohol-metabolizing enzyme activities following acute alcohol intake in rats. Blood ethanol concentrations and the activities of alcohol-metabolizing enzymes, such as alcohol dehydrogenase (ADH) and low and high Km aldehyde dehydrogenase (ALDH), were measured in the liver following acute ethanol administration in rats; the ethanol was administered 30 min after the treatment with amino acids [such as leucine (Leu), isoleucine (Ile), valine (Val) or alanine (Ala)]. Leu significantly decreased the blood ethanol concentration 1 h after ethanol administration compared to the water-treated control (C) [C 0.46 ± 0.09, Leu 0.18 ± 0.04, Ile 0.27 ± 0.09, Val 0.46 ± 0.1, Ala 0.43 ± 0.06, mean ± SEM (g/l), P < 0.05]. In addition, leucine significantly stimulated ADH activity 30 min after ethanol intake [C 0.042 ± 0.014, Leu 0.090 ± 0.016, Ile 0.042 ± 0.008, Val 0.022 ± 0.010, Ala 0.070 ± 0.016, mean ± SEM (unit/mg protein), P < 0.05] and low Km ALDH activity 15 min after ethanol intake [C 0.51 ± 0.63, Leu 3.72 ± 0.66, Ile 1.26 ± 0.89, Val: ND, Ala 1.86 ± 1.57, mean ± SEM (unit/mg protein), P < 0.05]. However, leucine and its metabolite α-keto-isocaproic acid did not enhance ethanol clearance in isolated rat hepatocytes. These results indicate that leucine accelerates ethanol oxidation by indirectly enhancing ADH and low Km ALDH activities in the liver.

  13. Melatonin is able to prevent the liver of old castrated female rats from oxidative and pro-inflammatory damage.

    PubMed

    Kireev, R A; Tresguerres, A C F; Garcia, C; Ariznavarreta, C; Vara, E; Tresguerres, Jesus A F

    2008-11-01

    The aim of this study was to investigate the effect of aging and ovariectomy on various physiological parameters related to inflammation and oxidative stress in livers obtained from old female rats, and the influence of chronic administration of melatonin on these animals. Twenty-four female Wistar rats of 22 months of age were used. Animals were divided into four experimental groups: two intact groups that were untreated or given melatonin (1 mg/kg/day), and two ovariectomized groups that also untreated and treated with melatonin (1 mg/kg/day). After 10 wk of treatment, rats were sacrificed by decapitation, and livers were collected and homogenized. A group of 2-month-old female rats was used as young controls. Protein expression of inducible nitric oxide synthase (iNOS), heme oxygenase-1 (HO-1), IL-6, TNF-alpha and IL-1beta were determined by Western blot analysis. The levels of nitric oxide metabolites (NO(x)), lipid hydroperoxide (LPO), TNF-alpha, IL-1beta, IL-6 and IL-10 were determined. Levels of LPO in the liver homogenates as well as iNOS protein expression and NO(x) levels were increased in old rats as compared with young animals; this effect was more evident in ovariectomized animals. Pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6 were significantly increased and anti-inflammatory IL-10 decreased during aging and after ovariectomy. Aging also significantly increased the expression of HO-1 protein, and ovariectomized rats showed an additional increase. Administration of melatonin, both to intact and to the ovariectomized animals significantly reduced NO(x), LPO levels and pro-inflammatory cytokines in the liver as compared with untreated rats. Significant rice in IL-10 and reductions in the iNOS, HO-1, IL-6, TNF-alpha and IL-1beta protein expression were also found in rats treated with melatonin. Oxidative stress and inflammation induced during aging in the liver are more marked in castrated than in intact females. Administration of melatonin

  14. Protective effect of olive oil and colocynth oil against cadmium-induced oxidative stress in the liver of Wistar rats.

    PubMed

    Amamou, Fouzia; Nemmiche, Saïd; Meziane, Radjaa Kaouthar; Didi, Amal; Yazit, Sidi Mohamed; Chabane-Sari, Daoudi

    2015-04-01

    Cadmium (Cd) is one of the most common heavy metal pollutants. It is accumulated particularly in liver and kidney. The present study examined the possible protective effect of olive oil and colocynth oil consumption against Cd-induced damage on plasma lipids and stress biochemical parameters of rats. Male albino Wistar rats were randomly divided into 6 groups of 5 animals each and treated orally with Cd (50 mg/l), olive oil and colocynth oil (4%) alone or in combination with cadmium for 8 weeks. It was shown that Cd exposure induced significant increases in the activities of serum alanine aminotransferase, aspartate aminotransferase, lipid peroxidation levels (MDA) and protein carbonyl contents in exposed groups of rats compared to control group while the antioxidant enzymes, reduced glutathione and vitamins (C, A and E) were significantly decreased. Co-treatment with olive oil or colocynth oil significantly improved the oxidative damage induced by Cd. The antioxidant potential in plasma and liver were markedly restored with a significant decline in MDA levels and activity of transaminases. In conclusion, these results suggest that olive oil or colocynth oil consumption could protect the rat liver against Cd-induced injury by increasing the activities of antioxidant enzymes and reducing oxidative stress.

  15. Lutein decreases oxidative stress and inflammation in liver and eyes of guinea pigs fed a hypercholesterolemic diet

    PubMed Central

    Kim, Jung Eun; Clark, Richard M.; Park, Youngki; Lee, Jiyoung

    2012-01-01

    Guinea pigs were fed a hypercholesterolemic diet (0.25 g/100 g cholesterol) and randomly allocated either to a Control group (n = 9) or to a Lutein (0.1 g/100 g) group (n = 10) for 12 weeks to evaluate oxidative stress and inflammation in both liver and eyes. Malondialdehyde (MDA) concentrations and inflammatory cytokines were measured as well as hepatic nuclear factor-kappaB (NF-κB) binding. Lutein concentrations were greater in eyes (P < 0.01) and liver (P < 0.001) in the Lutein group. All guinea pigs had high concentrations of hepatic cholesterol as well as high plasma ALT and AST levels indicative of liver injury. However, the Lutein group had 43% lower hepatic free cholesterol than the Controls (P < 0.05). Hepatic MDA and MDA in the eye were lower in the Lutein compared to the Control group (P < 0.05). Hepatic tumor necrosis factor-α was 32% lower in the Lutein group (P < 0.05). Lastly, the Lutein group presented lower NF-κB DNA binding activity than the Control group (P < 0.001). These results suggest that in the presence of high cholesterol, lutein exerts both antioxidant and anti-inflammatory effects, which can be explained by attenuated NF-κB DNA binding activity. Furthermore, results also suggest that lutein accumulates in the eyes of guinea pigs to protect against oxidative stress. PMID:22586499

  16. Role of melatonin in reducing hypoxia-induced oxidative stress and morphological changes in the liver of male mice.

    PubMed

    El-Sokkary, Gamal H; Khidr, Bothaina M; Younes, Hala A

    2006-07-01

    Oxygen deficiency during critical illness may cause profound changes in cellular metabolism and subsequent tissue and organ dysfunction. Thus, the present study was designed to determine the effects of hypoxia and reoxygenation on the levels of lipid peroxidation and the morphological changes in the liver of male mice as well as the protective role of melatonin as an antioxidant. Two experiments were carried out in this study. Experiment I includes three groups of mice (control, hypoxic, and hypoxic+melatonin) while the experiment II includes two groups (reoxygenated and reoxygenated+melatonin). The levels of oxidized lipids were measured and the morphological changes were investigated using light and electron microscopy. In experiment I, hypoxia strongly stimulated lipid peroxidation levels (88%) while melatonin administration inhibited this increase (69%). Severe morphological changes (necrosis, dilated congested blood vessels, collection of inflammatory cells, condensed heterochromatic with irregular outlines nuclei, and mitochondrial degeneration) were detected in the liver of hypoxic mice. In experiment II, reoxygenation inhibited the levels of oxidized lipids (42%) versus hypoxic mice and some morphological changes were detected. When melatonin was given before reoxygenation, it inhibited the levels of lipid peroxidation by 66% versus hypoxic mice. Also, melatonin enhanced the recovery profile by 41% when compared with mice that reoxygenated with room air only. All morphological alterations that detected in both hypoxic and reoxygenated mice were repaired when melatonin administered. These results indicate that hypoxia and reoxygenation induce severe alterations in the liver and that melatonin exerts beneficial role in restoring tissue alterations after subjection to hypoxia.

  17. Acetic acid upregulates the expression of genes for fatty acid oxidation enzymes in liver to suppress body fat accumulation.

    PubMed

    Kondo, Tomoo; Kishi, Mikiya; Fushimi, Takashi; Kaga, Takayuki

    2009-07-08

    We investigated the effect of acetic acid (AcOH) on the prevention of obesity in high-fat-fed mice. The mice were intragastrically administrated with water or 0.3 or 1.5% AcOH for 6 weeks. AcOH administration inhibited the accumulation of body fat and hepatic lipids without changing food consumption or skeletal muscle weight. Significant increases were observed in the expressions of genes for peroxisome-proliferator-activated receptor alpha (PPARalpha) and for fatty-acid-oxidation- and thermogenesis-related proteins: acetyl-CoA oxidase (ACO), carnitine palmitoyl transferase-1 (CPT-1), and uncoupling protein-2 (UCP-2), in the liver of the AcOH-treatment groups. PPARalpha, ACO, CPT-1, and UCP-2 gene expressions were increased in vitro by acetate addition to HepG2 cells. However, the effects were not observed in cells depleted of alpha2 5'-AMP-activated protein kinase (AMPK) by siRNA. In conclusion, AcOH suppresses accumulation of body fat and liver lipids by upregulation of genes for PPARalpha and fatty-acid-oxidation-related proteins by alpha2 AMPK mediation in the liver.

  18. In Vivo Processing of Ceria Nanoparticles inside Liver: Impact on Free-Radical Scavenging Activity and Oxidative Stress.

    PubMed

    Graham, Uschi M; Tseng, Michael T; Jasinski, Jacek B; Yokel, Robert A; Unrine, Jason M; Davis, Burtron H; Dozier, Alan K; Hardas, Sarita S; Sultana, Rukhsana; Grulke, Eric A; Allan Butterfield, D

    2014-08-01

    The cytotoxicity of ceria ultimately lies in its electronic structure, which is defined by the crystal structure, composition, and size. Despite previous studies focused on ceria uptake, distribution, biopersistance, and cellular effects, little is known about its chemical and structural stability and solubility once sequestered inside the liver. Mechanisms will be presented that elucidate the in vivo transformation in the liver. In vivo processed ceria reveals a particle-size effect towards the formation of ultrafines, which represent a second generation of ceria. A measurable change in the valence reduction of the second-generation ceria can be linked to an increased free-radical scavenging potential. The in vivo processing of the ceria nanoparticles in the liver occurs in temporal relation to the brain cellular and protein clearance responses that stem from the ceria uptake. This information is critical to establish a possible link between cellular processes and the observed in vivo transformation of ceria. The temporal linkage between the reversal of the pro-oxidant effect (brain) and ceria transformation (liver) suggests a cause-effect relationship.

  19. The Nitric Oxide Donor S-Nitrosoglutathione Reduces Apoptotic Primary Liver Cell Loss in a Three-Dimensional Perfusion Bioreactor Culture Model Developed for Liver Support

    PubMed Central

    Prince, Jose M.; Vodovotz, Yoram; Baun, Matthew J.; Monga, Satdarshan Pal; Billiar, Timothy R.

    2010-01-01

    Introduction Artificial extracorporeal support for hepatic failure has met with limited clinical success. In hepatocytes, nitric oxide (NO) functions as an antiapoptotic modulator in response to a variety of stresses. We hypothesized that NO administration would yield improved viability and hepatocellular restructuring in a four-compartment, hollow fiber-based bioreactor with integral oxygenation for dynamic three-dimensional perfusion of hepatic cells in bioartificial liver support systems. Methods Isolated adult rat liver cells were placed in culture medium alone (control) or medium supplemented with various concentrations of an NO donor (S-nitrosoglutathione [GSNO]) in the bioreactors. Media samples were obtained from the cell perfusion circuit to monitor cellular response. After 24 and 72 h, histology biopsies were taken to investigate spontaneous restructuring of the cells. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to quantify apoptotic nuclei. Results Control bioreactors exhibited 47.9 ± 2.9% (mean ± standard error of the mean) apoptotic nuclei. In contrast, NO-treated bioreactors exhibited a biphasic response. Fewer apoptotic nuclei were seen in the 200 and 500 μM GSNO groups (14.4 ± 0.4%). No effect was observed in the 10 μM GSNO group (47.3%), and increased TUNEL staining was observed in the 1000 μM GSNO group (82.6%). Media lactate dehydrogenase levels were lower in bioreactor groups treated with 200 or 500 μM GSNO (310 ± 38 IU/L) compared with the control group (919 ± 188 IU/L; p < 0.05). Protein synthesis was not affected, as measured by albumin levels in the media (115 ± 19 μg/day/cell inoculum in GSNO-treated bioreactors at 24 h vs. 110 ± 13 in controls; p = 0.851). Histologically, all of the bioreactor groups exhibited liver cell aggregates with some attached to the bioreactor capillaries. Increased numbers of cells in the aggregates and

  20. Tea polyphenols protect against ischemia/reperfusion-induced liver injury in mice through anti-oxidative and anti-apoptotic properties

    PubMed Central

    Tao, Jin; Shen, Xinhong; Ai, Yonghong; Han, Xiaojing

    2016-01-01

    Tea polyphenols (TPs), which are derived from tea extracts, are a class of chemicals containing polyphenol hydroxyls that have been observed to have strong anti-oxidative properties. Previous studies have demonstrated that TP can protect against hepatic ischemia/reperfusion (I/R) injury; however, the underlying mechanism remains unknown. In the present study, the mechanism underlying TPs protective effects against I/R-induced liver damage was investigated, focusing on its anti-oxidative and anti-apoptotic bioactivities. C57BL/6 mice were used to establish a hepatic I/R-induced injury model, and liver injury was analyzed using a biochemical assay. The results from the current study demonstrated that the serum expression levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were significantly increased in mice following hepatic I/R injury, while the ratio of hepatic glutathione (GSH)/oxidized GSH (GSSG) was reduced, indicating that liver damage had occurred. In mice that were orally administered with TP (50 mg/kg) 1 h prior to I/R-induced injury, the extent of liver injury was significantly attenuated. It was also observed that I/R injury significantly decreased the mRNA and protein expression levels of cytokine-inducible nitric oxide synthase in liver tissues, and this was also attenuated by pretreatment with TP. Furthermore, pretreatment with TP significantly attenuated the I/R-induced increase in liver cell apoptosis, and the expression level and activity of pro-apoptotic proteins in the liver, indicating that I/R-induced liver cell apoptosis is inhibited by TP. In conclusion, the results in the present study suggest that TP protects against hepatic I/R-induced injury by inhibiting I/R-induced oxidative damage and liver cell apoptosis. PMID:27882175

  1. Effect of acetaminophen exposure in Oncorhynchus mykiss gills and liver: detoxification mechanisms, oxidative defence system and peroxidative damage.

    PubMed

    Ramos, A S; Correia, A T; Antunes, S C; Gonçalves, F; Nunes, B

    2014-05-01

    The increasing presence of pharmaceutical drugs in nature is cause of concern due to the occurrence of oxidative stress in non-target species. Acetaminophen is widely used in human medicine as an analgesic and antipyretic drug, and it is one of the most sold non-prescription drugs. The present study aimed to assess the toxic effects of acetaminophen (APAP) in Oncorhynchus mykiss following acute and chronic exposures in realistic levels. In order to evaluate the APAP effects in the rainbow trout, gills and liver were analyzed with biochemical biomarkers, such as catalase (CAT), total and selenium-dependent glutathione peroxidase (GPx), glutathione reductase (GRed) and glutathione-S-transferases (GSTs) activity and also lipid peroxidation levels (TBARS). The results obtained in all tests indicate that a significant response of oxidative stress was established, along with the increase of APAP concentrations. The establishment of an oxidative stress scenario occurred with the involvement of all tested biomarkers, sustaining a generalized set of pro-oxidative effects elicited by APAP. Additionally, the occurrence of oxidative damage strongly suggests the impairment of the antioxidant defense mechanism of O. mykiss. It is important to note that the occurrence of oxidative deleterious effects and peroxidative damages occurred for concentrations similar to those already reported for several freshwater ecosystems. The importance of these assumptions is further discussed under the scope of ecological relevance of the assessment of effects caused by pharmaceuticals in non-target organisms.

  2. Acute exposure to waterborne cadmium induced oxidative stress and immunotoxicity in the brain, ovary and liver of zebrafish (Danio rerio).

    PubMed

    Zheng, Jia-Lang; Yuan, Shuang-Shuang; Wu, Chang-Wen; Lv, Zhen-Ming

    2016-11-01

    Cadmium (Cd) is an environmental contaminant that poses serious risks to aquatic organisms and their associated ecosystem. The mechanisms underlying Cd-induced oxidative stress and immunotoxicity in fish remain largely unknown. In this study, adult female zebrafish were exposed to 0 (control), 1mgL(-1) Cd for 24h and 96h, and the oxidative stress and inflammatory responses induced by Cd were evaluated in the brain, liver and ovary. Reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA) increased in a time-dependent manner after treatment with Cd in the brain and liver. The increase may result from the disturbance of genes including copper and zinc superoxide dismutase (Cu/Zn-SOD), catalase (CAT), inducible nitric oxide synthase (iNOS), and ciclooxigenase-2 (COX-2) at mRNA, protein and activity levels. Although ROS, NO and MDA were not significantly affected by Cd in the ovary, the up-regulation of Cu/Zn-SOD, CAT, iNOS, and COX-2 was observed. Exposure to Cd induced a sharp increase in the protein levels of tumor necrosis factor alpha (TNF-α) in the brain, liver and ovary, possibly contributing to activate inflammatory responses. Furthermore, we also found a dramatic increase in mRNA levels of NF-E2-related factor 2 (Nrf2) and nuclear transcription factor κB (NF-κB) at 24h in the liver and ovary. The corresponding changes in the mRNA levels of Kelch-like-ECH-associated protein 1 (Keap1a and Keap1b) and the inhibitor of κBα (IκBαa and IκBαb) may contribute to regulate the transcriptional activity of Nrf2 and NF-κB, respectively. Contrarily, mRNA levels of Nrf2, NF-κB, Keap1, Keap1b, IκBαa and IκBαb remained stable at 24 and 96h in the brain. Taken together, we demonstrated Cd-induced oxidative stress and immunotoxicity in fish, possibly through transcriptional regulation of Nrf2 and NF-κB and gene modifications at transcriptional, translational, post-translational levels, which would greatly extend our understanding on the Cd

  3. The intake of high fat diet with different trans fatty acid levels differentially induces oxidative stress and non alcoholic fatty liver disease (NAFLD) in rats

    PubMed Central

    2011-01-01

    Background Trans-fatty acids (TFA) are known as a risk factor for coronary artery diseases, insulin resistance and obesity accompanied by systemic inflammation, the features of metabolic syndrome. Little is known about the effects on the liver induced by lipids and also few studies are focused on the effect of foods rich in TFAs on hepatic functions and oxidative stress. This study investigates whether high-fat diets with different TFA levels induce oxidative stress and liver dysfunction in rats. Methods Male Wistar rats were divided randomly into four groups (n = 12/group): C receiving standard-chow; Experimental groups that were fed high-fat diet included 20% fresh soybean oil diet (FSO), 20% oxidized soybean oil diet (OSO) and 20% margarine diet (MG). Each group was kept on the treatment for 4 weeks. Results A liver damage was observed in rats fed with high-fat diet via increase of liver lipid peroxidation and decreased hepatic antioxidant enzyme activities (superoxide dismutase, catalase and glutathione peroxidase). The intake of oxidized oil led to higher levels of lipid peroxidation and a lower concentration of plasma antioxidants in comparison to rats fed with FSO. The higher inflammatory response in the liver was induced by MG diet. Liver histopathology from OSO and MG groups showed respectively moderate to severe cytoplasm vacuolation, hypatocyte hypertrophy, hepatocyte ballooning, and necroinflammation. Conclusion It seems that a strong relationship exists between the consumption of TFA in the oxidized oils and lipid peroxidation and non alcoholic fatty liver disease (NAFLD). The extent of the peroxidative events in liver was also different depending on the fat source suggesting that feeding margarine with higher TFA levels may represent a direct source of oxidative stress for the organism. The present study provides evidence for a direct effect of TFA on NAFLD. PMID:21943357

  4. Involvement of CYP2D6 in oxidative metabolism of cinnarizine and flunarizine in human liver microsomes.

    PubMed

    Narimatsu, S; Kariya, S; Isozaki, S; Ohmori, S; Kitada, M; Hosokawa, S; Masubuchi, Y; Suzuki, T

    1993-06-30

    Oxidative metabolism of cinnarizine (CZ) and its fluorine derivative flunarizine (FZ), both of which are selective calcium entry blockers, was examined in human liver microsomes. The ring-hydroxylations and the N-desalkylations constituted primary metabolic pathways in microsomal metabolism of CZ and FZ. Among these pathways, the ring-hydroxylase (p-hydroxylation) activities at the cinnamyl moiety of both drugs were highly correlated with debrisoquine 4-hydroxylase activity and CYP2D6 content. Quinidine, a selective inhibitor of CYP2D6, suppressed the ring-hydroxylase activities of CZ and FZ. These results suggest that CYP2D6 is involved in the ring-hydroxylation of the cinnamyl moiety of both CZ and FZ in human liver microsomes.

  5. [The role of paracetamol in transition reactions of alpha-nitrogen and oxidative stress in the liver].

    PubMed

    Polaniak, Renata; Bułdak, Rafał Jakub; Birkner, Ewa; Karbowska, Dorota; Ochocki, Karol; Szkilnik, Ryszard

    2012-12-01

    Paracetamol (Acetaminophen, PC) is metabolized in liver to N-acetyl-p-benzoquinon-imine (NAPQI), that is in turn conjugated by glutathione S-transferase with glutathione. NAPQI inhibits the respiratory chain. It may cause a 90% decrease of ATP concentration in mitochondria of hepatocytes. The oxidation of paracetamol to quinine form can also generate free radicals. Both above mentioned processes, can injure the mitochondria and cells. There have not been found in accessible literature any data dealing with paracetamol influence on the process elimination of the alpha nitrogen in the liver. The ATP concentration decline may lead to disturbances in mitochondrial enzymes. There are discrepant data of the role of free radicals in the mechanism of toxic action of paracetamol.

  6. Liver tumor promoting effect of orphenadrine in rats and its possible mechanism of action including CAR activation and oxidative stress.

    PubMed

    Morita, Reiko; Yafune, Atsunori; Shiraki, Ayako; Itahashi, Megu; Ishii, Yuji; Akane, Hirotoshi; Nakane, Fumiyuki; Suzuki, Kazuhiko; Shibutani, Makoto; Mitsumori, Kunitoshi

    2013-01-01

    Orphenadrine (ORPH), an anticholinergic agent, is a cytochrome P450 (CYP) 2B inducer. CYP2B inducers are known to have liver tumor-promoting effects in rats. In this study, we performed a rat two-stage liver carcinogenesis bioassay to examine the tumor-promoting effect of ORPH and to clarify its possible mechanism of action. Male rats were given a single intraperitoneal injection of N-diethylnitrosamine (DEN) as an initiation treatment. Two weeks after DEN administration, rats were fed a diet containing ORPH (0, 750, or 1,500 ppm) for 6 weeks. One week after the ORPH-administration rats were subjected to two-thirds partial hepatectomy for the acceleration of hepatocellular proliferation. The number and area of glutathione S-transferase placental form-positive foci significantly increased in the DEN-ORPH groups. Real-time RT-PCR revealed increased mRNA expression levels of Cyp2b1/2, Mrp2 and Cyclin D1 in the DEN-ORPH groups and of Gpx2 and Gstm3 in the DEN-High ORPH group. Microsomal reactive oxygen species (ROS) production and oxidative stress markers such as thiobarbituric acid-reactive substances and 8-hydroxydeoxyguanosine were increased in the DEN-High ORPH group. Immunohistochemically, constitutively active/androstane receptor (CAR) were clearly localized in the nuclei of hepatocytes in the DEN-ORPH groups. These results suggest that ORPH causes nuclear translocation of CAR resulting in the induction of the liver tumor-promoting activity. Furthermore, oxidative stress resulting from ROS production is also involved in the liver tumor-promoting activity of ORPH.

  7. Aldosterone induces fibrosis, oxidative stress and DNA damage in livers of male rats independent of blood pressure changes.

    PubMed

    Queisser, Nina; Happ, Kathrin; Link, Samuel; Jahn, Daniel; Zimnol, Anna; Geier, Andreas; Schupp, Nicole

    2014-11-01

    Mineralocorticoid receptor blockers show antifibrotic potential in hepatic fibrosis. The mechanism of this protective effect is not known yet, although reactive oxygen species seem to play an important role. Here, we investigated the effects of elevated levels of aldosterone (Ald), the primary ligand of the mineralocorticoid receptor, on livers of rats in a hyperaldosteronism model: aldosterone-induced hypertension. Male Sprague-Dawley rats were treated for 4 weeks with aldosterone. To distinguish if damage caused in the liver depended on increased blood pressure or on increased Ald levels, the mineralocorticoid receptor antagonist spironolactone was given in a subtherapeutic dose, not normalizing blood pressure. To investigate the impact of oxidative stress, the antioxidant tempol was administered. Aldosterone induced fibrosis, detected histopathologically, and by expression analysis of the fibrosis marker, α-smooth muscle actin. Further, the mRNA amount of the profibrotic cytokine TGF-β was increased significantly. Fibrosis could be reduced by scavenging reactive oxygen species, and also by blocking the mineralocorticoid receptor. Furthermore, aldosterone treatment caused oxidative stress and DNA double strand breaks in livers, as well as the elevation of DNA repair activity. An increase of the transcription factor Nrf2, the main regulator of the antioxidative response could be observed, and of its target genes heme oxygenase-1 and γ-glutamylcysteine synthetase. All these effects of aldosterone were prevented by spironolactone and tempol. Already after 4 weeks of treatment, aldosteroneinfusion induced fibrosis in the liver. This effect was independent of elevated blood pressure. DNA damage caused by aldosterone might contribute to fibrosis progression when aldosterone is chroni