Sample records for a-induced oxidative liver

  1. 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

  2. Melatonin protects against taurolithocholic-induced oxidative stress in rat liver.

    PubMed

    Fuentes-Broto, Lorena; Miana-Mena, Francisco J; Piedrafita, Eduardo; Berzosa, César; Martínez-Ballarín, Enrique; García-Gil, Francisco A; Reiter, Russel J; García, Joaquín J

    2010-08-01

    Cholestasis, encountered in a variety of clinical disorders, is characterized by intracellular accumulation of toxic bile acids in the liver. Furthermore, oxidative stress plays an important role in the pathogenesis of bile acids. Taurolithocholic acid (TLC) was revealed in previous studies as the most pro-oxidative bile acid. Melatonin, a well-known antioxidant, is a safe and widely used therapeutic agent. Herein, we investigated the hepatoprotective role of melatonin on lipid and protein oxidation induced by TLC alone and in combination with FeCl(3) and ascorbic acid in rat liver homogenates and hepatic membranes. The lipid peroxidation products, malondialdehyde and 4-hydroxyalkenals (MDA + 4-HDA), and carbonyl levels were quantified as indices of oxidative damage to hepatic lipids and proteins, respectively. In the current study, the rise in MDA + 4-HDA levels induced by TLC was inhibited by melatonin in a concentration-dependent manner in both liver homogenates and in hepatic membranes. Melatonin also had protective effects against structural damage to proteins induced by TLC in membranes. These results suggest that the indoleamine melatonin may potentially act as a protective agent in the therapy of those diseases that involve bile acid toxicity. Published 2010 Wiley-Liss, Inc.

  3. A small-molecule inhibitor of NF-κB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injury.

    PubMed

    Ren, Xiaomeng; Li, Xinzhi; Jia, Linna; Chen, Deheng; Hou, Hai; Rui, Liangyou; Zhao, Yujun; Chen, Zheng

    2017-02-01

    Potent and selective chemical probes are valuable tools for discovery of novel treatments for human diseases. NF-κB-inducing kinase (NIK) is a key trigger in the development of liver injury and fibrosis. Whether inhibition of NIK activity by chemical probes ameliorates liver inflammation and injury is largely unknown. In this study, a small-molecule inhibitor of NIK, B022, was found to be a potent and selective chemical probe for liver inflammation and injury. B022 inhibited the NIK signaling pathway, including NIK-induced p100-to-p52 processing and inflammatory gene expression, both in vitro and in vivo Furthermore, in vivo administration of B022 protected against not only NIK but also CCl 4 -induced liver inflammation and injury. Our data suggest that inhibition of NIK is a novel strategy for treatment of liver inflammation, oxidative stress, and injury.-Ren, X., Li, X., Jia, L., Chen, D., Hou, H., Rui, L., Zhao, Y., Chen, Z. A small-molecule inhibitor of NF-κB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injury. © FASEB.

  4. 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.

  5. Thymoquinone restores liver fibrosis and improves oxidative stress status in a lipopolysaccharide-induced inflammation model in rats.

    PubMed

    Asgharzadeh, Fereshteh; Bargi, Rahimeh; Beheshti, Farimah; Hosseini, Mahmoud; Farzadnia, Mehdi; Khazaei, Majid

    2017-01-01

    Liver fibrosis is the primary sign of chronic liver injury induced by various causes. Thymoquinone (TQ) is the major ingredient of Nigella sativa with several beneficial effects on the body. In the present study, we aimed to investigate the effect of TQ on liver fibrosis in a lipopolysaccharide (LPS)-induced inflammation in male rats. Fifty male Wistar rats were randomly divided into five groups (n=10 in each group) as follow: (1) control; (2) LPS (1 mg/kg/day; i.p); (3) LPS+TQ 2 mg/kg/day (i.p) (LPs+TQ2); (4) LPS+TQ 5 mg/kg/day (LPS+TQ5); (5) LPS+ TQ 10 mg/kg/day (LPS+ TQ10). After three weeks, blood samples were taken for evaluation of liver function tests. Then, the livers were harvested for histological evaluation of fibrosis and collagen content and measurement of oxidative stress markers including malondialdehyde (MDA), total thiol groups, superoxide dismutase (SOD) and catalase activity in tissue homogenates. LPS group showed higher levels of fibrosis and collagen content stained by Masson's trichrome in liver tissue with impaired liver function test and increased oxidative stress markers (p<0.05). Treatment by TQ restored liver fibrosis, improved liver function tests and increased the levels of anti-oxidative enzymes (SOD and catalase), while reduced MDA concentration (p<0.05). Treatment by TQ restores inflammation-induced liver fibrosis possibly through affecting oxidative stress status. It seems that administration of TQ can be considered as a part of liver fibrosis management.

  6. 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

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

    PubMed Central

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

    2014-01-01

    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. PMID:24398069

  9. 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.

  10. Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis.

    PubMed

    Forsyth, Christopher B; Farhadi, Ashkan; Jakate, Shriram M; Tang, Yueming; Shaikh, Maliha; Keshavarzian, Ali

    2009-03-01

    Because only 30% of alcoholics develop alcoholic liver disease (ALD), a factor other than heavy alcohol consumption must be involved in the development of alcohol-induced liver injury. Animal and human studies suggest that bacterial products, such as endotoxins, are the second key co-factors, and oxidant-mediated gut leakiness is one of the sources of endotoxemia. Probiotics have been used to prevent and treat diseases associated with gut-derived bacterial products and disorders associated with gut leakiness. Indeed, "probiotic"Lactobacillus rhamnosus has been successfully used to treat alcohol-induced liver injury in rats. However, the mechanism of action involved in the potential beneficial effects of L. rhamnosus in alcohol liver injury is not known. We hypothesized that probiotics could preserve normal barrier function in an animal model of ALD by preventing alcohol-induced oxidative stress and thus prevent the development of hyperpermeability and subsequent alcoholic steatohepatitis (ASH). Male Sprague-Dawley rats were gavaged with alcohol twice daily (8 gm/kg) for 10 weeks. In addition, alcoholic rats were also treated with once daily gavage of either 2.5 x 10(7) live L. rhamnosus Gorbach-Goldin (LGG) or vehicle (V). Intestinal permeability (baseline and at 10 weeks) was determined using a sugar bolus and GC analysis of urinary sugars. Intestinal and liver tissues were analyzed for markers of oxidative stress and inflammation. In addition, livers were assessed histologically for severity of ASH and total fat (steatosis). Alcohol+LGG (ALC+LGG)-fed rats had significantly (P< or =.05) less severe ASH than ALC+V-fed rats. L. rhamnosus Gorbach-Goldin also reduced alcohol-induced gut leakiness and significantly blunted alcohol-induced oxidative stress and inflammation in both intestine and the liver. L. rhamnosus Gorbach-Goldin probiotic gavage significantly ameliorated ASH in rats. This improvement was associated with reduced markers of intestinal and liver

  11. 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

  12. Role of Oxygen Free Radicals, Nitric Oxide and Mitochondria in Mediating Cardiac Alterations During Liver Cirrhosis Induced by Thioacetamide.

    PubMed

    Amirtharaj, G Jayakumar; Natarajan, Sathish Kumar; Pulimood, Anna; Balasubramanian, K A; Venkatraman, Aparna; Ramachandran, Anup

    2017-04-01

    Thioacetamide (TAA) administration is widely used for induction of liver cirrhosis in rats, where reactive oxygen radicals (ROS) and nitric oxide (NO) participate in development of liver damage. Cardiac dysfunction is an important complication of liver cirrhosis, but the role of ROS or NO in cardiac abnormalities during liver cirrhosis is not well understood. This was investigated in animals after TAA-induced liver cirrhosis and temporal changes in oxidative stress, NO and mitochondrial function in the heart evaluated. TAA induced elevation in cardiac levels of nitrate before development of frank liver cirrhosis, without gross histological alterations. This was accompanied by an early induction of P38 MAP kinase, which is influenced by ROS and plays an important signaling role for induction of iNOS. Increased nitrotyrosine, protein oxidation and lipid peroxidation in the heart and cardiac mitochondria, suggestive of oxidative stress, also preceded frank liver cirrhosis. However, compromised cardiac mitochondrial function with a decrease in respiratory control ratio and increased mitochondrial swelling was seen later, when cirrhosis was evident. In conclusion, TAA induces elevations in ROS and NO in the heart in parallel to early liver damage. This leads to later development of functional deficits in cardiac mitochondria after development of liver cirrhosis.

  13. Differential effects of experimental and cold-induced hyperthyroidism on factors inducing rat liver oxidative damage.

    PubMed

    Venditti, P; Pamplona, R; Ayala, V; De Rosa, R; Caldarone, G; Di Meo, S

    2006-03-01

    Thyroid hormone-induced increase in metabolic rates is often associated with increased oxidative stress. The aim of the present study was to investigate the contribution of iodothyronines to liver oxidative stress in the functional hyperthyroidism elicited by cold, using as models cold-exposed and 3,5,3'-triiodothyronine (T3)- or thyroxine (T4)-treated rats. The hyperthyroid state was always associated with increases in both oxidative capacity and oxidative damage of the tissue. The most extensive damage to lipids and proteins was found in T3-treated and cold-exposed rats, respectively. Increase in oxygen reactive species released by mitochondria and microsomes was found to contribute to tissue oxidative damage, whereas the determination of single antioxidants did not provide information about the possible contribution of a reduced effectiveness of the antioxidant defence system. Indeed, liver oxidative damage in hyperthyroid rats was scarcely related to levels of the liposoluble antioxidants and activities of antioxidant enzymes. Conversely, other biochemical changes, such as the degree of fatty acid unsaturation and hemoprotein content, appeared to predispose hepatic tissue to oxidative damage associated with oxidative challenge elicited by hyperthyroid state. As a whole, our results confirm the idea that T3 plays a key role in metabolic changes and oxidative damage found in cold liver. However, only data concerning changes in glutathione peroxidase activity and mitochondrial protein content favour the idea that dissimilarities in effects of cold exposure and T3 treatment could depend on differences in serum levels of T4.

  14. 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

  15. 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.

  16. Protective effect of Anoectochilus roxburghii polysaccharide against CCl4-induced oxidative liver damage in mice.

    PubMed

    Yang, Zhenguo; Zhang, Xiaohui; Yang, Lawei; Pan, Qunwen; Li, Juan; Wu, Yongfu; Chen, Meizhen; Cui, Shichao; Yu, Jie

    2017-03-01

    This study investigated the isolation and characterization of Anoectochilus roxburghii polysaccharides (ARP), and further evaluated whether ARP possessed hepatoprotective activities against CCl 4 -induced oxidative liver damage in mice. ARP is comprised of glucose and galactose in a 1.9:1 molar ratio, and the molecular weight is 19.5kDa. ARP displayed significant scavenging effects against hydroxyl radical, superoxide anion radical, DPPH radical and a strong reducing power. In vivo experiment demonstrated ARP (150mg/kg) administrated to mice for 7days prior to carbon tetrachloride treatment, attenuated the elevated expression levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG) in serum and inhibited the formation of hepatic malondialdehyde (MDA). ARP pretreatment also increased antioxidant enzyme activities such as glutathione (GSH), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC) in the liver of CCl 4 -induced mice. Furthermore, hepatic histopathological changes induced by CCl 4 were significantly normalized by ARP pretreatment. These findings demonstrated that ARP possessed hepatoprotective effect against acute CCl 4 -induced liver damage by reducing lipid oxidation. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. 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.

  18. Oxidative phosphorylation flexibility in the liver of mice resistant to high-fat diet-induced hepatic steatosis.

    PubMed

    Poussin, Carinne; Ibberson, Mark; Hall, Diana; Ding, Jun; Soto, Jamie; Abel, E Dale; Thorens, Bernard

    2011-09-01

    To identify metabolic pathways that may underlie susceptibility or resistance to high-fat diet-induced hepatic steatosis. We performed comparative transcriptomic analysis of the livers of A/J and C57Bl/6 mice, which are, respectively, resistant and susceptible to high-fat diet-induced hepatosteatosis and obesity. Mice from both strains were fed a normal chow or a high-fat diet for 2, 10, and 30 days, and transcriptomic data were analyzed by time-dependent gene set enrichment analysis. Biochemical analysis of mitochondrial respiration was performed to confirm the transcriptomic analysis. Time-dependent gene set enrichment analysis revealed a rapid, transient, and coordinate upregulation of 13 oxidative phosphorylation genes after initiation of high-fat diet feeding in the A/J, but not in the C57Bl/6, mouse livers. Biochemical analysis using liver mitochondria from both strains of mice confirmed a rapid increase by high-fat diet feeding of the respiration rate in A/J but not C57Bl/6 mice. Importantly, ATP production was the same in both types of mitochondria, indicating increased uncoupling of the A/J mitochondria. Together with previous data showing increased expression of mitochondrial β-oxidation genes in C57Bl/6 but not A/J mouse livers, our present study suggests that an important aspect of the adaptation of livers to high-fat diet feeding is to increase the activity of the oxidative phosphorylation chain and its uncoupling to dissipate the excess of incoming metabolic energy and to reduce the production of reactive oxygen species. The flexibility in oxidative phosphorylation activity may thus participate in the protection of A/J mouse livers against the initial damages induced by high-fat diet feeding that may lead to hepatosteatosis.

  19. Methionine sulfoxide reductase A deficiency exacerbates acute liver injury induced by acetaminophen

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Singh, Mahendra Pratap; School of Bioengineering and Biosciences, Department of Zoology, Lovely Professional University, Phagwara, 144411, Punjab; Kim, Ki Young

    Acetaminophen (APAP) overdose induces acute liver injury via enhanced oxidative stress and glutathione (GSH) depletion. Methionine sulfoxide reductase A (MsrA) acts as a reactive oxygen species scavenger by catalyzing the cyclic reduction of methionine-S-sulfoxide. Herein, we investigated the protective role of MsrA against APAP-induced liver damage using MsrA gene-deleted mice (MsrA{sup −/−}). We found that MsrA{sup −/−} mice were more susceptible to APAP-induced acute liver injury than wild-type mice (MsrA{sup +/+}). The central lobule area of the MsrA{sup −/−} liver was more impaired with necrotic lesions. Serum alanine transaminase, aspartate transaminase, and lactate dehydrogenase levels were significantly higher in MsrA{supmore » −/−} than in MsrA{sup +/+} mice after APAP challenge. Deletion of MsrA enhanced APAP-induced hepatic GSH depletion and oxidative stress, leading to increased susceptibility to APAP-induced liver injury in MsrA-deficient mice. APAP challenge increased Nrf2 activation more profoundly in MsrA{sup −/−} than in MsrA{sup +/+} livers. Expression and nuclear accumulation of Nrf2 and its target gene expression were significantly elevated in MsrA{sup −/−} than in MsrA{sup +/+} livers after APAP challenge. Taken together, our results demonstrate that MsrA protects the liver from APAP-induced toxicity. The data provided herein constitute the first in vivo evidence of the involvement of MsrA in hepatic function under APAP challenge. - Highlights: • MsrA deficiency increases APAP-induced liver damage. • MsrA deletion enhances APAP-induced hepatic GSH depletion and oxidative stress. • MsrA deficiency induces more profound activation of Nrf2 in response to APAP. • MsrA protects the liver from APAP-induced toxicity.« less

  20. Rac2 deficiency attenuates CCl4-induced liver injury through suppressing inflammation and oxidative stress.

    PubMed

    Zou, Yan; Xiong, Ji-Bin; Ma, Ke; Wang, Ai-Zhong; Qian, Ke-Jian

    2017-10-01

    Oxidative stress is a leading cause to liver injury. Rac2 is a Ras-associated guanosine triphosphatase, an important molecule modulating a large number of cells and involved in the regulation of reactive oxygen species (ROS). For the study described here, we supposed that Rac2 knockout protects mice against CCl 4 -induced acute liver injury. We found that Rac2 expressed highly in CCl 4 -induced liver tissues. CCl 4 -treated Rac2 knockout (Rac2-/-) mice had reduced CD24 levels and steatosis. In addition, CCl 4 -induced high expression of pro-inflammatory cytokines and chemokine were reversed by Rac2 deficiency compared to CCl 4 -treated wild type (WT) mice. We also found that fibrosis-related signals of MMP-9, MMP-2 and TGF-β1 were also down-regulated in Rac2 knockout mice induced by CCl 4 . Significantly, oxidative stress induced by CCl 4 was also suppressed owing to the lack of Rac2, evidenced by enhanced superoxide dismutase (SOD) activity, and reduced malondialdehyde (MDA) levels, superoxide radical, H 2 O 2 , xanthine oxidase (XO), xanthine dehydrogenase (XDH) and XO/XDH ratio. Moreover, c-Jun N-terminal protein kinase mitogen-activated protein kinases (JNK MAPK) was activated by CCl 4 , which was reversed in the liver of Rac2-/- mice through western blot and immunohistochemical analysis. In vitro, endotoxin (LPS) was treated to hepatocytes isolated from WT mice and Rac2-/- mice. The data further confirmed the role of Rac2 deficiency suppressed pro-inflammatory cytokines and chemokine, as well as fibrosis-related signals. Of note, production of ROS induced by LPS was reduced in Rac2-/- cells, accompanied with enhanced SOD1, SOD2 and reduced XO and phosphorylated-JNK expressions. Our results indicated that Rac2 played an essential role in acute liver injury induced by CCl 4 , providing the compelling information of the effects of Rac2 on liver injury, and revealing a novel regulatory mechanism for acute liver injury. Copyright © 2017. Published by Elsevier

  1. Betanin attenuates paraquat-induced liver toxicity through a mitochondrial pathway.

    PubMed

    Han, Junyan; Zhang, Zongju; Yang, Shaobin; Wang, Jun; Yang, Xuelian; Tan, Dehong

    2014-08-01

    We attempted to determine whether betanin (from natural pigments) that has anti-oxidant properties would be protective against paraquat-induced liver injury in Sprague-Dawley rats. Paraquat was injected intraperitoneally into rats to induce liver toxicity. The rats were randomly divided into four groups: a control group, a paraquat group, and two groups that received betanin at doses of 25 and 100mg/kg/day three days before and two days after they were administered paraquat. We evaluated liver histopathology, serum liver enzymatic activities, oxidative stress, cytochrome P450 (CYP) 3A2 mRNA expression, and mitochondrial damage. The rats that were injected with paraquat incurred liver injury, evidenced by histological changes and elevated serum aspartate aminotransferase and alanine aminotransferase levels; paraquat also led to oxidative stress, an increase of cytochrome P450 3A2 mRNA expression, and mitochondrial damage, indicated by mitochondrial membrane swelling, reduced mitochondrial cytochrome C, and apoptosis-inducing factor protein levels. Pathological damage and all of the above mentioned markers were lesser in the animals treated with betanin than in those who received paraquat alone. Betanin had a protective effect against paraquat-induced liver damage in rats. The mechanism of the protection appears to be the inhibition of CYP 3A2 expression and protection of mitochondria. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Protective effects of Ziyang tea polysaccharides on CCl4-induced oxidative liver damage in mice.

    PubMed

    Wang, Dongying; Zhao, Yan; Sun, Yanfei; Yang, Xingbin

    2014-01-15

    This study was designed to investigate the hepatoprotective effects of the tea polysaccharides (ZTPs) extracted from a selenium-enriched Ziyang green tea (Camellia sinensis). ZTPs were identified as the heteropolysaccharides with glucose (31.4%), arabinose (23.5%) and galactose (21.8%) being the main constitutive monosaccharides. ZTPs displayed noteworthy scavenging effects against DPPH, OH and O2(-), and high antioxidant effects in vitro, and the effects were further verified by suppressing CCl4-induced oxidative liver damage in mice at 100, 200 and 400mg/kg BW. Administration of ZTPs in mice prior to CCl4 significantly prevented the CCl4-induced increases in serum alanine aminotransferase, aspartate aminotransferase and lactic dehydrogenase, as well as hepatic malondialdehyde level. Mice treated with ZTPs showed normal glutathione peroxidase and superoxide dismutase activities, relative to CCl4-treated group. ZTPs also prevented the CCl4-caused liver histological alteration, as indicated by histopathological evaluation. These findings demonstrate that ZTPs have protective effects against acute CCl4-induced oxidative liver damage. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. 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.

  4. Nilotinib counteracts thioacetamide-induced hepatic oxidative stress and attenuates liver fibrosis progression.

    PubMed

    Shaker, Mohamed E; Salem, Hatem A; Shiha, Gamal E; Ibrahim, Tarek M

    2011-04-01

    The aim of this study was to evaluate and compare the effects of imatinib and nilotinib to that of silymarin on established liver fibrosis and oxidative stress in a thioacetamide (TAA) rat model. Male Wistar rats received intraperitoneal (i.p.) injections of TAA (150mg/kg, twice weekly) for 12weeks. Daily treatments with imatinib (10mg/kg), nilotinib (10mg/kg), and silymarin (100mg/kg) were administered orally during the last 4weeks of TAA-administration. At the end of the study, hepatic damage was evaluated by analysis of liver function tests in serum. Hepatic histopathology and collagen content were employed to quantify liver fibrosis. Hepatic oxidative stress was assessed by measuring malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), total nitrate/nitrite (NOx), and reduced glutathione (GSH) contents, as well as myeloperoxidase (MPO) and superoxide dismutase (SOD) activities. Nilotinib, silymarin and, to a lesser extent, imatinib treatments ameliorated TAA-induced hepatic oxidative stress and damage as indicated by hepatic MDA, 4-HNE, NOx, GSH, MPO and SOD levels, as well as liver function tests. Hepatic histopathology results revealed that nilotinib, imatinib, and silymarin treatments decreased the mean score of fibrosis in TAA-treated rats by 24, 14, and 3%, respectively. However, nilotinib and silymarin, but not imatinib, treatments decreased hepatic collagen content in TAA-treated rats by 17 and 36%, respectively. In conclusion, we demonstrated for the first time that nilotinib not only protected against hepatic oxidative stress, but also slowed down liver fibrosis progression. Thus, we provide the first evidence that nilotinib might be a promising anti-fibrotic drug. © 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.

  5. 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-induced

  6. 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

  7. 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. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Caveolin 1-related autophagy initiated by aldosterone-induced oxidation promotes liver sinusoidal endothelial cells defenestration.

    PubMed

    Luo, Xiaoying; Dan Wang; Luo, Xuan; Zhu, Xintao; Wang, Guozhen; Ning, Zuowei; Li, Yang; Ma, Xiaoxin; Yang, Renqiang; Jin, Siyi; Huang, Yun; Meng, Ying; Li, Xu

    2017-10-01

    Aldosterone, with pro-oxidation and pro-autophagy capabilities, plays a key role in liver fibrosis. However, the mechanisms underlying aldosterone-promoted liver sinusoidal endothelial cells (LSECs) defenestration remain unknown. Caveolin 1 (Cav1) displays close links with autophagy and fenestration. Hence, we aim to investigate the role of Cav1-related autophagy in LSECs defenestration. We found the increase of aldosterone/MR (mineralocorticoid receptor) level, oxidation, autophagy, and defenestration in LSECs in the human fibrotic liver, BDL or hyperaldosteronism models; while antagonizing aldosterone or inhibiting autophagy relieved LSECs defenestration in BDL-induced fibrosis or hyperaldosteronism models. In vitro, fenestrae of primary LSECs gradually shrank, along with the down-regulation of the NO-dependent pathway and the augment of the AMPK-dependent autophagy; these effects were aggravated by rapamycin (an autophagy activator) or aldosterone treatment. Additionally, aldosterone increased oxidation mediated by Cav1, reduced ATP generation, and subsequently induced the AMPK-dependent autophagy, leading to the down-regulation of the NO-dependent pathway and LSECs defenestration. These effects were reversed by MR antagonist spironolactone, antioxidants or autophagy inhibitors. Besides, aldosterone enhanced the co-immunoprecipitation of Cav1 with p62 and ubiquitin, and induced Cav1 co-immunofluorescence staining with LC3, ubiquitin, and F-actin in the perinuclear area of LSECs. Furthermore, aldosterone treatment increased the membrane protein level of Cav1, whereas decrease the cytoplasmic protein level of Cav1, indicating that aldosterone induced Cav1-related selective autophagy and F-actin remodeling to promote defenestration. Consequently, Cav1-related selective autophagy initiated by aldosterone-induced oxidation promotes LSECs defenestration via activating the AMPK-ULK1 pathway and inhibiting the NO-dependent pathway. Copyright © 2017 The Authors

  9. 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

  10. 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.

  11. Size and oxidative susceptibility of low-density lipoprotein particles in breast cancer patients with tamoxifen-induced fatty liver.

    PubMed

    Wakatsuki, Akihiko; Ogawa, Yasuhiro; Saibara, Toshiji; Okatani, Yuji; Fukaya, Takao

    2002-08-01

    The purpose of the present study was to investigate the effects of tamoxifen on the size and oxidative susceptibility of low-density lipoprotein (LDL) particles in breast cancer patients with tamoxifen-induced fatty liver. We investigated the following breast cancer patients: 13 receiving no tamoxifen (group A), 13 receiving tamoxifen 40 mg daily but without fatty liver (group B), and 13 receiving tamoxifen 40 mg daily with fatty liver (group C). Plasma lipids and diameter of LDL particles were measured. Susceptibility of LDL to oxidation was analyzed by incubation with CuSO(4) while monitoring conjugated diene formation and assaying thiobarbituric acid reactive substances (TBARS). Plasma total and LDL cholesterol concentrations in groups B and C were significantly lower than those in group A. In group C, concentrations of plasma triglyceride (TG) and TBARS were significantly greater, but LDL particle diameter and lag time for LDL oxidation were significantly smaller than those in groups A and B. Plasma TG concentrations correlated negatively with computed tomography ratio of liver to spleen (r = -0.76; P < 0.001). LDL particle diameter correlated negatively with plasma TG (r = -0.62; P < 0.001) and TBARS (r = -0.44; P < 0.01), but positively with LDL lag time (r = 0.47; P < 0.01). Tamoxifen-induced fatty liver in breast cancer patients may be atherogenic, via increased TG and consequent small, easily oxidized LDL particles.

  12. Oxaliplatin-induced Oxidative Stress Provokes Toxicity in Isolated Rat Liver Mitochondria.

    PubMed

    Tabassum, Heena; Waseem, Mohammad; Parvez, Suhel; Qureshi, M Irfan

    2015-11-01

    Oxaliplatin is a widely employed platinum-derived chemotherapeutic agent commonly used for the treatment of colorectal cancer. Unfortunately, the benefit of this important drug is compromised by severe side effects such as neuropathy, ototoxicity, gastrointestinal toxicity, and hematological toxicity. Recently, few studies have also suggested the occurrence of hepatotoxicity in oxaliplatin-treated patients. Mitochondria have emerged as targets for anticancer drugs in various kinds of toxicity including hepatotoxicity that can lead to neoplastic disease. Oxidative stress is a well-established biomarker of mitochondrial toxicity. The purpose of this study was to investigate the dose-dependent damage caused by oxaliplatin on isolated liver mitochondria under in vitro conditions. The study was conducted in mitochondria isolated from liver of Wistar rats. Oxaliplatin was incubated with mitochondria in a dose-dependent manner under in vitro conditions. Oxidative stress indexes, non-enzymatic and enzymatic antioxidants were evaluated, looking at the overall armamentarium against the toxicity induced by oxaliplatin. Oxaliplatin caused a significant rise in the mitochondrial oxidative stress indexes lipid peroxidation and protein carbonyl. Alterations in the levels of non-enzymatic antioxidants and activities of enzymatic antioxidants were also observed. Oxidative stress plays an important role in the mitochondrial toxicity of oxaliplatin. The integrity of the hepatic tissue is compromised by the reactive oxygen species-mediated lipid peroxidation and protein carbonyl formation. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhou, Yan; College of Food Safety, Guizhou Medical University, Guiyang 550025; Ruan, Zheng, E-mail: ruanzheng@ncu.edu.cn

    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 thatmore » 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.« less

  14. Arsenite induced oxidative damage in mouse liver is associated with increased cytokeratin 18 expression.

    PubMed

    Gonsebatt, M E; Del Razo, L M; Cerbon, M A; Zúñiga, O; Sanchez-Peña, L C; Ramírez, P

    2007-09-01

    Cytokeratins (CK) constitute a family of cytoskeletal intermediate filament proteins that are typically expressed in epithelial cells. An abnormal structure and function are effects that are clearly related to liver diseases as non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. We have previously observed that sodium arsenite (SA) induced the synthesis of CK18 protein and promotes a dose-related disruption of cytoplasmic CK18 filaments in a human hepatic cell line. Both abnormal gene expression and disturbance of structural organization are toxic effects that are likely to cause liver disease by interfering with normal hepatocyte function. To investigate if a disruption in the CK18 expression pattern is associated with arsenite liver damage, we investigated CK18 mRNA and protein levels in liver slices treated with low levels of SA. Organotypic cultures were incubated with 0.01, 1 and 10 microM of SA in the absence and presence of N-acetyl cysteine (NAC). Cell viability and inorganic arsenic metabolism were determined. Increased expression of CK18 was observed after exposure to SA. The addition of NAC impeded the oxidative effects of SA exposure, decreasing the production of thiobarbituric acid-reactive substances and significantly diminishing the up regulation of CK18 mRNA and protein. Liver arsenic levels correlated with increased levels of mRNA. Mice treated with intragastric single doses of 2.5 and 5 mg/kg of SA showed an increased expression of CK18. Results suggest that CK18 expression may be a sensible early biomarker of oxidative stress and damage induced by arsenite in vitro and in vivo. Then, during SA exposure, altered CK expression may compromise liver function.

  15. Methionine sulfoxide reductase A deficiency exacerbates acute liver injury induced by acetaminophen.

    PubMed

    Singh, Mahendra Pratap; Kim, Ki Young; Kim, Hwa-Young

    2017-02-26

    Acetaminophen (APAP) overdose induces acute liver injury via enhanced oxidative stress and glutathione (GSH) depletion. Methionine sulfoxide reductase A (MsrA) acts as a reactive oxygen species scavenger by catalyzing the cyclic reduction of methionine-S-sulfoxide. Herein, we investigated the protective role of MsrA against APAP-induced liver damage using MsrA gene-deleted mice (MsrA -/- ). We found that MsrA -/- mice were more susceptible to APAP-induced acute liver injury than wild-type mice (MsrA +/+ ). The central lobule area of the MsrA -/- liver was more impaired with necrotic lesions. Serum alanine transaminase, aspartate transaminase, and lactate dehydrogenase levels were significantly higher in MsrA -/- than in MsrA +/+ mice after APAP challenge. Deletion of MsrA enhanced APAP-induced hepatic GSH depletion and oxidative stress, leading to increased susceptibility to APAP-induced liver injury in MsrA-deficient mice. APAP challenge increased Nrf2 activation more profoundly in MsrA -/- than in MsrA +/+ livers. Expression and nuclear accumulation of Nrf2 and its target gene expression were significantly elevated in MsrA -/- than in MsrA +/+ livers after APAP challenge. Taken together, our results demonstrate that MsrA protects the liver from APAP-induced toxicity. The data provided herein constitute the first in vivo evidence of the involvement of MsrA in hepatic function under APAP challenge. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. 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

  17. Parboiled Germinated Brown Rice Protects Against CCl4-Induced Oxidative Stress and Liver Injury in Rats.

    PubMed

    Wunjuntuk, Kansuda; Kettawan, Aikkarach; Charoenkiatkul, Somsri; Rungruang, Thanaporn

    2016-01-01

    Parboiled germinated brown rice (PGBR) of Khao Dawk Mali 105 variety was produced by steaming germinated paddy rice, which is well-known for its nutrients and bioactive compounds. In this study we determined the in vivo antioxidant and hepatoprotective effects of PGBR in carbon tetrachloride (CCl(4))-induced oxidative stress in rats. Male Sprague-Dawley rats, (weight 200-250 g) were randomly divided into (1) control, (2) CCl(4), (3) white rice (WR)+CCl(4), (4) brown rice (BR)+CCl(4), and (5) PGBR+CCl(4) groups. PGBR, BR, and WR diets were produced by replacing corn starch in the AIN76A diet with cooked PGBR, BR, and WR powders, respectively. All rats except the control group were gavaged with 50% CCl4 in olive oil (v/v, 1 mL/kg) twice a week for 8 weeks. CCl(4)-treated rats exhibited significant liver injury, lipid peroxidation, protein oxidation, and DNA damage, as well as obvious changes to liver histopathology compared to control. In addition, CCl(4) treatment decreased the activities of CYP2E1 and antioxidant enzymes: glutathione S-transferase, glutathione peroxidase, superoxide dismutase and catalase, and glutathione (GSH) content. However, the PGBR+CCl(4) group exhibited less liver injury, lipid peroxidation, protein oxidation, and DNA damage, as well as better antioxidant enzyme activities and GSH content. Furthermore, PGBR inhibited degradation of CYP2E1 in CCl(4)-induced decrease of CYP2E1 activity. These data suggest that PGBR may prevent CCl(4)-induced liver oxidative stress and injury through enhancement of the antioxidant capacities, which may be due to complex actions of various bioactive compounds, including phenolic acids, γ-oryzanol, tocotrienol, and GABA.

  18. 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

  19. Quercetin ameliorates liver injury induced with Tripterygium glycosides by reducing oxidative stress and inflammation.

    PubMed

    Wang, Junming; Miao, Mingsan; Zhang, Yueyue; Liu, Ruixin; Li, Xaobing; Cui, Ying; Qu, Lingbo

    2015-06-01

    Quercetin (Que) is one of main compounds in Lysimachia christinae Hance (Christina loosestrife), and has both medicinal and nutritional value. Glycosides from Tripterygium wilfordii Hook.f. (léi gōng téng [the thunder duke vine]; TG) have diverse and broad bioactivities but with a high incidence of liver injury. Our previous study reported on the hepatoprotective properties of an ethanol extract from L. christinae against TG-induced liver injury in mice. This research is designed to observe, for the first time, the possible protective properties of the compound Que against TG-induced liver injury, and the underlying mechanisms that are involved in oxidative stress and anti-inflammation. The results indicated that TG caused excessive elevation in serum levels of alanine/aspartate transaminase (ALT/AST), alkaline phosphatase (ALP), gamma glutamyl transferase (γ-GT), and pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α), as well as hepatic lipid peroxidation (all P < 0.01). On the other hand, following TG exposure, we observed significantly reduced levels of biomarkers, including hepatic glutathione (GSH), glutathione-S-transferase (GST), glutathione peroxidase (GPx), and the anti-inflammatory cytokine interleukin (IL)-10, as well as the enzyme activity and mRNA expression of copper- and zinc-containing superoxide dismutase (CuZn-SOD) and catalase (CAT) (all P < 0.01). Nevertheless, all of these alterations were reversed by the pre-administration of Que or the drug bifendate (positive control) for 7 consecutive days. Therefore, this study suggests that Que ameliorates TG-induced acute liver injury, probably through its ability to reduce oxidative stress and its anti-inflammatory properties.

  20. Diet-induced obesity associated with steatosis, oxidative stress, and inflammation in liver.

    PubMed

    Peng, Yanhua; Rideout, Drew; Rakita, Steven; Lee, James; Murr, Michel

    2012-01-01

    Obesity induces steatosis and increases oxidative stress, as well as chronic inflammation in the liver. The balance between lipogenesis and lipolysis is disrupted in obese animals. At a cellular level, the changes in metabolic sensors and energy regulators are poorly understood. We hypothesized that diet-induced steatosis increases oxidative stress, inflammation, and changes the metabolic regulators to promote energy storage in mice. The setting was a university-affiliated basic science research laboratory. Four-week-old C57BL mice were fed a high-fat diet (n = 8) or regular chow (n = 8) for 7 weeks. The liver sections were stained for fat content and immunofluorescence. Liver homogenates were used for protein analysis by immunoblotting and mRNA analysis by reverse transcriptase-polymerase chain reaction. The gels were quantified using densitometry P ≤ .05 was considered significant. The high-fat diet upregulated protein kinase-C atypical isoforms ζ and λ and decreased glucose tolerance and the interaction of insulin receptor substrate 2 with phosphoinositide kinase-3. The high-fat diet increased the transcriptional factors liver X receptor (4321 ± 98 versus 2981 ± 80) and carbohydrate response element-binding protein (5132 ± 135 versus 3076 ± 91), the lipogenesis genes fatty acid binding protein 5, stearoyl-co-enzyme A desaturase-1, and acetyl-co-enzyme A carboxylase protein, and fatty acid synthesis. The high-fat diet decreased 5'-adenosine monophosphate-activated protein kinase (2561 ± 78 versus 1765 ± 65), glucokinase-3β (2.214 ± 34 versus 3356 ± 86), and SIRT1 (2015 ± 76 versus 3567 ± 104) and increased tumor necrosis factor-α (3415 ± 112 versus 2042 ± 65), nuclear factor kappa B (5123 ± 201 versus 2562 ± 103), cyclooxygenase-2 (4230 ± 113 versus 2473 ± 98), nicotinamide-adenine dinucleotide phosphate oxidase (3501 ± 106 versus 1600 ± 69) and reactive oxygen species production (all P < .001, obese mice versus lean mice). A high-fat diet

  1. Heme oxygenase-1 upregulated by Ginkgo biloba extract: potential protection against ethanol-induced oxidative liver damage.

    PubMed

    Yao, Ping; Li, Ke; Song, Fangfang; Zhou, Shaoliang; Sun, Xiufa; Zhang, Xiping; Nüssler, Andreas K; Liu, Liegang

    2007-08-01

    Oxidative stress plays a pivotal role in the pathogenesis and progression of alcoholic liver disease (ALD) and HO-1 induction is suggested to protect hepatocytes from ethanol hepatotoxicity. Here, we present the data to explore the hepatoprotective effect and underlying mechanism(s) of Ginkgo biloba extract (EGB), a naturally occurring HO-1 inducer, against ethanol-induced oxidative damage. Ethanol-fed (2.4 g/kg) male rats were pretreated by EGB (48 or 96 mg/kg) for 90 days. Liver damage was evaluated by histopathology and serum aminotransferase assay. Hepatic redox parameters were measured by spectrophotometry. Heme oxygenase-1 (HO-1) expression was determined by RT-PCR and flow cytometry on mRNA and protein level, respectively. Our results showed that EGB, especially at high dose, ameliorated ethanol-induced macrovesicular steatosis and parenchymatous degeneration in hepatocytes, and decreased serum aminotransferases level. Furthermore, EGB reduced ethanol-derived glutathione depletion and lipid peroxidation, and inhibited the inactivation of superoxide dismutase, glutathione peroxidase and catalase, although EGB itself had no influence on such parameters. Importantly, EGB induced hepatic microsomal HO-1 on mRNA, protein expression and enzymatic activity, which is paralleled to the EGB-derived hepatoprotective effect. Hence, HO-1 upregulation by EGB may enhance the antioxidative capacity against the ethanol-induced oxidative stress and maintain the cellular redox balance.

  2. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver.

    PubMed

    Lanaspa, Miguel A; Sanchez-Lozada, Laura G; Choi, Yea-Jin; Cicerchi, Christina; Kanbay, Mehmet; Roncal-Jimenez, Carlos A; Ishimoto, Takuji; Li, Nanxing; Marek, George; Duranay, Murat; Schreiner, George; Rodriguez-Iturbe, Bernardo; Nakagawa, Takahiko; Kang, Duk-Hee; Sautin, Yuri Y; Johnson, Richard J

    2012-11-23

    Uric acid is an independent risk factor in fructose-induced fatty liver, but whether it is a marker or a cause remains unknown. Hepatocytes exposed to uric acid developed mitochondrial dysfunction and increased de novo lipogenesis, and its blockade prevented fructose-induced lipogenesis. Rather than a consequence, uric acid induces fatty liver Hyperuricemic people are more prone to develop fructose-induced fatty liver. Metabolic syndrome represents a collection of abnormalities that includes fatty liver, and it currently affects one-third of the United States population and has become a major health concern worldwide. Fructose intake, primarily from added sugars in soft drinks, can induce fatty liver in animals and is epidemiologically associated with nonalcoholic fatty liver disease in humans. Fructose is considered lipogenic due to its ability to generate triglycerides as a direct consequence of the metabolism of the fructose molecule. Here, we show that fructose also stimulates triglyceride synthesis via a purine-degrading pathway that is triggered from the rapid phosphorylation of fructose by fructokinase. Generated AMP enters into the purine degradation pathway through the activation of AMP deaminase resulting in uric acid production and the generation of mitochondrial oxidants. Mitochondrial oxidative stress results in the inhibition of aconitase in the Krebs cycle, resulting in the accumulation of citrate and the stimulation of ATP citrate lyase and fatty-acid synthase leading to de novo lipogeneis. These studies provide new insights into the pathogenesis of hepatic fat accumulation under normal and diseased states.

  3. 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

  4. Autoxidation and toxicant-induced oxidation of lipid and DNA in monkey liver: reduction of molecular damage by melatonin.

    PubMed

    Cabrer, J; Burkhardt, S; Tan, D X; Manchester, L C; Karbownik, M; Reiter, R J

    2001-11-01

    Melatonin, the main secretory product of the pineal gland, is a free radical scavenger and antioxidant which protects against oxidative damage due to a variety of toxicants. However, there is little information regarding melatonin's antioxidative capacity in tissues of primates. In this study we examined the protective effects of melatonin in monkey liver homogenates against lipid damage that occurred as a result of autoxidation or that induced by exogenous addition of H202 and ferrous iron (Fe2+). Additionally, we tested melatonin's protective effect against oxidative damage to DNA induced by chromium(III) (CrIII) plus H202. The levels of malondialdehyde and 4-hydroxyalkenals were assayed as an index of lipid peroxidation, and the concentrations of 8-hydroxydeoxyguanosine (8-OHdG) as an endpoint of oxidative DNA damage. The increases in malondialdehyde+4-hydroxyalkenals concentrations as a consequence of autoxidation or after the addition of H202 plus Fe2+ to the homogenates were time-dependent. The accumulation of these damaged products due to either auto-oxidative processes or induced by H202 and Fe2+ were significantly reduced by melatonin in a concentration-dependent-manner. The levels of 8-OHdG were elevated in purified monkey liver DNA incubated with a combination of CrCl3 plus H2O2. This rise in oxidatively damaged DNA was prevented by 10 microM concentration of melatonin. Also, melatonin reduced the damage to DNA that was caused by auto-oxidative processes. These findings in monkey liver tissue document the ability of melatonin to protect against oxidative damage to both lipid and DNA in primate tissue, as observed previously in rodent tissue. The findings provide support for the use of melatonin as suitable agent to reduce damage inflicted by free radical species in primates.

  5. Aldosterone induces fibrosis, oxidative stress and DNA damage in livers of male rats independent of blood pressure changes

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Queisser, Nina; Happ, Kathrin; Link, Samuel

    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.more » 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

  6. 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

  7. Pre- vs. post-treatment with melatonin in CCl4-induced liver damage: Oxidative stress inferred from biochemical and pathohistological studies.

    PubMed

    Ničković, Vanja P; Novaković, Tatjana; Lazarević, Slavica; Šulović, Ljiljana; Živković, Zorica; Živković, Jovan; Mladenović, Bojan; Stojanović, Nikola M; Petrović, Vladmir; Sokolović, Dušan T

    2018-06-01

    The present study was designed to compare the ameliorating potential of pre- and post-treatments with melatonin, a potent natural antioxidant, in the carbon tetrachloride-induced rat liver damage model by tracking changes in enzymatic and non-enzymatic liver tissue defense parameters, as well as in the occurring pathohistological changes. Rats from two experimental groups were treated with melatonin before and after CCl 4 administration, while the controls, negative and positive, received vehicle/melatonin and CCl 4 , respectively. Serum levels of transaminases, alkaline phosphates, γ-GT, bilirubin, and albumin, as well as a wide panel of oxidative stress-related parameters in liver tissue, were determined in all experimental animals. Liver tissue specimens were stained with hematoxylin and eosin and further evaluated for morphological changes. Both pre- and post-treatment with melatonin prevented a CCl 4 -induced increase in serum (ALT, AST, and γ-GT) and tissue (MDA and XO) liver damage markers and a decrease in the tissue total antioxidant capacity, in both enzymatic and non-enzymatic systems. The intensity of pathological changes, hepatocyte vacuolar degeneration, necrosis and inflammatory cell infiltration, was suppressed by the treatment with melatonin. In conclusion, melatonin, especially as a post-intoxication treatment, attenuated CCl 4 -induced liver oxidative damage, increased liver antioxidant capacities and improved liver microscopic appearance. The results are of interest due to the great protective potential of melatonin that was even demonstrated to be stronger if applied after the tissue damage. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. Pathological Lesions and Inducible Nitric Oxide Synthase Expressions in the Liver of Mice Experimentally Infected with Clonorchis sinensis.

    PubMed

    Yang, Qing-Li; Shen, Ji-Qing; Xue, Yan; Cheng, Xiao-Bing; Jiang, Zhi-Hua; Yang, Yi-Chao; Chen, Ying-Dan; Zhou, Xiao-Nong

    2015-12-01

    The nitric oxide (NO) formation and intrinsic nitrosation may be involved in the possible mechanisms of liver fluke-associated carcinogenesis. We still do not know much about the responses of inducible NO synthase (iNOS) induced by Clonorchis sinensis infection. This study was conducted to explore the pathological lesions and iNOS expressions in the liver of mice with different infection intensity levels of C. sinensis. Extensive periductal inflammatory cell infiltration, bile duct hyperplasia, and fibrosis were commonly observed during the infection. The different pathological responses in liver tissues strongly correlated with the infection intensity of C. sinensis. Massive acute spotty necrosis occurred in the liver parenchyma after a severe infection. The iNOS activity in liver tissues increased, and iNOS-expressing cells with morphological differences were observed after a moderate or severe infection. The iNOS-expressing cells in liver tissues had multiple origins.

  9. 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

  10. 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

  11. Stevia Prevents Acute and Chronic Liver Injury Induced by Carbon Tetrachloride by Blocking Oxidative Stress through Nrf2 Upregulation

    PubMed Central

    Ramos-Tovar, Erika; Hernández-Aquino, Erika; Casas-Grajales, Sael; Buendia-Montaño, Laura D.; Tsutsumi, Víctor

    2018-01-01

    The effect of stevia on liver cirrhosis has not been previously investigated. In the present study, the antioxidant and anti-inflammatory properties of stevia leaves were studied in male Wistar rats with carbon tetrachloride- (CCl4-) induced acute and chronic liver damage. Acute and chronic liver damage induced oxidative stress, necrosis, and cholestasis, which were significantly ameliorated by stevia. Chronic CCl4 treatment resulted in liver cirrhosis, as evidenced by nodules of hepatocytes surrounded by thick bands of collagen and distortion of the hepatic architecture, and stevia significantly prevented these alterations. Subsequently, the underlying mechanism of action of the plant was analyzed. Our study for the first time shows that stevia upregulated Nrf2, thereby counteracting oxidative stress, and prevented necrosis and cholestasis through modulation of the main proinflammatory cytokines via NF-κB inhibition. These multitarget mechanisms led to the prevention of experimental cirrhosis. Given the reasonable safety profile of stevia, our results indicated that it may be useful for the clinical treatment of acute and chronic liver diseases. PMID:29849889

  12. aí (Euterpe oleracea Mart.) attenuates alcohol-induced liver injury in rats by alleviating oxidative stress and inflammatory response.

    PubMed

    Zhou, Jianyu; Zhang, Jianjun; Wang, Chun; Qu, Shengsheng; Zhu, Yingli; Yang, Zhihui; Wang, Linyuan

    2018-01-01

    The present study aimed to investigate the therapeutic effects of Euterpe oleracea Mart. (EO) on alcoholic liver diseases (ALD). A total of 30 Wistar rats were randomly divided into three groups (10 rats per group), including alcohol group (alcohol intake), EO group (alcohol + EO puree intake) and control group (distilled water intake). The activity of superoxide dismutase (SOD) and alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the levels of cholesterol (CHO), triglyceride (TG), malondialdehyde (MDA) and glutathione (GSH) in the serum as well as the liver tissue levels of interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) were measured. Histopathological changes in liver tissues were observed by hematoxylin and eosin staining. Reverse-transcription quantitative PCR analysis was performed for detecting the expression of nuclear factor (NF)-κB and CD68. The results indicated that EO intake significantly decreased ALT, AST, ALP, TG and CHO as well as the hepatic index in alcohol-treated rats. In addition, EO treatment relieved alcohol-induced oxidative stress by decreasing the levels of MDA and TG, and increasing the activity of SOD and GSH levels. In addition, the expression of TNF-α, TGF-β, IL-8, NF-κB and CD-68 in the liver were decreased by EO treatment. Furthermore, EO intake alleviated the histopathological liver damage, including severe steatosis and abundant infiltrated inflammatory cells. In conclusion, EO alleviated alcohol-induced liver injury in rats by alleviating oxidative stress and inflammatory response.

  13. aí (Euterpe oleracea Mart.) attenuates alcohol-induced liver injury in rats by alleviating oxidative stress and inflammatory response

    PubMed Central

    Zhou, Jianyu; Zhang, Jianjun; Wang, Chun; Qu, Shengsheng; Zhu, Yingli; Yang, Zhihui; Wang, Linyuan

    2018-01-01

    The present study aimed to investigate the therapeutic effects of Euterpe oleracea Mart. (EO) on alcoholic liver diseases (ALD). A total of 30 Wistar rats were randomly divided into three groups (10 rats per group), including alcohol group (alcohol intake), EO group (alcohol + EO puree intake) and control group (distilled water intake). The activity of superoxide dismutase (SOD) and alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the levels of cholesterol (CHO), triglyceride (TG), malondialdehyde (MDA) and glutathione (GSH) in the serum as well as the liver tissue levels of interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) were measured. Histopathological changes in liver tissues were observed by hematoxylin and eosin staining. Reverse-transcription quantitative PCR analysis was performed for detecting the expression of nuclear factor (NF)-κB and CD68. The results indicated that EO intake significantly decreased ALT, AST, ALP, TG and CHO as well as the hepatic index in alcohol-treated rats. In addition, EO treatment relieved alcohol-induced oxidative stress by decreasing the levels of MDA and TG, and increasing the activity of SOD and GSH levels. In addition, the expression of TNF-α, TGF-β, IL-8, NF-κB and CD-68 in the liver were decreased by EO treatment. Furthermore, EO intake alleviated the histopathological liver damage, including severe steatosis and abundant infiltrated inflammatory cells. In conclusion, EO alleviated alcohol-induced liver injury in rats by alleviating oxidative stress and inflammatory response. PMID:29399060

  14. N-acetylcysteine modulates doxorubicin-induced oxidative stress and antioxidant vitamin concentrations in liver of rats.

    PubMed

    Koçkar, M Cem; Nazıroğlu, Mustafa; Celik, Omer; Tola, H Tahsin; Bayram, Dilek; Koyu, Ahmet

    2010-12-02

    Doxorubicin (DOX) is a chemotherapeutic agent, and is widely used in cancer treatment. The most common side effect of DOX was indicated on cardiovascular system by experimental studies. There are some studies suggesting oxidative stress-induced toxic changes on liver related to DOX administration. The aim of the present study was to evaluate whether antioxidant N-acetylcysteine (NAC) relieves oxidative stress in DOX- induced liver injury in rat. Twenty-four male rats were equally divided into three groups. First group was used as a control. Second group received single dose of DOX. NAC for 10 days was given to constituting the third group after giving one dose of DOX. After 10 days of the experiment, liver tissues were taken from all animals. Lipid peroxidation (LP) levels were higher in the DOX group than in control whereas LP levels were lower in the DOX+NAC group than in control. Vitamin C and vitamin E levels were lower in the DOX group than in control whereas vitamin C and vitamin E levels were higher in the DOX+NAC group than in the DOX group. Reduced glutathione levels were higher in the DOX+NAC group than in control and DOX group. Glutathione peroxidase, vitamin A and β-carotene values were not changed in the three groups by DOX and NAC administrations. In histopathological evaluation of DOX group, there were mononuclear cell infiltrations, vacuolar degeneration, hepatocytes with basophilic nucleus and sinusoidal dilatations. The findings were totally recovered by NAC administration. In conclusion, N-acetylcysteine induced modulator effects on the doxorubicin-induced hepatoxicity by inhibiting free radical production and supporting the antioxidant vitamin levels. Copyright © 2010 John Wiley & Sons, Ltd.

  15. Protective mechanisms of Moringa oleifera against CCl(4)-induced oxidative stress in precision-cut liver slices.

    PubMed

    Sreelatha, S; Padma, P R

    2010-01-01

    The present study was designed to evaluate the efficacy of Moringa oleifera leaves against carbon tetrachloride (CCl(4))-treated liver slices in vitro. The study evaluated the antioxidant properties of Moringa oleifera leaves against CCl(4)-induced oxidative damage in liver slices. CCl(4) treatment significantly decreased the activities of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase and caused decreased glutathione content and increased the thiobarbituric acid-reacting substances (TBARS). Treatment with Moringa oleifera extract increased the activities of antioxidant enzymes and glutathione content and reduced the levels of TBARS significantly. Observed reduction in the level of lipid peroxides showed a decreased tendency of peroxidative damage. We conclude that, under these experimental conditions, the leaf extracts effectively suppress CCl(4)-induced oxidative stress. Our findings provide evidence to demonstrate that the possible mechanism of this activity may be due to the strong antioxidant property of the leaves. Copyright 2010 S. Karger AG, Basel.

  16. 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

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

    PubMed

    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. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis.

    PubMed

    DeZwaan-McCabe, Diane; Sheldon, Ryan D; Gorecki, Michelle C; Guo, Deng-Fu; Gansemer, Erica R; Kaufman, Randal J; Rahmouni, Kamal; Gillum, Matthew P; Taylor, Eric B; Teesch, Lynn M; Rutkowski, D Thomas

    2017-05-30

    The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Inhibitory Effect of Glutathione on Oxidative Liver Injury Induced by Dengue Virus Serotype 2 Infections in Mice

    PubMed Central

    Wang, Juan; Chen, Yanlei; Gao, Na; Wang, Yisong; Tian, Yanping; Wu, Jiangman; Zhang, Junlei; Zhu, Junping; Fan, Dongying; An, Jing

    2013-01-01

    The pathogenesis of dengue virus (DV) infection has not been completely defined and change of redox status mediated by depletion of glutathione (GSH) in host cell is a common result of viral infection. Our previous study has demonstrated that DV serotype 2 (DV2) infection alters host intracellular GSH levels, and exogenous GSH inhibits viral production by modulating the activity of NF-κB in HepG2 cells. GSH is the most powerful intracellular antioxidant and involved in viral infections. Thus, this study was to investigate whether DV2 infection can induce alteration in redox balance and effect of GSH on the disease in HepG2 xenografts SCID mice. Our results revealed that mice infected with DV2 showed alterations in oxidative stress by increasing the level of malondialdehyde (MDA), an end product of lipid peroxidation, and GSSG/GSH ratio. DV2-infected mice also showed a decrease in the activity of catalase (CAT) and total superoxide dismutase (T-SOD) in the serum and/or observed organs, especially the liver. Moreover, DV2 infection resulted in elevated serum levels of the cytokines tumor necrosis factor-α and interlukin-6 and obvious histopathological changes in the liver. The administration of exogenous GSH significantly reversed all of the aforementioned pathological changes and prevented significant liver damage. Furthermore, in vitro treatment of HepG2 cells with antioxidants such as GSH inhibited viral entry as well as the production of reactive oxygen species in HepG2 cells. These results suggest that GSH prevents DV2-induced oxidative stress and liver injury in mice by inhibiting proinflammatory cytokine production, and GSH and may be a promising therapeutic agent for prevention of oxidative liver damage during DV infection. PMID:23383181

  20. 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

  1. Curcumin alleviates lipopolysaccharide induced sepsis and liver failure by suppression of oxidative stress-related inflammation via PI3K/AKT and NF-κB related signaling.

    PubMed

    Zhong, Wenhui; Qian, Kejian; Xiong, Jibin; Ma, Ke; Wang, Aizhong; Zou, Yan

    2016-10-01

    In many liver disorders, oxidative stress-related inflammation and apoptosis are important pathogenic components, finally resulting in acute liver failure. Erythropoietin and its analogues are well known to influence the interaction between apoptosis and inflammation in brain and kidney. The study is to clarify the effect of curcumin, a natural plant phenolic food additive, on lipopolysaccharides (LPS)-induced acute liver injury of mice with endotoxemia and associated molecular mechanism from inflammation, apoptosis and oxidative stress levels. And curcumin, lowered serum cytokines, including Interleukin 1beta (IL-1β), Interleukin 6 (IL-6) and tumor necrosis factor (TNF-α), and improved liver apoptosis through suppressing phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway and inhibiting Cyclic AMP-responsive element-binding protein (CREB)/Caspase expression, and decreased oxidative stress-associated protein expression, mainly involving 2E1 isoform of cytochrome P450/nuclear factor E2-related factor 2/reactive oxygen species (CYP2E/Nrf2/ROS) signaling pathway, as well as liver nitric oxide (NO) production in LPS-induced mice. Moreover, curcumin regulated serum alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP), accelerated liver antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GSH-px) levels, and inhibited activation of the mitogen-activated protein kinases/c-Jun NH2-terminal kinase (P38/JNK) cascade in the livers of LPS-induced rats. Thus, curcumin treatment attenuates LPS-induced PI3K/AKT and CYP2E/Nrf2/ROS signaling and liver injury. Strategies to inhibit inflammation and apoptosis signaling may provide alternatives to the current clinical approaches to improve oxidative responses of endotoxemia. Copyright © 2016. Published by Elsevier Masson SAS.

  2. Cytotoxicity and the induction of the stress protein Hsp 70 in Chang liver cells in response to zearalenone-induced oxidative stress.

    PubMed

    Lee, Hyungkyoung; Kang, Changgeun; Yoo, Yong-San; Hah, Do-Yun; Kim, Chung Hui; Kim, Euikyung; Kim, Jong Shu

    2013-09-01

    Zearalenone (ZEN) has been implicated in several cases of mycotoxicosis in farm animals and humans. The toxic effects of ZEN have been well characterized, but little is known regarding the mechanisms of ZEN toxicity, including the involvement of the oxidative stress pathway. Using Chang liver cells as a model, the aim of this study was to determine if ZEN could elevate the expression of the heat shock protein Hsp 70, induce cytotoxicity and modulate the levels of glutathione (GSH) and thiobarbituric acid reactive substance (TBARS). In addition, the cytoprotective effects of N-acetylcysteine amide (NACA) pre-treatment were assessed. Finally, the involvement of oxidative stress in ZEN-induced toxicity was confirmed. The results of this study demonstrated that ZEN-induced Hsp 70 expression in a dose- and time-dependent manners. This effect occurred at low-ZEN concentrations, and could therefore be considered a biomarker of ZEN-induced toxicity. The cytotoxicity was reduced when Chang liver cells were exposed to sub-lethal heat shock prior to ZEN treatment, demonstrating a cytoprotective effect of Hsp 70. This cytoprotective effect suggested that Hsp 70 might play a key role in the cellular defense mechanism. When cells were pre-treated with NACA prior to ZEN treatment, the cells were also protected from toxicity. This NACA cytoprotective effect suggested the involvement of oxidative stress in ZEN-induced toxicity, and this mechanism was supported by reduced Hsp 70 expression, inhibited cytolethality, increased GSH levels and decreased TBARS formation when cells were pre-treated with NACA prior to ZEN exposure. Our data clearly demonstrated that ZEN induced cytotoxicity in Chang liver cells by inhibiting cell proliferation, decreasing GSH levels and increasing TBARS formation in a dose-dependent manner. ZEN also, induced Hsp 70 expression, and the side effects of ZEN were significantly alleviated by pre-treatment with NACA. Oxidative stress is likely to be one of the

  3. Role of nitric oxide and KATP channel in the protective effect mediated by nicorandil in bile duct ligation-induced liver fibrosis in rats.

    PubMed

    Mohamed, Yasmin S; Ahmed, Lamiaa A; Salem, Hesham A; Agha, Azza M

    2018-05-01

    Liver fibrosis is one of the most serious conditions affecting patients worldwide. In the present study, the role of nitric oxide and KATP channel was investigated for the first time in the possible protection mediated by nicorandil in bile duct ligation-induced liver fibrosis in rats. Nicorandil (3 mg/kg/day) was given orally 24 h after bile duct ligation for 14 days till the end of the experiment. Nicorandil group showed marked improvement in liver function tests, hepatic oxidative stress and inflammatory markers as well as inducible and endothelial nitric oxide synthase protein expressions. Furthermore, nicorandil administration led to significant decrement of phosphorylated protein kinase C, fibrosis and hepatic stellate cells activation as indicated by decreased alpha smooth muscle actin expression. Oral co-administration of glibenclamide (5 mg/kg/day) (a KATP channel blocker) with nicorandil mostly showed similar improvement though not reaching to that of nicorandil group. However, co-adminstration of L-NAME (15 mg/kg/day) (an inhibitor of nitric oxide synthase) completely abolished the protective effects of nicorandil and produced more or less similar results to that of untreated bile duct ligated group. In conclusion, nicorandil is an effective therapy against the development of bile duct ligation-induced liver fibrosis in rats where nitric oxide plays a more prominent role in the protective effect of nicorandil than KATP channel opening. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. 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

  5. Detrimental effects of nicotine on thioacetamide-induced liver injury in mice.

    PubMed

    Zhou, Zixiong; Park, Surim; Kim, Jong Won; Zhao, Jing; Lee, Moo-Yeol; Choi, Kyung Chul; Lim, Chae Woong; Kim, Bumseok

    2017-09-01

    Nicotine exerts a number of physiological effects. The purpose of this study was to determine the effects of nicotine on thioacetamide (TAA)-induced liver fibrosis in mice. For in vivo experiments, hepatic fibrosis was induced by TAA (0.25 g/kg, i.p.) three times a week for 6 weeks. Mice of TAA treated groups were administered daily with distilled water and nicotine (50 or 100 μg/mL) via gastrogavage throughout the experimental period. For in vitro experiments, HepG2 (human liver cancer cell line) and LX-2 (human hepatic stellate cell line) were used to determine oxidative stress and fibrosis, respectively. Compared to control groups, TAA treated groups had significantly differences in serum alanine transferase and aspartate aminotransferase levels and nicotine accentuated liver injury. Moreover, nicotine increased the mRNA levels of TAA-induced transforming growth factor-β (TGF-β) and collagen type I alpha 1 in the liver. Nicotine also increased TAA-induced oxidative stress. Histological examination confirmed that nicotine aggravated the degree of fibrosis caused by TAA treatment. Additionally, nicotine enhanced hepatic stellate cell activation via promoting the expression of α-smooth muscle actin. Oral administration of nicotine significantly aggravated TAA-induced hepatic fibrosis in mice through enhancing TGF-β secretion and TAA-induced oxidative stress. The increase in TGF-β levels might be associated with the strengthening of oxidative processes, subsequently leading to increased hepatic stellate cell activation and extracellular matrix deposition. These results suggest that patients with liver disease should be advised to abandon smoking since nicotine may exacerbate hepatic fibrosis.

  6. Halloysite nanotubes-induced Al accumulation and oxidative damage in liver of mice after 30-day repeated oral administration.

    PubMed

    Wang, Xue; Gong, Jiachun; Gui, Zongxiang; Hu, Tingting; Xu, Xiaolong

    2018-06-01

    Halloysite (Al 2 Si 2 O 5 (OH) 4 ·nH 2 O) nanotubes (HNTs) are natural clay materials and widely applied in many fields due to their natural hollow tubular structures. Many in vitro studies indicate that HNTs exhibit a high level of biocompatibility, however the in vivo toxicity of HNTs remains unclear. The objective of this study was to assess the hepatic toxicity of the purified HNTs in mice via oral route. The purified HNTs were orally administered to mice at 5, 50, and 300 mg/kg body weight (BW) every day for 30 days. Oral administration of HNTs stimulated the growth of the mice at the low dose (5 mg/kg BW) with no liver toxicity, but inhibited the growth of the mice at the middle (50 mg/kg BW) and high (300 mg/kg BW) doses. In addition, oral administration of HNTs at the high dose caused Al accumulation in the liver but had no marked effect on the Si content in the organ. The Al accumulation caused significant oxidative stress in the liver, which induced hepatic dysfunction and histopathologic changes. These findings demonstrated that Al accumulation-induced oxidative stress played an important role in the oral HNTs-caused liver injury. © 2018 Wiley Periodicals, Inc.

  7. Dietary Effects of Oxidized Eicosapentaenoic Acid (EPA) and Intact EPA on Hepatic Steatosis Induced by a High-sucrose Diet and Liver-X-receptor α Agonist in Mice.

    PubMed

    Furumoto, Hidehiro; Nanthirudjanar, Tharnath; Hirata, Takashi; Sugawara, Tatsuya

    2016-01-01

    Numerous studies have shown that dietary omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA), improve lipid metabolism. The beneficial effects of PUFA-derived oxidation products have been increasingly reported. However, EPA is easily oxidized in food products and in the human body, generating various derivatives of oxidized EPA (oxEPA), such that these oxidation products may partially contribute to EPA's effect. We previously reported that oxEPA was more potent than intact EPA in reducing liver-X-receptor α (LXRα)-induced cellular triacylglycerol (TG) accumulation. However, the in vivo hypolipidemic effects of oxEPA remain unclear. In the present study, we evaluated the effect of oral administration of EPA and oxEPA on hepatic steatosis in mice induced by a high-sucrose diet and a synthetic LXRα agonist, TO-901317. Both EPA and oxEPA reduced TG accumulation in the liver and plasma biomarkers of liver injury. Furthermore, they suppressed the expression of lipogenic genes, but not β-oxidation genes, in a similar pattern as the biomarkers. Our results suggest that oxEPA and intact EPA suppress de novo lipogenesis to ameliorate hepatic steatosis.

  8. Tucum-Do-Cerrado (Bactris setosa Mart.) Consumption Modulates Iron Homeostasis and Prevents Iron-Induced Oxidative Stress in the Rat Liver

    PubMed Central

    Fustinoni-Reis, Adriana M.; Arruda, Sandra F.; Dourado, Lívia P. S.; da Cunha, Marcela S. B.; Siqueira, Egle M. A.

    2016-01-01

    This study investigated the effect of tucum-do-cerrado consumption in the oxidative status of iron-supplemented rats. Four groups of rats were treated: Control (AIN-93G), Tuc (AIN-93G added of tucum-do-cerrado), Fe (AIN-93G iron-enriched), or TucFe (AIN-93G with tucum-do-cerrado and iron-enriched) diet, for 30 days. Iron-enriched diet increased serum, liver, spleen, and intestine iron levels; transferrin saturation; liver lipid oxidation; mRNA levels of hepatic Hamp and Bmp6, and Nrf2 in the intestine. Tucum-do-cerrado consumption reduced spleen lipid and protein oxidation; mRNA levels of hepatic Hamp and Ftl, and increased serum antioxidant capacity and hepatic mRNA levels of Bmp6, Hmox1, Nqo1, and Nrf2. TucFe diet consumption abrogated the liver Hamp iron-induced up-regulation, prevented intestinal iron accumulation; hepatic lipid peroxidation; splenic protein damage, and the increase of catalase, glutathione reductase, and glutathione peroxidase activity in some tissues. These results suggest that tucum-do-cerrado protects tissues against oxidative damage, by reducing iron availability in liver and consequently inhibiting liver Hamp expression. PMID:26901220

  9. 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.

  10. 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.

  11. Anti-oxidative protection against iron overload-induced liver damage in mice by Cajanus cajan (L.) Millsp. leaf extract.

    PubMed

    Sarkar, Rhitajit; Hazra, Bibhabasu; Mandal, Nripendranath

    2013-02-01

    In view of the contribution of iron deposition in the oxidative pathologic process of liver disease, the potential of 70% methanolic extract of C. cajan leaf (CLME) towards antioxidative protection against iron-overload-induced liver damage in mice has been investigated. DPPH radical scavenging and protection of Fenton reaction induced DNA damage was conducted in vitro. Post oral administration of CLME to iron overloaded mice, the levels of antioxidant and serum enzymes, hepatic iron, serum ferritin, lipid peroxidation, and protein carbonyl and hydroxyproline contents were measured, in comparison to deferasirox treated mice. Oral treatment of the plant extract effectively lowered the elevated levels of liver iron, lipid peroxidation, protein carbonyl and hydroxyproline. There was notable increment in the dropped levels of hepatic antioxidants. The dosage of the plant extract not only made the levels of serum enzymes approach normal value, but also counteracted the overwhelmed serum ferritin level. The in vitro studies indicated potential antioxidant activity of CLME. The histopathological observations also substantiated the ameliorative function of the plant extract. Accordingly, it is suggested that Cajanus cajan leaf can be a useful herbal remedy to suppress oxidative damage caused by iron overload.

  12. 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.

  13. Nrf2 activation prevents cadmium-induced acute liver injury

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wu, Kai C.; Liu, Jie J.; Klaassen, Curtis D., E-mail: cklaasse@kumc.edu

    2012-08-15

    Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5 mg Cd/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-nullmore » mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H{sub 2}DCFDA (2′,7′-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd. -- Highlights: ► Cadmium caused extensive hepatic hemorrhage and necrosis in Nrf2-null mice. ► Keap1-KD and Keap1

  14. Genotoxicity and oxidative stress induced by the fungicide azoxystrobin in zebrafish (Danio rerio) livers.

    PubMed

    Han, Yingnan; Liu, Tong; Wang, Jinhua; Wang, Jun; Zhang, Cheng; Zhu, Lusheng

    2016-10-01

    Azoxystrobin is a frequently used fungicide in agriculture. Its toxicological effects on non-target organisms have aroused attention. In the present work, the toxic effects of azoxystrobin on zebrafish (Danio rerio) were investigated. Male and female zebrafish were separately exposed to a control solution and three azoxystrobin treatments (1, 10, and 100μg/L) and were sampled on days 7, 14, 21, and 28. Reactive oxygen species (ROS) were accumulated in excess in the zebrafish livers. Superoxide dismutase (SOD) activity was significantly inhibited in the male zebrafish. Moreover, a notable decrease was also observed after day 21 in the female zebrafish. Catalase (CAT) activity was induced by the azoxystrobin treatments with the exception of the 1μg/L treatment. A significant increase in glutathione-S-transferase (GST) activity was observed after day 21. Lipid peroxidation (LPO) was generated, and DNA damage was enhanced in a concentration-dependent manner. In conclusion, azoxystrobin induced oxidative stress and genotoxicity in zebrafish livers. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. 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.

  16. Nitric oxide protects murine embryonic liver cells (BNL CL.2) from cytotoxicity induced by glucose deprivation.

    PubMed

    Pae, H O; Kim, H G; Paik, Y S; Paik, S G; Kim, Y M; Oh, G S; Chung, H T

    2000-03-01

    We investigated the protective effects of nitric oxide on cell death of murine embryonic liver cells (BNL CL.2) after glucose deprivation. Endogenous nitric oxide production by BNL CL.2 cells was induced by 6 hr pretreatment with interferon-gamma and lipopolysaccharide. We used sodium nitroprusside and S-nitroso-L-glutathione as exogenous nitric oxide-generating compounds. All agents were used at doses that did not show direct cytotoxicity as measured by crystal violet staining assay. In the BNL CL.2 cells, the viability dropped very steeply after 24 hr incubation with glucose-free media. Endogenous nitric oxide produced by treatment of the cells with interferon-gamma and lipopolysaccharide protected the cells from glucose deprivation-induced cytotoxicity, but did not protect them in the presence of the nitric oxide synthesis inhibitor, N(G)-monomethyl-L-arginine. Exogenous nitric oxide protected the cells from glucose deprivation-induced cytotoxicity in a concentration-dependent manner. Cytoprotection by nitric oxide donors was abolished by the use of nitric oxide scavenger, 2-phenyl-4,4,5,5,-tetramethylimidazole, but not by the soluble guanosine cyclase inhibitor, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one. In addition, cytoprotective effects comparable to endogenous or exogenous nitric oxide were not observed when the cells were incubated with dibutyl guanosine 3',5'-cyclic monophosphate. Based upon these results, we suggest that nitric oxide may enhance the cell survival of BNL CL.2 cells after glucose deprivation via a guanosine 3',5'-cyclic monophosphate-independent pathway.

  17. Liver antioxidant stores protect the brain from electromagnetic radiation (900 and 1800 MHz)-induced oxidative stress in rats during pregnancy and the development of offspring.

    PubMed

    Çetin, Hasan; Nazıroğlu, Mustafa; Çelik, Ömer; Yüksel, Murat; Pastacı, Nural; Özkaya, Mehmet Okan

    2014-12-01

    The present study determined the effects of mobile phone (900 and 1800 MHz)-induced electromagnetic radiation (EMR) exposure on oxidative stress in the brain and liver as well as the element levels in growing rats from pregnancy to 6 weeks of age. Thirty-two rats and their offspring were equally divided into three different groups: the control, 900 MHz, and 1800 MHz groups. The 900 MHz and 1800 MHz groups were exposed to EMR for 60 min/d during pregnancy and neonatal development. At the 4th, 5th, and 6th weeks of the experiment, brain samples were obtained. Brain and liver glutathione peroxidase activities, as well as liver vitamin A and β-carotene concentrations decreased in the EMR groups, although brain iron, vitamin A, and β-carotene concentrations increased in the EMR groups. In the 6th week, selenium concentrations in the brain decreased in the EMR groups. There were no statistically significant differences in glutathione, vitamin E, chromium, copper, magnesium, manganese, and zinc concentrations between the three groups. EMR-induced oxidative stress in the brain and liver was reduced during the development of offspring. Mobile phone-induced EMR could be considered as a cause of oxidative brain and liver injury in growing rats.

  18. Ginseng essence, a medicinal and edible herbal formulation, ameliorates carbon tetrachloride-induced oxidative stress and liver injury in rats.

    PubMed

    Lu, Kuan-Hung; Weng, Ching-Yi; Chen, Wei-Cheng; Sheen, Lee-Yan

    2017-07-01

    Ginseng essence (GE) is a formulation comprising four medicinal and edible herbs including ginseng ( Panax ginseng ), American ginseng ( Panax quinquefolius ), lotus seed ( Nelumbo nucifera ), and lily bulb ( Lilium longiflorum ). This study was aimed at investigating the hepatoprotective effect of GE against carbon tetrachloride (CCl 4 )-induced liver injury in rats. We treated Wistar rats daily with low, medium, and high [0.625 g/kg body weight (bw), 1.25 g/kg bw, and 3.125 g/kg bw, respectively] doses of GE for 9 wk. After the 1 st wk of treatment, rats were administered 20% CCl 4 (1.5 mL/kg bw) two times a week to induce liver damage until the treatment ended. Serum biochemical analysis indicated that GE ameliorated the elevation of aspartate aminotransferase and alanine aminotransferase and albumin decline in CCl 4 -treated rats. Moreover, CCl 4 -induced accumulation of hepatic total cholesterol and triglyceride was inhibited. The hepatoprotective effects of GE involved enhancing the hepatic antioxidant defense system including glutathione, glutathione peroxidase, glutathione reductase, glutathione S -transferase, superoxide dismutase, and catalase. In addition, histological analysis using hematoxylin and eosin and Masson's trichrome staining showed that GE inhibited CCl 4 -induced hepatic inflammation and fibrosis. Furthermore, immunohistochemical staining of alpha-smooth muscle actin indicated that CCl 4 -triggered activation of hepatic stellate cells was reduced. These findings demonstrate that GE improves CCl 4 -induced liver inflammation and fibrosis by attenuating oxidative stress. Therefore, GE could be a promising hepatoprotective herbal formulation for future development of phytotherapy.

  19. 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.

  20. 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

  1. Fructose-induced inflammation, insulin resistance and oxidative stress: A liver pathological triad effectively disrupted by lipoic acid.

    PubMed

    Castro, María Cecilia; Massa, María Laura; Arbeláez, Luisa González; Schinella, Guillermo; Gagliardino, Juan J; Francini, Flavio

    2015-09-15

    Fructose administration induces hepatic oxidative stress, insulin resistance, inflammatory and metabolic changes. We tested their potential pathogenic relationship and whether these alterations can be prevented by R/S-α-lipoic acid. Wistar rats received during 21days a commercial diet or the same diet supplemented with 10% fructose in drinking water without/with R/S-α-lipoic acid injection. After this period, we measured a) serum glucose, triglyceride, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), insulin glucose ratio (IGR) and Matsuda indexes and b) liver oxidative stress, inflammatory markers and insulin signaling pathway components. Fructose fed rats had hyperinsulinemia, hypertriglyceridemia, higher HOMA-IR, IGR and lower Matsuda indices compared to control animals, together with increased oxidative stress markers, TNFα, IL1β and PAI-1 gene expression, and TNFα and COX-2 protein content. Whereas insulin receptor level was higher in fructose fed rats, their tyrosine-residue phosphorylation was lower. IRS1/IRS2 protein levels and IRS1 tyrosine-phosphorylation rate were lower in fructose fed rats. All changes were prevented by R/S-α-lipoic acid co-administration. Fructose-induced hepatic oxidative stress, insulin resistance and inflammation form a triad that constitutes a vicious pathogenic circle. This circle can be effectively disrupted by R/S-α-lipoic acid co-administration, thus suggesting mutual positive interaction among the triad components. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Protective Effects of Crocus Sativus L. Extract and Crocin against Chronic-Stress Induced Oxidative Damage of Brain, Liver and Kidneys in Rats

    PubMed Central

    Bandegi, Ahmad Reza; Rashidy-Pour, Ali; Vafaei, Abbas Ali; Ghadrdoost, Behshid

    2014-01-01

    Purpose: Chronic stress has been reported to induce oxidative damage of the brain. A few studies have shown that Crocus Sativus L., commonly known as saffron and its active constituent crocin may have a protective effect against oxidative stress. The present work was designed to study the protective effects of saffron extract and crocin on chronic – stress induced oxidative stress damage of the brain, liver and kidneys. Methods: Rats were injected with a daily dose of saffron extract (30 mg/kg, IP) or crocin (30 mg/kg, IP) during a period of 21 days following chronic restraint stress (6 h/day). In order to determine the changes of the oxidative stress parameters following chronic stress, the levels of the lipid peroxidation product, malondialdehyde (MDA), the total antioxidant reactivity (TAR), as well as antioxidant enzyme activities glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase (SOD) were measured in the brain, liver and kidneys tissues after the end of chronic stress. Results: In the stressed animals that receiving of saline, levels of MDA, and the activities of GPx, GR, and SOD were significantly higher (P<0.0001) and the TAR capacity were significantly lower than those of the non-stressed animals (P<0.0001). Both saffron extract and crocin were able to reverse these changes in the stressed animals as compared with the control groups (P<0.05). Conclusion: These observations indicate that saffron and its active constituent crocin can prevent chronic stress–induced oxidative stress damage of the brain, liver and kidneys and suggest that these substances may be useful against oxidative stress. PMID:25671180

  3. Anti-oxidant and anti-inflammatory effects of hydrogen-rich water alleviate ethanol-induced fatty liver in mice.

    PubMed

    Lin, Ching-Pin; Chuang, Wen-Chen; Lu, Fung-Jou; Chen, Chih-Yen

    2017-07-21

    To investigate the effects of hydrogen-rich water (HRW) treatment on prevention of ethanol (EtOH)-induced early fatty liver in mice. In vitro reduction of hydrogen peroxide by HRW was determined with a chemiluminescence system. Female mice were randomly divided into five groups: control, EtOH, EtOH + silymarin, EtOH + HRW and EtOH + silymarin + HRW. Each group was fed a Lieber-DeCarli liquid diet containing EtOH or isocaloric maltose dextrin (control diet). Silymarin was used as a positive control to compare HRW efficacy against chronic EtOH-induced hepatotoxicity. HRW was freshly prepared and given at a dosage of 1.2 mL/mouse trice daily. Blood and liver tissue were collected after chronic-binge liquid-diet feeding for 12 wk. The in vitro study showed that HRW directly scavenged hydrogen peroxide. The in vivo study showed that HRW increased expression of acyl ghrelin, which was correlated with food intake. HRW treatment significantly reduced EtOH-induced increases in serum alanine aminotransferase, aspartate aminotransferase, triglycerol and total cholesterol levels, hepatic lipid accumulation and inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6. HRW attenuated malondialdehyde level, restored glutathione depletion and increased superoxide dismutase, glutathione peroxidase and catalase activities in the liver. Moreover, HRW reduced TNF-α and IL-6 levels but increased IL-10 and IL-22 levels. HRW protects against chronic EtOH-induced liver injury, possibly by inducing acyl ghrelin to suppress the pro-inflammatory cytokines TNF-α and IL-6 and induce IL-10 and IL-22, thus activating antioxidant enzymes against oxidative stress.

  4. Anti-oxidant and anti-inflammatory effects of hydrogen-rich water alleviate ethanol-induced fatty liver in mice

    PubMed Central

    Lin, Ching-Pin; Chuang, Wen-Chen; Lu, Fung-Jou; Chen, Chih-Yen

    2017-01-01

    AIM To investigate the effects of hydrogen-rich water (HRW) treatment on prevention of ethanol (EtOH)-induced early fatty liver in mice. METHODS In vitro reduction of hydrogen peroxide by HRW was determined with a chemiluminescence system. Female mice were randomly divided into five groups: control, EtOH, EtOH + silymarin, EtOH + HRW and EtOH + silymarin + HRW. Each group was fed a Lieber-DeCarli liquid diet containing EtOH or isocaloric maltose dextrin (control diet). Silymarin was used as a positive control to compare HRW efficacy against chronic EtOH-induced hepatotoxicity. HRW was freshly prepared and given at a dosage of 1.2 mL/mouse trice daily. Blood and liver tissue were collected after chronic-binge liquid-diet feeding for 12 wk. RESULTS The in vitro study showed that HRW directly scavenged hydrogen peroxide. The in vivo study showed that HRW increased expression of acyl ghrelin, which was correlated with food intake. HRW treatment significantly reduced EtOH-induced increases in serum alanine aminotransferase, aspartate aminotransferase, triglycerol and total cholesterol levels, hepatic lipid accumulation and inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6. HRW attenuated malondialdehyde level, restored glutathione depletion and increased superoxide dismutase, glutathione peroxidase and catalase activities in the liver. Moreover, HRW reduced TNF-α and IL-6 levels but increased IL-10 and IL-22 levels. CONCLUSION HRW protects against chronic EtOH-induced liver injury, possibly by inducing acyl ghrelin to suppress the pro-inflammatory cytokines TNF-α and IL-6 and induce IL-10 and IL-22, thus activating antioxidant enzymes against oxidative stress. PMID:28785146

  5. 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

  6. Maresin 1, a Proresolving Lipid Mediator, Mitigates Carbon Tetrachloride-Induced Liver Injury in Mice

    PubMed Central

    Li, Ruidong; Wang, Yaxin; Zhao, Ende; Wu, Ke; Li, Wei; Shi, Liang; Wang, Di; Xie, Gengchen; Yin, Yuping; Deng, Meizhou; Zhang, Peng; Tao, Kaixiong

    2016-01-01

    Maresin 1 (MaR 1) was recently reported to have protective properties in several different animal models of acute inflammation by inhibiting inflammatory response. However, its function in acute liver injury is still unknown. To address this question, we induced liver injury in BALB/c mice with intraperitoneal injection of carbon tetrachloride with or without treatment of MaR 1. Our data showed that MaR 1 attenuated hepatic injury, oxidative stress, and lipid peroxidation induced by carbon tetrachloride, as evidenced by increased thiobarbituric acid reactive substances and reactive oxygen species levels were inhibited by treatment of MaR 1. Furthermore, MaR 1 increased activities of antioxidative mediators in carbon tetrachloride-treated mice liver. MaR 1 decreased indices of inflammatory mediators such as tumor necrosis factor-α, interleukin-6, interleukin-1β, monocyte chemotactic protein 1, myeloperoxidase, cyclooxygenase-2, and inducible nitric oxide synthase. Administration of MaR 1 inhibited activation of nuclear factor kappa B (NF-κb) and mitogen-activated protein kinases (MAPKs) in the liver of CCl4 treated mice. In conclusion, these results suggested the antioxidative, anti-inflammatory properties of MaR 1 in CCl4 induced liver injury. The possible mechanism is partly implicated in its abilities to inhibit ROS generation and activation of NF-κb and MAPK pathway. PMID:26881046

  7. Insight into the oxidative stress induced by lead and/or cadmium in blood, liver and kidneys.

    PubMed

    Matović, Vesna; Buha, Aleksandra; Ðukić-Ćosić, Danijela; Bulat, Zorica

    2015-04-01

    Besides being important occupational hazards, lead and cadmium are nowadays metals of great environmental concern. Both metals, without any physiological functions, can induce serious adverse health effects in various organs and tissues. Although Pb and Cd are non-redox metals, one of the important mechanisms underlying their toxicity is oxidative stress induction as a result of the generation of reactive species and/or depletion of the antioxidant defense system. Considering that the co-exposure to both metals is a much more realistic scenario, the effects of these metals on oxidative status when simultaneously present in the organism have become one of the contemporary issues in toxicology. This paper reviews short and long term studies conducted on Pb or Cd-induced oxidative stress in blood, liver and kidneys as the most prominent target organs of the toxicity of these metals and proposes the possible molecular mechanisms of the observed effects. The review is also focused on the results obtained for the effects of the combined treatment with Pb and Cd on oxidative status in target organs and on the mechanisms of their possible interactions. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Polydatin attenuates d-galactose-induced liver and brain damage through its anti-oxidative, anti-inflammatory and anti-apoptotic effects in mice.

    PubMed

    Xu, Lie-Qiang; Xie, You-Liang; Gui, Shu-Hua; Zhang, Xie; Mo, Zhi-Zhun; Sun, Chao-Yue; Li, Cai-Lan; Luo, Dan-Dan; Zhang, Zhen-Biao; Su, Zi-Ren; Xie, Jian-Hui

    2016-11-09

    Accumulating evidence has shown that chronic injection of d-galactose (d-gal) can mimic natural aging, with accompanying liver and brain injury. Oxidative stress and apoptosis play a vital role in the aging process. In this study, the antioxidant ability of polydatin (PD) was investigated using four established in vitro systems. An in vivo study was also conducted to investigate the possible protective effect of PD on d-gal-induced liver and brain damage. The results showed that PD had remarkable in vitro free radical scavenging activity on 2,2-diphenyl-1-picryl-hydrazyl (DPPH˙), 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) (ABTS + ˙) radical ions, and hydroxyl and superoxide anions. Results in vivo indicated that, in a group treated with d-gal plus PD, PD remarkably decreased the depression of body weight and organ indexes, reduced the levels of the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and alleviated alterations in liver and brain histopathology. PD also significantly decreased the level of MDA and elevated SOD, GSH-Px, CAT activity and T-AOC levels in the liver and brain. In addition, the levels of inflammatory mediators, such as TNF-α, IL-1β and IL-6 in serum were markedly reduced after PD treatment. Western blotting results revealed that PD treatment noticeably attenuated the d-gal-induced elevation of Bcl-2/Bax ratio and caspase-3 protein expression in liver and brain. Overall, our findings indicate that PD treatment could effectively attenuate d-gal-induced liver and brain damage, and the mechanism might be associated with decreasing the oxidative stress, inflammation and apoptosis caused by d-gal. PD holds good potential for further development into a promising pharmaceutical candidate for the treatment of age-associated diseases.

  9. Protective effects of azelaic acid against high-fat diet-induced oxidative stress in liver, kidney and heart of C57BL/6J mice.

    PubMed

    Muthulakshmi, Shanmugam; Saravanan, Ramalingam

    2013-05-01

    Excess fat intake induces hyperinsulinaemia, increases nutrient uptake and lipid accumulation, amplifies ROS generation, establishes oxidative stress and morphological changes leading to tissue injury in the liver, kidney and heart of high-fat diet (HFD)-fed mice. The effect of azelaic acid (AzA), a C9 α,ω-dicarboxylic acid, against HFD-induced oxidative stress was investigated by assaying the activities and levels of antioxidants and oxidative stress markers in the liver, kidney and heart of C57BL/6J mice. Mice were segregated into two groups, one fed standard diet (NC) and the other fed high-fat diet (HFD) for 15 weeks. HFD-fed mice were subjected to intragastric administration of AzA (80 mg/kg BW)/RSG (10 mg/kg BW) during 11-15 weeks. Glucose, insulin, triglycerides, hepatic and nephritic markers were analysed in the plasma and the activity of enzymatic, non-enzymatic antioxidants and lipid peroxidation markers were examined in the plasma/erythrocytes, liver, kidney and heart of normal and experimental mice. We inferred significant decrease in enzymatic and non-enzymatic antioxidants along with significant increase in glucose, insulin, hepatic and nephritic markers, triglycerides and lipid peroxidation markers in HFD-fed mice. Administration of AzA could positively restore the levels of plasma glucose, insulin, triglycerides, hepatic and nephritic markers to near normal. AzA increased the levels of enzymatic and nonenzymatic antioxidants with significant reduction in the levels of lipid peroxidation markers. Histopathological examination of liver, kidney and heart substantiated these results. Hence, we put forward that AzA could counteract the potential injurious effects of HFD-induced oxidative stress in C57BL/6J mice.

  10. Beta-carotene and lutein protect HepG2 human liver cells against oxidant-induced damage.

    PubMed

    Martin, K R; Failla, M L; Smith, J C

    1996-09-01

    Numerous epidemiological studies support a strong inverse relationship between consumption of carotenoid-rich fruits and vegetables and the incidence of some degenerative diseases. One proposed mechanism of protection by carotenoids centers on their putative antioxidant activity, although direct evidence in support of this contention is limited at the cellular level. The antioxidant potential of beta-carotene (BC) and lutein (LUT), carotenoids with or without provitamin A activity, respectively, was evaluated using the human liver cell line HepG2. Pilot studies showed that a 90-min exposure of confluent cultures to 500 mumol/L tert-butylhydroperoxide (TBHP) at 37 degrees C significantly (P < 0.05) increased lipid peroxidation and cellular leakage of lactate dehydrogenase (LDH), and decreased the uptake of 3H-alpha-aminoisobutyric acid and 3H-2-deoxyglucose. Protein synthesis, mitochondrial activity and glucose oxidation were not affected by TBHP treatment, suggesting that the plasma membrane was the primary site of TBHP-induced damage. Overnight incubation of cultures with > or = 1 mumol/L dl-alpha-tocopherol protected cells against oxidant-induced changes. In parallel studies, overnight incubation of HepG2 in medium containing micelles with either BC or LUT (final concentrations of 1.1 and 10.9 mumol/L, respectively), the cell content of the carotenoids increased from < 0.04 to 0.32 and 3.39 nmol/mg protein, respectively. Carotenoid-loaded cells were partially or completely protected against oxidant-induced changes in lipid peroxidation, LDH release and amino acid and deoxyglucose transport. These data demonstrate that BC and LUT or their metabolites protect HepG2 cells against oxidant-induced damage and that the protective effect is independent of provitamin A activity.

  11. Effects of Antioxidant N-acetylcysteine Against Paraquat-Induced Oxidative Stress in Vital Tissues of Mice

    PubMed Central

    Ortiz, Maricelly Santiago; Forti, Kevin Muñoz; Suárez Martinez, Edu B.; Muñoz, Lenin Godoy; Husain, Kazim

    2016-01-01

    Paraquat (PQ) is a commonly used herbicide that induces oxidative stress via reactive oxygen species (ROS) generation. This study aimed to investigate the effects of the antioxidant N-acetylcysteine (NAC) against PQ-induced oxidative stress in mice. Male Balb/C mice (24) were randomly divided into 4 groups and treated for 3 weeks: 1) control (saline), 2) NAC (0.5% in diet), 3) PQ (20 mg/kg, IP) and 4) combination (PQ + NAC). Afterwards mice were sacrificed and oxidative stress markers were analyzed. Our data showed no significant change in serum antioxidant capacity. PQ enhanced lipid peroxidation (MDA) levels in liver tissue compared to control whereas NAC decreased MDA levels (p<0.05). NAC significantly increased MDA in brain tissue (p<0.05). PQ significantly depleted glutathione (GSH) levels in liver (p=0.001) and brain tissue (p<0.05) but non-significant GSH depletion in lung tissue. NAC counteracted PQ, showing a moderate increase GSH levels in liver and brain tissues. PQ significantly increased 8-oxodeoxyguanosine (8-OH-dG) levels (p<0.05) in liver tissue compared to control without a significant change in brain tissue. NAC treatment ameliorated PQ-induced oxidative DNA damage in the liver tissue. PQ significantly decreased the relative mtDNA amplification and increased the frequency of lesions in liver and brain tissue (p<0.0001), while NAC restored the DNA polymerase activity in liver tissue but not in brain tissue. In conclusion, PQ induced lipid peroxidation, oxidative nuclear DNA and mtDNA damage in liver tissues and depleted liver and brain GSH levels. NAC supplementation ameliorated the PQ-induced oxidative stress response in liver tissue of mice. PMID:27398384

  12. 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.

  13. Oxidative Inactivation of Liver Mitochondria in High Fructose Diet-Induced Metabolic Syndrome in Rats: Effect of Glycyrrhizin Treatment.

    PubMed

    Sil, Rajarshi; Chakraborti, Abhay Sankar

    2016-09-01

    Metabolic syndrome is a serious health problem in the present world. Glycyrrhizin, a triterpenoid saponin of licorice (Glycyrrhiza glabra) root, has been reported to ameliorate the primary complications and hepatocellular damage in rats with the syndrome. In this study, we have explored metabolic syndrome-induced changes in liver mitochondrial function and effect of glycyrrhizin against the changes. Metabolic syndrome was induced in rats by high fructose (60%) diet for 6 weeks. The rats were then treated with glycyrrhizin (50 mg/kg body weight) by single intra-peritoneal injection. After 2 weeks of the treatment, the rats were sacrificed to collect liver tissue. Elevated mitochondrial ROS, lipid peroxidation and protein carbonyl, and decreased reduced glutathione content indicated oxidative stress in metabolic syndrome. Loss of mitochondrial inner membrane cardiolipin was observed. Mitochondrial complex I activity did not change but complex IV activity decreased significantly. Mitochondrial MTT reduction ability, membrane potential, phosphate utilisation and oxygen consumption decreased in metabolic syndrome. Reduced mitochondrial aconitase activity and increased aconitase carbonyl content suggested oxidative damage of the enzyme. Elevated Fe(2+) ion level in mitochondria might be associated with increased ROS generation in metabolic syndrome. Glycyrrhizin effectively attenuated mitochondrial oxidative stress and aconitase degradation, and improved electron transport chain activity. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  14. Arsenic induces apoptosis in mouse liver is mitochondria dependent and is abrogated by N-acetylcysteine

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Santra, Amal; Chowdhury, Abhijit; Ghatak, Subhadip

    2007-04-15

    Arsenicosis, caused by arsenic contamination of drinking water supplies, is a major public health problem in India and Bangladesh. Chronic liver disease, often with portal hypertension occurs in chronic arsenicosis, contributes to the morbidity and mortality. The early cellular events that initiate liver cell injury due to arsenicosis have not been studied. Our aim was to identify the possible mechanisms related to arsenic-induced liver injury in mice. Liver injury was induced in mice by arsenic treatment. The liver was used for mitochondrial oxidative stress, mitochondrial permeability transition (MPT). Evidence of apoptosis was sought by TUNEL test, caspase assay and histology.more » Pretreatment with N-acetyl-L-cysteine (NAC) was done to modulate hepatic GSH level. Arsenic treatment in mice caused liver injury associated with increased oxidative stress in liver mitochondria and alteration of MPT. Altered MPT facilitated cytochrome c release in the cytosol, activation of caspase 9 and caspase 3 activities and apoptotic cell death. Pretreatment of NAC to arsenic-treated mice abrogated all these alteration suggesting a glutathione (GSH)-dependent mechanism. Oxidative stress in mitochondria and inappropriate MPT are important in the pathogenesis of arsenic induced apoptotic liver cell injury. The phenomenon is GSH dependent and supplementation of NAC might have beneficial effects.« less

  15. Protective effect of grape seed and skin extract against high-fat diet-induced liver steatosis and zinc depletion in rat.

    PubMed

    Charradi, Kamel; Elkahoui, Salem; Karkouch, Ines; Limam, Ferid; Ben Hassine, Fethy; El May, Michèle Veronique; Aouani, Ezzedine

    2014-08-01

    Obesity is a tremendous public health problem, characterized by ectopic deposition of fat into non-adipose tissues as liver generating an oxidative stress that could lead to steato-hepatitis. Grape seed and skin extract (GSSE) is a complex mixture of polyphenolics exhibiting robust antioxidative properties. We hypothesize that GSSE could protect the liver from fat-induced lipotoxicity and have a beneficial effect on liver function. Hepatoprotective effect of GSSE was measured by using an experimental model of fat-induced rat liver steatosis. Male rats were fed a standard diet or a high-fat diet (HFD) during 6 weeks and treated or not with 500 mg/kg bw GSSE. Lipid deposition into the liver was assessed by triglyceride, cholesterol and phospholipid measurements. Fat-induced lipoperoxidation, carbonylation, depletion of glutathione and of antioxidant enzyme activities were used as oxidative stress markers with a special emphasis on transition metal distribution. HFD induced liver hypertrophy and inflammation as assessed by high liver transaminases. HFD also induced an oxidative stress characterized by increased lipid and protein oxidation, a drop in glutathione and antioxidant enzyme activities as glutathione peroxidase and superoxide dismutase and a drastic depletion in liver zinc. Importantly, GSSE prevented all the deleterious effects of HFD treatment. Data suggest that GSSE could be used as a safe preventive agent against fat-induced liver lipotoxicity which could also have potential applications in other non-alcoholic liver diseases.

  16. Cav-1 deficiency promotes liver fibrosis in carbon tetrachloride (CCl4)-induced mice by regulation of oxidative stress and inflammation responses.

    PubMed

    Ji, De-Gang; Zhang, Yan; Yao, Song-Mei; Zhai, Xu-Jie; Zhang, Li-Rong; Zhang, Yao-Zhong; Li, Hui

    2018-06-01

    Caveolin-1 (Cav-1), as a membrane protein involved in the formation of caveolae, binds steroid receptors and endothelial nitric oxide synthase, limiting its translocation and activation. In the present study, we investigated the role of Cav-1 in the progression of hepatic fibrosis induced by carbon tetrachloride (CCl 4 ) in murine animals. Therefore, the wild type (WT) and Cav-1-knockout (Cav-1 -/- ) mice were used in our study and subjected to CCl 4 . The results indicated that CCl 4 induced the decrease of Cav-1 expression in liver tissue samples. And Cav-1 -/- intensified CCl 4 -triggered hepatic injury, evidenced by the stronger hepatic histological alterations, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. CCl 4 led to oxidative stress, supported by the reduced superoxide dismutase (SOD) activity and glutathione (GSH) levels, as well as enhanced malondialdehyde (MDA) and O 2 - levels in liver samples. And the process was intensified by Cav-1 -/- . Additionally, CCl 4 -caused hepatic inflammation was aggregated by Cav-1 -/- via further increasing the secretion of pro-inflammatory cytokines. Moreover, CCl 4 -caused fibrosis was strengthened by Cav-1 -/- , which was evidenced by the up-regulation of α-smooth muscle actin (α-SMA), collagen alpha 1 type 1 (Col1A1), lysyl oxidase (Lox) and transforming growth factor-β1 (TGF-β1) in liver tissues. Similar results were observed in TGF-β1-stimulated hepatic stellate cells (HSCs) and LX-2 cells without Cav-1 expressions that in vitro, suppressing Cav-1 further accelerated TGF-β1-induced oxidative stress, inflammation and fibrosis development. In conclusion, our results indicated that Cav-1 played an important role in CCl 4 -induced hepatic injury, which may be used as potential therapeutic target for hepatic fibrosis treatment. Copyright © 2018. Published by Elsevier Masson SAS.

  17. Withaferin-A Reduces Acetaminophen-Induced Liver Injury in Mice.

    PubMed

    Jadeja, Ravirajsinh N; Urrunaga, Nathalie H; Dash, Suchismita; Khurana, Sandeep; Saxena, Neeraj Kumar

    2015-09-01

    Withaferin-A (WA) has anti-oxidant activities however, its therapeutic potential in acetaminophen (APAP) hepatotoxicity is unknown. We performed a proof-of-concept study to assess the therapeutic potential of WA in a mouse model that mimics APAP-induced liver injury (AILI) in humans. Overnight fasted C57BL/6NTac (5-6 wk. old) male mice received 200 mg/kg APAP intraperitoneally (i.p.). After 1 h mice were treated with 40 mg/kg WA or vehicle i.p., and euthanized 4 and 16 h later; their livers were harvested and serum collected for analysis. At 4 h, compared to vehicle-treated mice, WA-treated mice had reduced serum ALT levels, hepatocyte necrosis and intrahepatic hemorrhage. All APAP-treated mice had reduced hepatic glutathione (GSH) levels however, reduction in GSH was lower in WA-treated when compared to vehicle-treated mice. Compared to vehicle-treated mice, livers from WA-treated mice had reduced APAP-induced JNK activation, mitochondrial Bax translocation, and nitrotyrosine generation. Compared to vehicle-treated mice, WA-treated mice had increased hepatic up-regulation of Nrf2, Gclc and Nqo1, and down-regulation of Il-6 and Il-1β. The hepatoprotective effect of WA persisted at 16 h. Compared to vehicle-treated mice, WA-treated mice had reduced hepatocyte necrosis and hepatic expression of Il-6, Tnf-α and Il-1β, increased hepatic Gclc and Nqo1 expression and GSH levels, and reduced lipid peroxidation. Finally, in AML12 hepatocytes, WA reduced H₂O₂-induced oxidative stress and necrosis by preventing GSH depletion. Collectively, these data show mechanisms whereby WA reduces necrotic hepatocyte injury, and demonstrate that WA has therapeutic potential in AILI. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Hydrogen sulfide attenuates carbon tetrachloride-induced hepatotoxicity, liver cirrhosis and portal hypertension in rats.

    PubMed

    Tan, Gang; Pan, Shangha; Li, Jie; Dong, Xuesong; Kang, Kai; Zhao, Mingyan; Jiang, Xian; Kanwar, Jagat R; Qiao, Haiquan; Jiang, Hongchi; Sun, Xueying

    2011-01-01

    Hydrogen sulfide (H(2)S) displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. Impaired production of H(2)S contributes to the increased intrahepatic resistance in cirrhotic livers. The study aimed to investigate the roles of H(2)S in carbon tetrachloride (CCl(4))-induced hepatotoxicity, cirrhosis and portal hypertension. Sodium hydrosulfide (NaHS), a donor of H(2)S, and DL-propargylglycine (PAG), an irreversible inhibitor of cystathionine γ-lyase (CSE), were applied to the rats to investigate the effects of H(2)S on CCl(4)-induced acute hepatotoxicity, cirrhosis and portal hypertension by measuring serum levels of H(2)S, hepatic H(2)S producing activity and CSE expression, liver function, activity of cytochrome P450 (CYP) 2E1, oxidative and inflammatory parameters, liver fibrosis and portal pressure. CCl(4) significantly reduced serum levels of H(2)S, hepatic H(2)S production and CSE expression. NaHS attenuated CCl(4)-induced acute hepatotoxicity by supplementing exogenous H(2)S, which displayed anti-oxidative activities and inhibited the CYP2E1 activity. NaHS protected liver function, attenuated liver fibrosis, inhibited inflammation, and reduced the portal pressure, evidenced by the alterations of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), albumin, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and soluble intercellular adhesion molecule (ICAM)-1, liver histology, hepatic hydroxyproline content and α-smooth muscle actin (SMA) expression. PAG showed opposing effects to NaHS on most of the above parameters. Exogenous H(2)S attenuates CCl(4)-induced hepatotoxicity, liver cirrhosis and portal hypertension by its multiple functions including anti-oxidation, anti-inflammation, cytoprotection and anti-fibrosis, indicating that targeting H(2)S may present a promising approach, particularly for its prophylactic effects, against liver cirrhosis and portal hypertension.

  19. Oxaloacetate Ameliorates Chemical Liver Injury via Oxidative Stress Reduction and Enhancement of Bioenergetic Fluxes.

    PubMed

    Kuang, Ye; Han, Xiaoyun; Xu, Mu; Wang, Yue; Zhao, Yuxiang; Yang, Qing

    2018-05-31

    Chemical injury is partly due to free radical lipid peroxidation, which can induce oxidative stress and produce a large number of reactive oxygen species (ROS). Oxaloacetic acid is an important intermediary in the tricarboxylic acid cycle (TCA cycle) and participates in metabolism and energy production. In our study, we found that oxaloacetate (OA) effectively alleviated liver injury which was induced by hydrogen peroxide (H₂O₂) in vitro and carbon tetrachloride (CCl₄) in vivo. OA scavenged ROS, prevented oxidative damage and maintained the normal structure of mitochondria. We further confirmed that OA increased adenosine triphosphate (ATP) by promoting the TCA production cycle and oxidative phosphorylation (OXPHOS). Finally, OA inhibited the mitogen-activated protein kinase (MAPK) and apoptotic pathways by suppressing tumor necrosis factor-α (TNF-α). Our findings reveal a mechanism for OA ameliorating chemical liver injury and suggest a possible implementation for preventing the chemical liver injury.

  20. Thymidine kinase 2 deficiency-induced mtDNA depletion in mouse liver leads to defect β-oxidation.

    PubMed

    Zhou, Xiaoshan; Kannisto, Kristina; Curbo, Sophie; von Döbeln, Ulrika; Hultenby, Kjell; Isetun, Sindra; Gåfvels, Mats; Karlsson, Anna

    2013-01-01

    Thymidine kinase 2 (TK2) deficiency in humans causes mitochondrial DNA (mtDNA) depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2(-/-)) that progressively loses its mtDNA. The TK2(-/-) mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2(-/-) mouse model to clarify the pathological role of progressive mtDNA depletion in liver for the severe outcome of TK2 deficiency. We observed that a gradual depletion of mtDNA in the liver of the TK2(-/-) mice was accompanied by increasingly hypertrophic mitochondria and accumulation of fat vesicles in the liver cells. The levels of cholesterol and nonesterified fatty acids were elevated and there was accumulation of long chain acylcarnitines in plasma of the TK2(-/-) mice. In mice with hepatic mtDNA levels below 20%, the blood sugar and the ketone levels dropped. These mice also exhibited reduced mitochondrial β-oxidation due to decreased transport of long chain acylcarnitines into the mitochondria. The gradual loss of mtDNA in the liver of the TK2(-/-) mice causes impaired mitochondrial function that leads to defect β-oxidation and, as a result, insufficient production of ketone bodies and glucose. This study provides insight into the mechanism of encephalomyopathy caused by TK2 deficiency-induced mtDNA depletion that may be used to explore novel therapeutic strategies.

  1. Thymidine Kinase 2 Deficiency-Induced mtDNA Depletion in Mouse Liver Leads to Defect β-Oxidation

    PubMed Central

    von Döbeln, Ulrika; Hultenby, Kjell; Isetun, Sindra; Gåfvels, Mats; Karlsson, Anna

    2013-01-01

    Thymidine kinase 2 (TK2) deficiency in humans causes mitochondrial DNA (mtDNA) depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2−/−) that progressively loses its mtDNA. The TK2−/− mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2−/− mouse model to clarify the pathological role of progressive mtDNA depletion in liver for the severe outcome of TK2 deficiency. We observed that a gradual depletion of mtDNA in the liver of the TK2−/− mice was accompanied by increasingly hypertrophic mitochondria and accumulation of fat vesicles in the liver cells. The levels of cholesterol and nonesterified fatty acids were elevated and there was accumulation of long chain acylcarnitines in plasma of the TK2−/− mice. In mice with hepatic mtDNA levels below 20%, the blood sugar and the ketone levels dropped. These mice also exhibited reduced mitochondrial β-oxidation due to decreased transport of long chain acylcarnitines into the mitochondria. The gradual loss of mtDNA in the liver of the TK2−/− mice causes impaired mitochondrial function that leads to defect β-oxidation and, as a result, insufficient production of ketone bodies and glucose. This study provides insight into the mechanism of encephalomyopathy caused by TK2 deficiency-induced mtDNA depletion that may be used to explore novel therapeutic strategies. PMID:23505564

  2. Protective action of the immunomodulator ginsan against carbon tetrachloride-induced liver injury via control of oxidative stress and the inflammatory response

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shim, Ji-Young; Kim, Mi-Hyoung; Kim, Hyung-Doo

    2010-02-01

    The aim of the present study was to evaluate immunomodulator ginsan, a polysaccharide extracted from Panax ginseng, on carbon tetrachloride (CCl{sub 4})-induced liver injury. BALB/c mice were injected i.p. with ginsan 24 h prior to CCl{sub 4} administration. Serum liver enzyme levels, histology, expression of antioxidant enzymes, and several cytokines/chemokines were subsequently evaluated. Ginsan treatment markedly suppressed the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and hepatic histological necrosis increased by CCl{sub 4} treatment. Ginsan inhibited CCl{sub 4} induced lipid peroxidation through the cytochrome P450 2E1 (CYP2E1) downregulation. The hepatoprotective effect of ginsan was attributed to induction ofmore » anti-oxidant protein contents, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) as well as restoration of the hepatic glutathione (GSH) concentration. The marked increase of proinflammatory cytokines (IL-1beta, IFN-gamma) and chemokines (MCP-1, MIP-2beta, KC) in CCl{sub 4} treated mice was additionally attenuated by ginsan, thereby preventing leukocyte infiltration and local inflammation. Our results suggest that ginsan effectively prevent liver injury, mainly through downregulation of oxidative stress and inflammatory response.« less

  3. Cromoglycate, not ketotifen, ameliorated the injured effect of warm ischemia/reperfusion in rat liver: role of mast cell degranulation, oxidative stress, proinflammatory cytokine, and inducible nitric oxide synthase

    PubMed Central

    El-Shitany, Nagla A; El-Desoky, Karema

    2015-01-01

    Hepatic ischemia/reperfusion (ISCH/REP) is a major clinical problem that is considered to be the most common cause of postoperative liver failure. Recently, mast cells have been proposed to play an important role in the pathophysiology of ISCH/REP in many organs. In contrast, the role played by mast cells during ISCH/REP-induced liver damage has remained an issue of debate. This study aimed to investigate the protective role of mast cells in order to search for an effective therapeutic agent that could protect against fatal ISCH/REP-induced liver damage. A model of warm ISCH/REP was induced in the liver of rats. Four groups of rats were used in this study: Group I: SHAM (normal saline, intravenously [iv]); Group II: ISCH/REP; Group III: sodium cromoglycate + ISCH/REP (CROM + ISCH/REP), and Group IV: ketotifen (KET) + ISCH/REP (KET + ISCH/REP). Liver damage was assessed both histopathologically and biochemically. Mast cell degranulation was assessed histochemically. Lipid peroxidation (malondialdehyde [MDA]) as well as the levels of glutathione (GSH), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), the formation of nitric oxide (NO), and the expression of inducible NO synthase (iNOS) were determined. The results of this study revealed increased mast cell degranulation in the liver during the acute phase of ISCH/REP. Moreover, CROM, but not KET, decreased the activity of alanine aminotransferase, aspartate aminotransferase, and lactic dehydrogenase and maintained normal liver tissue histology. Both CROM and KET protected against mast cell degranulation in the liver. In addition, both CROM and KET decreased IL-6 and TNF-α. However, CROM, but not KET, decreased MDA formation and increased GSH. Furthermore, KET, but not CROM, increased both NO formation and iNOS expression. In conclusion, this study clearly demonstrated mast cell degranulation in warm ISCH/REP in the liver of rats. More importantly, CROM, but not KET, ameliorated the effect of ISCH/REP-induced

  4. Alpha-lipoic acid treatment of acetaminophen-induced rat liver damage.

    PubMed

    Mahmoud, Y I; Mahmoud, A A; Nassar, G

    2015-01-01

    Acetaminophen (paracetamol) is a well-tolerated analgesic and antipyretic drug when used at therapeutic doses. Overdoses, however, cause oxidative stress, which leads to acute liver failure. Alpha lipoic acid is an antioxidant that has proven effective for ameliorating many pathological conditions caused by oxidative stress. We evaluated the effect of alpha lipoic acid on the histological and histochemical alterations of liver caused by an acute overdose of acetaminophen in rats. Livers of acetaminophen-intoxicated rats were congested and showed centrilobular necrosis, vacuolar degeneration and inflammatory cell infiltration. Necrotic hepatocytes lost most of their carbohydrates, lipids and structural proteins. Liver sections from rats pre-treated with lipoic acid showed fewer pathological changes; the hepatocytes appeared moderately vacuolated with moderate staining of carbohydrates and proteins. Nevertheless, alpha lipoic acid at the dose we used did not protect the liver fully from acetaminophen-induced acute toxicity.

  5. Hepatocellular toxicity of oxalicumone A via oxidative stress injury and mitochondrial dysfunction in healthy human liver cells.

    PubMed

    Shi, Si; Yao, Limei; Guo, Kunbin; Wang, Xiangyu; Wang, Qi; Li, Weirong

    2018-01-01

    The marine‑derived oxalicumone A (POA) has been demonstrated as a potent anti‑tumor bioactive agent for a variety of human carcinoma, but to the best of our knowledge, remains to be evaluated in healthy liver cells. As many drugs distribute preferentially in the liver, the present study aimed to investigate the effects of POA on apoptosis, oxidative stress and mitochondrial function in L‑02 healthy liver cells. A Cell‑Counting kit‑8 assay demonstrated that POA inhibits the proliferation of L‑02 cells in a dose‑ and time‑dependent manner. Furthermore, POA induced apoptosis by increasing the percentage of cells in early apoptosis and the sub‑G1 cell cycle, along with causing S‑phase arrest in L‑02 cells. Additionally, POA activated caspase 3, increased the protein expression levels of Fas ligand and B‑cell lymphoma X‑associated protein, and decreased the expression of the anti‑apoptotic protein B‑cell lymphoma 2. POA additionally reduced the content of GSH and the activity of superoxide dismutase, elevated malondialdehyde and nitric oxide levels, increased reactive oxygen species production and the levels of alanine aminotransferase and aspartate aminotransferase, which suggested that POA induced lipid peroxidation injury in L‑02 cells and that oxidative stress serves an important role. Furthermore, POA caused alternations of mitochondrial function, including an abrupt depletion of adenosine triphosphate synthesis, mitochondrial permeability transition pore opening and depletion of mitochondrial membrane potential in L‑02 cells. These data suggested that POA exerts cytotoxicity, at least in part, by inducing oxidative stress, mitochondrial dysfunction, and eventually apoptosis. Changes in mitochondrial function and oxidative stress by POA may therefore be critical in POA‑induced toxicity in L‑02 cells.

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Qi, Xiaozhe; Yu, Tao; Zhu, Liye

    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 inmore » 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.« less

  7. Low-ω3 Fatty Acid and Soy Protein Attenuate Alcohol-Induced Fatty Liver and Injury by Regulating the Opposing Lipid Oxidation and Lipogenic Signaling Pathways

    PubMed Central

    Reyes-Gordillo, Karina; Shah, Ruchi; Varatharajalu, Ravi; Garige, Mamatha; Leckey, Leslie C.

    2016-01-01

    Chronic ethanol-induced downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1β) affect hepatic lipid oxidation and lipogenesis, respectively, leading to fatty liver injury. Low-ω3 fatty acid (Low-ω3FA) that primarily regulates PGC1α and soy protein (SP) that seems to have its major regulatory effect on PGC1β were evaluated for their protective effects against ethanol-induced hepatosteatosis in rats fed with Lieber-deCarli control or ethanol liquid diets with high or low ω3FA fish oil and soy protein. Low-ω3FA and SP opposed the actions of chronic ethanol by reducing serum and liver lipids with concomitant decreased fatty liver. They also prevented the downregulation of hepatic Sirtuin 1 (SIRT1) and PGC1α and their target fatty acid oxidation pathway genes and attenuated the upregulation of hepatic PGC1β and sterol regulatory element-binding protein 1c (SREBP1c) and their target lipogenic pathway genes via the phosphorylation of 5′ adenosine monophosphate-activated protein kinase (AMPK). Thus, these two novel modulators attenuate ethanol-induced hepatosteatosis and consequent liver injury potentially by regulating the two opposing lipid oxidation and lipogenic pathways. PMID:28074114

  8. Apocynin alleviated hepatic oxidative burden and reduced liver injury in hypercholesterolaemia.

    PubMed

    Lu, Long-Sheng; Wu, Chau-Chung; Hung, Li-Man; Chiang, Meng-Tsan; Lin, Ching-Ting; Lin, Chii-Wann; Su, Ming-Jai

    2007-05-01

    This study addressed the effects of apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, on hepatic oxidative burden and liver injury during diet-induced hypercholesterolaemia. Male Wistar rats were fed a 4% cholesterol-enriched diet for 3 weeks. Apocynin was administered in drinking water concurrently. The high-cholesterol diet (HC) significantly increased the serum level of cholesterol and hepatic cholesterol ester deposition, and these parameters were similar between the HC and high-cholesterol diet plus apocynin (HCA) groups. The HC group showed abnormal liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (Alk-P)] as well as increased Evans blue extravasation and macrophages infiltration. Apocynin treatment could suppress these inflammation-related parameters. In vivo measurement of NADPH-derived cellular autofluorescence suggested that HC increased oxidative stress in hepatocytes. Biochemical analysis of redox status including thiobarbituric acid reactive substances, reduced glutathione, and oxidized glutathione also confirmed the phenomenon. Apocynin treatment was able to alleviate these indices of oxidative burden owing to HC. Furthermore, apocynin-abrogated HC induced gp91(phox) expression, suggesting the involvement of NADPH oxidase in the pathogenesis. We concluded that apocynin suppressed NADPH oxidase activation and subsequent liver injuries owing to high-cholesterol intake in rats. The impacts of cholesterol metabolism disorders on pathogenesis and progression of steatohepatitis warrant further clinical investigation.

  9. A hot water extract of turmeric (Curcuma longa) suppresses acute ethanol-induced liver injury in mice by inhibiting hepatic oxidative stress and inflammatory cytokine production.

    PubMed

    Uchio, Ryusei; Higashi, Yohei; Kohama, Yusuke; Kawasaki, Kengo; Hirao, Takashi; Muroyama, Koutarou; Murosaki, Shinji

    2017-01-01

    Turmeric ( Curcuma longa ) is a widely used spice that has various biological effects, and aqueous extracts of turmeric exhibit potent antioxidant activity and anti-inflammatory activity. Bisacurone, a component of turmeric extract, is known to have similar effects. Oxidative stress and inflammatory cytokines play an important role in ethanol-induced liver injury. This study was performed to evaluate the influence of a hot water extract of C. longa (WEC) or bisacurone on acute ethanol-induced liver injury. C57BL/6 mice were orally administered WEC (20 mg/kg body weight; BW) or bisacurone (60 µg/kg BW) at 30 min before a single dose of ethanol was given by oral administration (3·0 g/kg BW). Plasma levels of aspartate aminotransferase and alanine aminotransferase were markedly increased in ethanol-treated mice, while the increase of these enzymes was significantly suppressed by prior administration of WEC. The increase of alanine aminotransferase was also significantly suppressed by pretreatment with bisacurone. Compared with control mice, animals given WEC had higher hepatic tissue levels of superoxide dismutase and glutathione, as well as lower hepatic tissue levels of thiobarbituric acid-reactive substances, TNF-α protein and IL-6 mRNA. These results suggest that oral administration of WEC may have a protective effect against ethanol-induced liver injury by suppressing hepatic oxidation and inflammation, at least partly through the effects of bisacurone.

  10. Protective activity of Panduratin A against Thioacetamide-induced oxidative damage: demonstration with in vitro experiments using WRL-68 liver cell line

    PubMed Central

    2013-01-01

    Background Chalcone Panduratin A (PA) has been known for its antioxidant property, but its merits against oxidative damage in liver cells has yet to be investigated. Hence, the paper aimed at accomplishing this task with normal embryonic cell line WRL-68. Methods PA was isolated from Boesenbergia rotunda rhizomes and its 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging and ferric reducing power (FRAP) activities were measured in comparison with that of the standard reference drug Silymarin (SI). Oxidative damage was induced by treating the cells with 0.04 g/ml of toxic thioacetamide for 60 minutes followed by treatment with 1, 10 and 100 μg/ml concentrations of either PA or SI. The severities of oxidative stress in the control and experimental groups of cells were measured by Malondialdehyde (MDA) levels, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities. Results PA exhibited an acceptable DPPH scavenging and FRAP activities close to that of Silymarin. Treating the injured cells with PA significantly reduced the MDA level and increased the cell viability, comparable to SI. The activities of SOD, CAT and GPx were significantly elevated in the PA-treated cells in a dose dependent manner and again similar to SI. Conclusion Collectively, data suggested that PA has capacity to protect normal liver cells from oxidative damage, most likely via its antioxidant scavenging ability. PMID:24156366

  11. In Situ Evaluation of Oxidative Stress in Rat Fatty Liver Induced by a Methionine- and Choline-Deficient Diet

    PubMed Central

    Freitas, Isabel; Boncompagni, Eleonora; Tarantola, Eleonora; Gruppi, Cristian; Bertone, Vittorio; Ferrigno, Andrea; Milanesi, Gloria; Vaccarone, Rita; Tira, M. Enrica; Vairetti, Mariapia

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a serious health problem in developed countries. We documented the effects of feeding with a NAFLD-inducing, methionine- and choline-deficient (MCD) diet, for 1–4 weeks on rat liver oxidative stress, with respect to a control diet. Glycogen, neutral lipids, ROS, peroxidated proteins, and SOD2 were investigated using histochemical procedures; ATP, GSH, and TBARS concentrations were investigated by biochemical dosages, and SOD2 expression was investigated by Western Blotting. In the 4-week-diet period, glycogen stores decreased whereas lipid droplets, ROS, and peroxidated proteins expression (especially around lipid droplets of hepatocytes) increased. SOD2 immunostaining decreased in poorly steatotic hepatocytes but increased in the thin cytoplasm of macrosteatotic cells; a trend towards a quantitative decrease of SOD expression in homogenates occurred after 3 weeks. ATP and GSH values were significantly lower for rats fed with the MCD diet with respect to the controls. An increase of TBARS in the last period of the diet is in keeping with the high ROS production and low antioxidant defense; these TBARS may promote protein peroxidation around lipid droplets. Since these proteins play key roles in lipid mobilization, storage, and metabolism, this last information appears significant, as it points towards a previously misconsidered target of NAFLD-associated oxidative stress that might be responsible for lipid dysfunction. PMID:26881047

  12. In Situ Evaluation of Oxidative Stress in Rat Fatty Liver Induced by a Methionine- and Choline-Deficient Diet.

    PubMed

    Freitas, Isabel; Boncompagni, Eleonora; Tarantola, Eleonora; Gruppi, Cristian; Bertone, Vittorio; Ferrigno, Andrea; Milanesi, Gloria; Vaccarone, Rita; Tira, M Enrica; Vairetti, Mariapia

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a serious health problem in developed countries. We documented the effects of feeding with a NAFLD-inducing, methionine- and choline-deficient (MCD) diet, for 1-4 weeks on rat liver oxidative stress, with respect to a control diet. Glycogen, neutral lipids, ROS, peroxidated proteins, and SOD2 were investigated using histochemical procedures; ATP, GSH, and TBARS concentrations were investigated by biochemical dosages, and SOD2 expression was investigated by Western Blotting. In the 4-week-diet period, glycogen stores decreased whereas lipid droplets, ROS, and peroxidated proteins expression (especially around lipid droplets of hepatocytes) increased. SOD2 immunostaining decreased in poorly steatotic hepatocytes but increased in the thin cytoplasm of macrosteatotic cells; a trend towards a quantitative decrease of SOD expression in homogenates occurred after 3 weeks. ATP and GSH values were significantly lower for rats fed with the MCD diet with respect to the controls. An increase of TBARS in the last period of the diet is in keeping with the high ROS production and low antioxidant defense; these TBARS may promote protein peroxidation around lipid droplets. Since these proteins play key roles in lipid mobilization, storage, and metabolism, this last information appears significant, as it points towards a previously misconsidered target of NAFLD-associated oxidative stress that might be responsible for lipid dysfunction.

  13. Chromium picolinate attenuates hyperglycemia-induced oxidative stress in streptozotocin-induced diabetic rats.

    PubMed

    Sundaram, Bhuvaneshwari; Aggarwal, Aanchal; Sandhir, Rajat

    2013-04-01

    Chromium picolinate is advocated as an anti-diabetic agent for impaired glycemic control. It is a transition metal that exists in various oxidation states and may thereby act as a pro-oxidant. The present study has been designed to examine the effect of chromium picolinate supplementation on hyperglycemia-induced oxidative stress. Diabetes was induced in male Wistar rats by a single intraperitoneal injection of streptozotocin (50mg/kg body weight) and chromium was administered orally as chromium picolinate (1mg/kg body weight) daily for a period of four weeks after the induction of diabetes. As is characteristic of diabetic condition, hyperglycemia was associated with an increase in oxidative stress in liver in terms of increased lipid peroxidation and decreased glutathione levels. The activity of antioxidant enzymes like superoxide dismutase, catalase and glutathione reductase were significantly reduced in liver of diabetic animals. Levels of α-tocopherol and ascorbic acid were found to be considerably lower in plasma of diabetic rats. Chromium picolinate administration on the other hand was found to have beneficial effect in normalizing glucose levels, lipid peroxidation and antioxidant status. The results from the present study demonstrate potential of chromium picolinate to attenuate hyperglycemia-induced oxidative stress in experimental diabetes. Copyright © 2012 Elsevier GmbH. All rights reserved.

  14. Seasonal variations in PM composition from Beijing, China drive liver oxidative stress

    NASA Astrophysics Data System (ADS)

    Pardo, M.; Rudich, Y.

    2017-12-01

    Air pollution can cause oxidative stress, inflammation and adverse health effects, but the underlying biological mechanisms are not completely understood. In order to understand how seasonal and chemical variations drive health impacts, we investigated the oxidative stress and inflammation in mice exposed to extracts (water and DCM) from urban PM collected in Beijing (China). Higher levels of pollution components were detected in the heating season (HS, winter) than in the non-heating season (NHS, summer). Higher concentrations of PM were measured in the heating season, mostly from coal and wood burning used for domestic heating. This was accompanied by increased levels of polyaromatic hydrocarbons (PAHs) in the DCM extracts. An increased inflammatory response was detected in the lung and liver with DCM extracts compared to the water extracts, and mostly in the winter aerosol. Reduced antioxidant response was observed in the lung, whereas it was activated in the liver. Gene expression of the Nrf2 transcription factor (A master regulator of stress response that controls the basal oxidative capacity and induces the expression of antioxidant response) and its related genes were induced. In the liver, higher levels of lipid peroxidation adducts were measured, correlated with histologic analysis that revealed morphologic features of damage/proliferation in the liver, indicating oxidative and toxic damage. Altogether, our study suggests that the acute effects of PM can vary by the season with the largest effect observed in winter than summer in Beijing, and that some secondary organs may be susceptible for exposure damage. This suggests that the liver is a potential organ to be influenced from PM especially by PAHs

  15. Estrogen protects the liver and intestines against sepsis-induced injury in rats.

    PubMed

    Sener, Göksel; Arbak, Serap; Kurtaran, Pelin; Gedik, Nursal; Yeğen, Berrak C

    2005-09-01

    Sepsis is commonly associated with enhanced generation of reactive oxygen metabolites, leading to multiple organ dysfunctions. The aim of this study was to examine the putative protective role of estradiol against sepsis-induced oxidative organ damage. Sepsis was induced by cecal ligation and puncture method in Wistar albino rats. Sham-operated (control) and sepsis groups received saline or estradiol propionate (10 mg/kg) intraperitoneally immediately after the operation and at 12 h. Twenty-four hours after the surgery, rats were decapitated and malondialdehyde, glutathione levels, and myeloperoxidase activity were determined in the liver and ileum, while oxidant-induced tissue fibrosis was determined by collagen contents. Tissues were also examined microscopically. Serum aspartate aminotransferase, alanine aminotransferase levels, and lactate dehydrogenase were measured for the evaluation of liver functions and tissue damage, respectively. Tumor necrosis factor-alpha was also assayed in serum samples. In the saline-treated sepsis group, glutathione levels were decreased significantly, while the malondialdehyde levels, myeloperoxidase activity, and collagen content were increased in the tissues (P < 0.01 to P < 0.001), suggesting oxidative organ damage, which was also verified histologically. In the estradiol-treated sepsis group, all of these oxidant responses were reversed significantly (P < 0.05 to P < 0.01). Liver function tests and tumor necrosis factor-alpha levels, which were increased significantly (P < 0.001) following sepsis, were decreased (P < 0.05 to P < 0.001) with estradiol treatment. The results demonstrate the role of oxidative mechanisms in sepsis-induced tissue damage, and estradiol, by its antioxidant properties, ameliorates oxidative organ injury, implicating that treatment with estrogens might be applicable in clinical situations to ameliorate multiple organ damage induced by sepsis.

  16. 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.

  17. Chlorogenic acid ameliorates alcohol-induced liver injuries through scavenging reactive oxygen species.

    PubMed

    Kim, Hyunjin; Pan, Jeong Hoon; Kim, Sung Hwan; Lee, Jin Hyup; Park, Jeen-Woo

    2018-05-19

    The key role of oxidative stress in alcoholic liver disease (ALD) has been established by the large body of evidence from previous studies. Excessive consumption of ethanol induces the production of a variety of reactive oxygen species (ROS) in the liver, such as superoxide, H 2 O 2 , and hydroxyl radical. These products activate oxidant-sensitive signaling cascades and modulators of apoptosis. Because ROS accumulation is closely related to ALD, a number of studies have investigated the benefits of antioxidants. Recent studies demonstrated that polyphenol chlorogenic acid (CGA) has antioxidant properties and health benefits, such as reduction of relative risk of cardiovascular diseases and hepatoprotective effects against acetaminophen toxicity. However, the protective effects of CGA against ALD have not been studied in detail. We hypothesize that CGA plays a role in preventing ALD through its antioxidant properties. In this study, we investigated the protective effects of CGA against liver injuries in vivo. Reduced alcohol-induced-steatosis, apoptotic cell death, and fibrosis due to reduced levels of oxidative stress were observed. These findings suggest that CGA treatment can be an effective approach to attenuate ALD through the suppression of oxidative stress. Copyright © 2018. Published by Elsevier B.V.

  18. Influence of alpha-lipoic acid on nicotine-induced lung and liver damage in experimental rats.

    PubMed

    Ateyya, Hayam; Nader, Manar A; Attia, Ghalia M; El-Sherbeeny, Nagla A

    2017-05-01

    Nicotine mediates some of the injurious effects caused by consuming tobacco products. This work aimed at investigating the defensive role of alpha-lipoic acid (ALA) with its known antioxidant and antiinflammatory effect in nicotine-induced lung and liver damage. Rats were arranged into 4 groups: control, nicotine, ALA, and ALA-nicotine groups. Oxidative stress and antioxidant status were determined by assessing thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), and glutathione (GSH) levels in lung and liver. Liver enzymes and lipid profiles were measured and pulmonary and hepatic damage were assessed by histopathological examination. Also, serum levels of transforming growth factor beta 1 (TGF-β1) and vascular cell adhesion molecule 1 (VCAM-1) were determined. The results revealed an increase in TBARS in tissues and a reduction in both SOD and GSH activity in the nicotine-treated rats. Nicotine induced high levels of liver enzymes, TGF-β1, VCAM-1, and dyslipidemia with histopathological changes in the lung and liver. ALA administration along with nicotine attenuated oxidative stress and normalized the SOD and GSH levels, ameliorated dyslipidemia, and improved TGF-β1 and VCAM-1 with better histopathology of the lung and liver. The study data revealed that ALA may be beneficial in alleviating nicotine-induced oxidative stress, dyslipidemia, and both lung and liver damage.

  19. Pomegranate protects liver against cecal ligation and puncture-induced oxidative stress and inflammation in rats through TLR4/NF-κB pathway inhibition.

    PubMed

    Makled, Mirhan N; El-Awady, Mohammed S; Abdelaziz, Rania R; Atwan, Nadia; Guns, Emma T; Gameil, Nariman M; Shehab El-Din, Ahmed B; Ammar, Elsayed M

    2016-04-01

    Acute liver injury secondary to sepsis is a major challenge in intensive care unit. This study was designed to investigate potential protective effects of pomegranate against sepsis-induced acute liver injury in rats and possible underlying mechanisms. Pomegranate was orally given (800mg/kg/day) for two weeks before sepsis induction by cecal ligation and puncture (CLP). Pomegranate improved survival and attenuated liver inflammatory response, likely related to downregulation of mRNA expression of toll like recptor-4, reduced nuclear translocation and DNA binding activity of proinflammatory transcription factor NF-κB subunit p65, decreased mRNA and protein expression of tumor necrosis factor-alpha and reduction in myeloperoxidase activity and mRNA expression. Pomegranate also decreased CLP-induced oxidative stress as reflected by decreased malondialdehyde content, and increased reduced glutathione level and superoxide dismutase activity. These results confirm the antiinflammatory and antioxidant effects of pomegranate in CLP-induced acute liver injury mediated through inhibiting TLR4/NF-κB pathway, lipid peroxidation and neutrophil infiltration. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Hypothermia can reverse hepatic oxidative stress damage induced by hypoxia in rats.

    PubMed

    Garnacho-Castaño, Manuel Vicente; Alva, Norma; Sánchez-Nuño, Sergio; Bardallo, Raquel G; Palomeque, Jesús; Carbonell, Teresa

    2016-12-01

    Our previous findings demonstrated that hypothermia enhances the reduction potential in the liver and helps to maintain the plasmatic antioxidant pool. Here, we aimed to elucidate if hypothermia protects against hypoxia-induced oxidative stress damage in rat liver. Several hepatic markers of oxidative stress were compared in three groups of animals (n = 8 in each group): control normothermic group ventilated with room air and two groups under extreme hypoxia (breathing 10 % O 2 ), one kept at normothermia (HN) (37 °C) and the other under deep hypothermia (HH) (central body temperature of 21-22 °C). Hypoxia in normothermia significantly increased the levels of hepatic nitric oxide, inducible nitric oxide synthase expression, protein oxidation, Carbonilated proteins, advanced oxidation protein products, 4-hydroxynonenal (HNE) protein adducts, and lipid peroxidation when compared to the control group (p < 0.05). However, when hypoxia was induced under hypothermia, results from the oxidative stress biomarker analyses did not differ significantly from those found in the control group. Indeed, 4-HNE protein adduct amounts were significantly lower in the HH versus HN group (p < 0.05). Therefore, hypothermia can mitigate hypoxia-induced oxidative stress damage in rat liver. These effects could help clarify the mechanisms of action of therapeutic hypothermia.

  1. Using a liver cell culture from Epinephelus coioides as a model to evaluate the nonylphenol-induced oxidative stress.

    PubMed

    Derakhshesh, Negin; Movahedinia, AbdolAli; Salamat, Negin; Hashemitabar, Mahmoud; Bayati, Vahid

    2017-09-15

    The present study aimed to use primary liver cell culture derived from the orange-spotted grouper, Epinephelus coioides, to assess the toxic effects of nonylphenol (NP) on the hepatocyte viability and the liver antioxidant system. E. coioides was selected due to its commercial importance. NP was used in this study because of its high potential of producing oxidative stress due to increased reactive oxygen species (ROS). A liver of E. coioides was digested with PBS containing 0.1% collagenase IV. The digested cells were moved to Leibovitz L-15 culture medium with 20% fetal bovine serum (FBS), 100IUmL -1 penicillin, 100μgmL -1 streptomycin. Aliquots of cell suspension were seeded as a monolayer into sterile 25cm 2 tissue culture flasks and incubated at 30°C for 14days. The medium, containing non-attached cells, was removed after 24 to 48h and a new medium was added. The IC50 of 10 -4 molL -1 was determined for nonylphenol using MTT assay. Cells were then incubated with L-15 medium containing 10 -5 , 2×10 -5 , 3×10 -5 molL -1 of NP and samples were taken after 6, 12 and 24h of incubation for analysis of LPO, SOD, CAT, GPx, LDH, AST, ALT, and ALP. Based on the results, the lowest concentration of NP was not markedly cytotoxic to primary hepatocytes and the cell sensitivity to NP increased dose-dependently. The activities of SOD, CAT and GPx decreased significantly, while activities of LPO, LDH, AST, ALT and ALP, increased significantly in a dose-related pattern in NP-treated cells. In conclusion, this study revealed that NP could induce the oxidative stress in cultivated hepatocytes of E. coioides during a short-term exposure. NP toxicity is mainly due to the induction of the reactive oxygen species (ROS), which lead to cell membrane disruption, damage of cellular metabolism, and interference with cellular macromolecules. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. 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

  3. Improvement in Serum Biochemical Alterations and Oxidative Stress of Liver and Pancreas following Use of Royal Jelly in Streptozotocin-Induced Diabetic Rats

    PubMed Central

    Ghanbari, Elham; Nejati, Vahid; Khazaei, Mozafar

    2016-01-01

    Objective This study aimed to evaluate the effects of royal jelly (RJ) on serum biochemical alterations and oxidative stress status in liver and pancreas of streptozotocin (STZ)- induced diabetic rats. Materials and Methods In this experimental study, thirty two male Wistar rats were divided into the following four groups (n=8/group): i. Control (C), ii. Diabetic (D), iii. Royal jelly (R), and iv. Royal jelly-treated diabetic (D/R) groups. Diabetes was induced by single intraperitoneal (IP) injection of STZ (60 mg/kg). The RJ [100 mg/kg body weight (BW)] was administered orally for 42 days. Blood samples were used to determine serum levels of insulin, high density lipoprotein cholesterol (HDL-c), total protein (TP), albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and fasting blood glucose (FBG). Also, the antioxidant status was evaluated by determining the levels of malondialdehyde (MDA), catalase (CAT) and ferric reducing antioxidant power (FRAP) in liver and pancreas. Data were analyzed by one-way analysis of variance (ANOVA) with P<0.05 as the significant level. Results STZ-induced diabetic rats showed a significant elevation in the serum levels of AST, ALT, ALP and FBG, whereas there was a significant decrease in serum levels of insulin, albumin, HDL-c and TP (P<0.05). Treatment of the diabetic rats with RJ restored the changes of the above parameters to their normal levels (P<0.05). In addition, RJ significantly improved reduced levels of FRAP and CAT as well as high MDA level in liver and pancreas (P<0.05). Conclusion RJ improves oxidative damage induced by STZ in the liver and pancreas of rats; therefore, it can be considered as an effective and alternative treatment for diabetes. PMID:27602318

  4. Improvement in Serum Biochemical Alterations and Oxidative Stress of Liver and Pancreas following Use of Royal Jelly in Streptozotocin-Induced Diabetic Rats.

    PubMed

    Ghanbari, Elham; Nejati, Vahid; Khazaei, Mozafar

    2016-01-01

    This study aimed to evaluate the effects of royal jelly (RJ) on serum biochemical alterations and oxidative stress status in liver and pancreas of streptozotocin (STZ)- induced diabetic rats. In this experimental study, thirty two male Wistar rats were divided into the following four groups (n=8/group): i. Control (C), ii. Diabetic (D), iii. Royal jelly (R), and iv. Royal jelly-treated diabetic (D/R) groups. Diabetes was induced by single intraperitoneal (IP) injection of STZ (60 mg/kg). The RJ [100 mg/kg body weight (BW)] was administered orally for 42 days. Blood samples were used to determine serum levels of insulin, high density lipoprotein cholesterol (HDL-c), total protein (TP), albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and fasting blood glucose (FBG). Also, the antioxidant status was evaluated by determining the levels of malondialdehyde (MDA), catalase (CAT) and ferric reducing antioxidant power (FRAP) in liver and pancreas. Data were analyzed by one-way analysis of variance (ANOVA) with P<0.05 as the significant level. STZ-induced diabetic rats showed a significant elevation in the serum levels of AST, ALT, ALP and FBG, whereas there was a significant decrease in serum levels of insulin, albumin, HDL-c and TP (P<0.05). Treatment of the diabetic rats with RJ restored the changes of the above parameters to their normal levels (P<0.05). In addition, RJ significantly improved reduced levels of FRAP and CAT as well as high MDA level in liver and pancreas (P<0.05). RJ improves oxidative damage induced by STZ in the liver and pancreas of rats; therefore, it can be considered as an effective and alternative treatment for diabetes.

  5. TRPM2 channels mediate acetaminophen-induced liver damage

    PubMed Central

    Kheradpezhouh, Ehsan; Ma, Linlin; Morphett, Arthur; Barritt, Greg J.; Rychkov, Grigori Y.

    2014-01-01

    Acetaminophen (paracetamol) is the most frequently used analgesic and antipyretic drug available over the counter. At the same time, acetaminophen overdose is the most common cause of acute liver failure and the leading cause of chronic liver damage requiring liver transplantation in developed countries. Acetaminophen overdose causes a multitude of interrelated biochemical reactions in hepatocytes including the formation of reactive oxygen species, deregulation of Ca2+ homeostasis, covalent modification and oxidation of proteins, lipid peroxidation, and DNA fragmentation. Although an increase in intracellular Ca2+ concentration in hepatocytes is a known consequence of acetaminophen overdose, its importance in acetaminophen-induced liver toxicity is not well understood, primarily due to lack of knowledge about the source of the Ca2+ rise. Here we report that the channel responsible for Ca2+ entry in hepatocytes in acetaminophen overdose is the Transient Receptor Potential Melanostatine 2 (TRPM2) cation channel. We show by whole-cell patch clamping that treatment of hepatocytes with acetaminophen results in activation of a cation current similar to that activated by H2O2 or the intracellular application of ADP ribose. siRNA-mediated knockdown of TRPM2 in hepatocytes inhibits activation of the current by either acetaminophen or H2O2. In TRPM2 knockout mice, acetaminophen-induced liver damage, assessed by the blood concentration of liver enzymes and liver histology, is significantly diminished compared with wild-type mice. The presented data strongly suggest that TRPM2 channels are essential in the mechanism of acetaminophen-induced hepatocellular death. PMID:24569808

  6. Effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors and antioxidant vitamins on free radical lipid oxidation in rat liver.

    PubMed

    Lankin, V Z; Ivanova, M V; Konovalova, G G; Tikhaze, A K; Kaminnyi, A I; Kukharchuk, V V

    2007-04-01

    We studied the effects of two inhibitors of beta-hydroxy-beta-methylglutaryl coenzyme A reductase, simvastatin and lovastatin, on the lag phase of ascorbate-dependent lipid oxidation in rat liver. Oxidizability of liver biological membranes significantly increased in intact animals and rats with induced hypercholesterolemia after peroral administration of these statins. The lag phase of ascorbate-dependent lipid oxidation in liver biomembranes decreased by 2.1 times in hypercholesterolemic rats. In animals of the lovastatin group this parameter decreased by 4.4 times compared to the control. In intact rats receiving simvastatin, the lag phase of oxidation in biomembranes from the liver decreased practically by 2 times. At the same time, in animals receiving simvastatin in combination with antioxidant vitamins (vitamins E and C, provitamin A) and selenium, the period of induction of oxidation increased by 3.3 times. Our results indicate that beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors produce a prooxidant effect on the liver, which can be prevented by administration of antioxidant agents.

  7. High-salt in addition to high-fat diet may enhance inflammation and fibrosis in liver steatosis induced by oxidative stress and dyslipidemia in mice.

    PubMed

    Uetake, Yuzaburo; Ikeda, Hitoshi; Irie, Rie; Tejima, Kazuaki; Matsui, Hiromitsu; Ogura, Sayoko; Wang, Hong; Mu, ShengYu; Hirohama, Daigoro; Ando, Katsuyuki; Sawamura, Tatsuya; Yatomi, Yutaka; Fujita, Toshiro; Shimosawa, Tatsuo

    2015-02-13

    It is widely known that salt is an accelerating factor for the progression of metabolic syndrome and causes cardiovascular diseases, most likely due to its pro-oxidant properties. We hypothesized that excessive salt intake also facilitates the development of nonalcoholic steatohepatitis (NASH), which is frequently associated with metabolic syndrome. We examined the exacerbating effect of high-salt diet on high-fat diet-induced liver injury in a susceptible model to oxidative stress, apoE knockout and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transgenic mice. High-salt diet led to NASH in high-fat diet-fed LOX-1 transgenic/apoE knockout mice without affecting high-fat diet-induced dyslipidemia or hepatic triglyceride accumulation. Additionally, a high-salt and high-fat diet stimulated oxidative stress production and inflammatory reaction to a greater extent than did a high-fat diet in the liver of LOX-1 transgenic/apoE knockout mice. We demonstrated that high-salt diet exacerbated NASH in high-fat diet-fed LOX-1 transgenic /apoE knockout mice and that this effect was associated with the stimulation of oxidative and inflammatory processes; this is the first study to suggest the important role of excessive salt intake in the development of NASH.

  8. Maltol, a Food Flavoring Agent, Attenuates Acute Alcohol-Induced Oxidative Damage in Mice

    PubMed Central

    Han, Ye; Xu, Qi; Hu, Jiang-ning; Han, Xin-yue; Li, Wei; Zhao, Li-chun

    2015-01-01

    The purpose of this study was to evaluate the hepatoprotective effect of maltol, a food-flavoring agent, on alcohol-induced acute oxidative damage in mice. Maltol used in this study was isolated from red ginseng (Panax ginseng C.A Meyer) and analyzed by high performance liquid chromatography (HPLC) and mass spectrometry. For hepatoprotective activity in vivo, pretreatment with maltol (12.5, 25 and 50 mg/kg; 15 days) drastically prevented the elevated activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and triglyceride (TG) in serum and the levels of malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) in liver tissue (p < 0.05). Meanwhile, the levels of hepatic antioxidant, such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) were elevated by maltol pretreatment, compared to the alcohol group (p < 0.05). Histopathological examination revealed that maltol pretreatment significantly inhibited alcohol-induced hepatocyte apoptosis and fatty degeneration. Interestingly, pretreatment of maltol effectively relieved alcohol-induced oxidative damage in a dose-dependent manner. Maltol appeared to possess promising anti-oxidative and anti-inflammatory capacities. It was suggested that the hepatoprotective effect exhibited by maltol on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties. PMID:25608939

  9. Apocynum venetum Attenuates Acetaminophen-Induced Liver Injury in Mice.

    PubMed

    Xie, Wenyan; Chen, Chen; Jiang, Zhihui; Wang, Jian; Melzig, Matthias F; Zhang, Xiaoying

    2015-01-01

    Apocynum venetum L. (A. venetum) has long been used in oriental folk medicine for the treatment of some liver diseases; however, the underlying mechanisms remain to be fully elucidated. Acetaminophen (APAP) is a widely used analgesic drug that can cause acute liver injury in overdose situations. In this study, we investigated the potential protective effect of A. venetum leaf extract (ALE) against APAP-induced hepatotoxicity. Mice were intragastrically administered with ALE once daily for 3 consecutive days prior to receiving a single intraperitoneal injection of APAP. The APAP group showed severe liver injury characterized by the noticeable fluctuations in the following parameters: serum aminotransferases; hepatic malondialdehyde (MDA), 3-nitrotyrosine (3-NT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione (GSH). These liver damages induced by APAP were significantly attenuated by ALE pretreatments. A collective analysis of histopathological examination, DNA laddering and western blot for caspase-3 and cytochrome c indicated that the ALE is also capable of preventing APAP-induced hepatocyte death. Hyperoside, isoquercitrin and their derivatives have been identified as the major components of ALE using HPLC-MS/MS. Taken together, the A. venetum possesses hepatoprotective effects partially due to its anti-oxidant action.

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

    PubMed

    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; Fernández-Checa, José C; Gomez-Quiroz, Luis Enrique

    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.

  11. Ameliorative efficacy of quercetin against cisplatin‑induced mitochondrial dysfunction: Study on isolated rat liver mitochondria.

    PubMed

    Waseem, Mohammad; Tabassum, Heena; Bhardwaj, Monica; Parvez, Suhel

    2017-09-01

    The present study aimed to investigate the hepatoprotective effects of the bioflavonoid quercetin (QR) on cisplatin (CP)‑induced mitochondrial oxidative stress in the livers of rats, to elucidate the role of mitochondria in CP‑induced hepatotoxicity, and its underlying mechanism. Isolated liver mitochondria were incubated with 100 µg/ml CP and/or 50 µM QR in vitro. CP treatment triggered a significant increase in membrane lipid peroxidation (LPO) levels, protein carbonyl (PC) contents, and a decrease in reduced glutathione (GSH) and non‑protein thiol (NP‑SH) levels. In addition, CP caused a marked decline in the activities of enzymatic antioxidants and mitochondrial complexes (I, II, III and V) in liver mitochondria. QR pre‑treatment significantly modulated the activities of enzymatic antioxidants and mitochondrial complex enzymes. Furthermore, QR reversed the alterations in LPO and PC levels, and GSH and NP‑SH contents in liver mitochondria. The results of the present study suggested that QR supplementation may suppress CP‑induced mitochondrial toxicity during chemotherapy, and provides a potential prophylactic and defensive candidate for anticancer agent‑induced oxidative stress.

  12. Effect of Pelargonium reniforme roots on alcohol-induced liver damage and oxidative stress.

    PubMed

    Adewusi, Emmanuel Adekanmi; Afolayan, Anthony Jide

    2010-09-01

    Ethnobotanical surveys conducted on Pelargonium reniforme Curtis (Geraniaceae) have shown that the aqueous root extracts are used to treat alcohol-induced liver damage. We evaluated the antioxidant properties of the extract and its effects on alcohol-induced hepatotoxicity using Wistar rats. Alcohol-induced hepatotoxicity studies were carried out by observing the effect of the aqueous root extract on some liver marker enzymes, bilirubin, and total protein after liver damage. The levels of some phenolic compounds were determined by standard methods. Also, the reducing power of the plant extract and its ability to scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH*) and 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS*+) radicals were determined to evaluate its antioxidant activity. The results obtained show that the plant extract possessed significant antioxidant activity. It had a significant level of phenolic compounds, scavenged DPPH* and ABTS*+ radicals effectively, and demonstrated good reducing power. This may indicate that the plant contained compounds which can remove toxic metabolites following alcohol abuse. Serum analysis of animals treated with only ethanol showed a significant increase in the levels of liver marker enzymes and total and unconjugated bilirubin, while a significant decrease was observed in the levels of conjugated bilirubin and total proteins. Administration of the plant extract restored the levels of these markers to normal levels, and this indicates the ability of the plant extract to restore normal functioning of a damaged liver. The study shows that P. reniforme is a potential source of antioxidants and compounds which are useful in treating alcoholic liver damage.

  13. Antifibrotic mechanism of deferoxamine in concanavalin A induced-liver fibrosis: Impact on interferon therapy.

    PubMed

    Darwish, Samar F; El-Bakly, Wesam M; El-Naga, Reem N; Awad, Azza S; El-Demerdash, Ebtehal

    2015-11-01

    Iron-overload is a well-known factor of hepatotoxicity and liver fibrosis, which found to be a common finding among hepatitis C virus patients and related to interferon resistance. We aimed to elucidate the potential antifibrotic effect of deferoxamine; the main iron chelator, and its additional usefulness to interferon-based therapy in concanavalin A-induced immunological model of liver fibrosis. Rats were treated with deferoxamine and/or pegylated interferon-α for 6 weeks. Hepatotoxicity indices, oxidative stress, inflammatory and liver fibrosis markers were assessed. Concanavalin A induced a significant increase in hepatotoxicity indices and lipid peroxidation accompanied with a significant depletion of total antioxidant capacity, glutathione level and superoxide dismutase activity. Besides, it increased CD4(+) T-cells content and the downstream inflammatory cascades, including NF-κB, TNF-α, iNOS, COX-2, IL-6 and IFN-γ. Furthermore, α-SMA, TGF-β1 and hydroxyproline were increased markedly, which confirmed by histopathology. Treatment with either deferoxamine or pegylated interferon-α alone reduced liver fibrosis markers significantly and improved liver histology. However, some of the hepatotoxicity indices and oxidative stress markers did not improve upon pegylated interferon-α treatment alone, besides the remarkable increase in IL-6. Combination therapy of deferoxamine with pegylated interferon-α further improved all previous markers, ameliorated IL-6 elevation, as well as increased hepcidin expression. In conclusion, our study provides evidences for the potent antifibrotic effects of deferoxamine and the underlying mechanisms that involved attenuating oxidative stress and subsequent inflammatory cascade, as well as the production of profibrogenic factors. Addition of deferoxamine to interferon regimen for HCV patients may offer a promising adjuvant modality to enhance therapeutic response. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Quantitative optical imaging of paracetamol-induced metabolism changes in the liver

    NASA Astrophysics Data System (ADS)

    Liang, Xiaowen; Wang, Haolu; Liu, Xin; Roberts, Michael

    2016-12-01

    Paracetamol is the most readily available and widely used painkiller. However, its toxicity remains the most common cause of liver injury. The toxicity of paracetamol has been attributing to its toxic metabolite, which depletes cellular glutathione (GSH) stores and reacts within cells to increase oxidative stress, leading to mitochondrial dysfunction and cell necrosis. Multiphoton microscopy (MPM) and fluorescence lifetime imaging (FLIM) can provide quantitative imaging of biological tissues and organs in vivo and allow direct visualization of cellular events, which were used to monitor cellular metabolism in paracetamol-induced toxicity in this study. To better understand mechanisms of paracetamol induced liver injury, the redox ratio of NADH/FAD in liver cells were detected and quantified by MPM imaging to represent the relative rates of glycolysis and oxidative phosphorylation within cells. Compared to normal liver, average fluorescence lifetime of NADH and redox ratio of NADH/FAD in hepatocytes was significantly decreased after paracetamol overdose for 12 and 24 hrs, reflecting impaired metabolic activity. GSH levels of treatment groups were significantly lower than those of normal livers, with gradually decreasing from periportal to centrilobular zonation. This imaging technique has significant implications for investigating metabolic mechanisms of paracetamol toxicity.

  15. Hepatoprotective Effect of Citral on Acetaminophen-Induced Liver Toxicity in Mice.

    PubMed

    Uchida, Nancy Sayuri; Silva-Filho, Saulo Euclides; Cardia, Gabriel Fernando Esteves; Cremer, Edivaldo; Silva-Comar, Francielli Maria de Souza; Silva, Expedito Leite; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

    2017-01-01

    High doses of acetaminophen (APAP) lead to acute liver damage. In this study, we evaluated the effects of citral in a murine model of hepatotoxicity induced by APAP. The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase ( γ GT) were determined to evaluate the hepatoprotective effects of citral. The livers were used to determine myeloperoxidase (MPO) activity and nitric oxide (NO) production and in histological analysis. The effect of citral on leukocyte migration and antioxidant activity was evaluated in vitro. Citral pretreatment decreased significantly the levels of ALT, AST, ALP, and γ GT, MPO activity, and NO production. The histopathological analysis showed an improvement of hepatic lesions in mice after citral pretreatment. Citral inhibited neutrophil migration and exhibited antioxidant activity. Our results suggest that citral protects the liver against liver toxicity induced by APAP.

  16. 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

  17. Protective effect of Allium sativum (garlic) aqueous extract against lead-induced oxidative stress in the rat brain, liver, and kidney.

    PubMed

    Manoj Kumar, V; Henley, A K; Nelson, C J; Indumati, O; Prabhakara Rao, Y; Rajanna, S; Rajanna, B

    2017-01-01

    The present investigation was undertaken to evaluate the ameliorative activity of Allium sativum against lead-induced oxidative stress in the brain, liver, and kidney of male rats. Four groups of male Wistar strain rats (100-120 g) were taken: group 1 received 1000 mg/L sodium acetate and group 2 was given 1000 mg/L lead acetate through drinking water for 2 weeks. Group 3 and 4 were treated with 250 mg/kg body weight/day of A. sativum and 500 mg/kg body weight/day of A. sativum, respectively, by oral intubation for a period of 2 weeks along with lead acetate. The rats were sacrificed after treatment and the brain, liver, and kidney were isolated on ice. In the brain, four important regions namely the hippocampus, cerebellum, cerebral cortex, and brain stem were separated and used for the present investigation. Blood was also drawn by cardiac puncture and preserved in heparinized vials at 4 °C for estimation of delta-aminolevulinic acid dehydratase (ALAD) activity. The results showed a significant (p < 0.05) increase in reactive oxygen species (ROS), lipid peroxidation products (LPP), total protein carbonyl content (TPCC), and lead in the selected brain regions, liver, and kidney of lead-exposed group compared with their respective controls. Blood delta-ALAD activity showed a significant (p < 0.05) decrease in the lead-exposed rats. However, the concomitant administration of A. sativum resulted in tissue-specific recovery of oxidative stress parameters namely ROS, LPP, and TPCC. A. sativum treatment also restored the blood delta-ALAD activity back to control. Overall, our results indicate that A. sativum administration could be an effective antioxidant treatment strategy for lead-induced oxidative insult.

  18. Sulforaphane induces Nrf2 and protects against CYP2E1-dependent binge alcohol-induced liver steatosis.

    PubMed

    Zhou, Richard; Lin, Jianjun; Wu, Defeng

    2014-01-01

    The mechanism(s) by which alcohol causes cell injury are still not clear but a major mechanism appears to be the role of lipid peroxidation and oxidative stress in alcohol toxicity. CYP2E1-generated ROS contributes to the ethanol-induced oxidant stress and inhibition of CYP2E1 activity decreases ethanol-induced fatty liver. The transcription factor Nrf2 regulates the expression of many cytoprotective enzymes which results in cellular protection against a variety of toxins. The current study was designed to evaluate the ability of sulforaphane, an activator of Nrf2, to blunt CYP2E1-dependent, ethanol-induced steatosis in vivo and in vitro. The sulforaphane treatment activated Nrf2, increased levels of the Nrf2 target heme oxygenase-1 and subsequently lowered oxidant stress as shown by the decline in lipid peroxidation and 3-nitrotyrosine protein adducts and an increase in GSH levels after the acute ethanol treatment. It decreased ethanol-elevated liver levels of triglycerides and cholesterol and Oil Red O staining. Similar results were found in vitro as addition of sulforaphane to HepG2 E47 cells, which express CYP2E1, elevated Nrf2 levels and decreased the accumulation of lipid in cells cultured with ethanol. Sulforaphane treatment had no effect on levels of or activity of CYP2E1. Sulforaphane proved to be an effective in vivo inhibitor of acute ethanol-induced fatty liver in mice. The possible amelioration of liver injury which occurs under these conditions by chemical activators of Nrf2 is of clinical relevance and worthy of further study. © 2013.

  19. Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine

    PubMed Central

    Hanczko, Robert; Fernandez, David R.; Doherty, Edward; Qian, Yueming; Vas, Gyorgy; Niland, Brian; Telarico, Tiffany; Garba, Adinoyi; Banerjee, Sanjay; Middleton, Frank A.; Barrett, Donna; Barcza, Maureen; Banki, Katalin; Landas, Steve K.; Perl, Andras

    2009-01-01

    Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1–/– and Taldo1+/– mice spontaneously developed HCC, and Taldo1–/– mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1–/– livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced β-catenin phosphorylation and enhanced c-Jun expression in Taldo1–/– livers reflected adaptation to oxidative stress. Taldo1–/– hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1–/– mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency. PMID:19436114

  20. 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.

  1. Hydroalcoholic extract of Stevia rebaudiana bert. leaves and stevioside ameliorates lipopolysaccharide induced acute liver injury in rats.

    PubMed

    S, Latha; Chaudhary, Sheetal; R S, Ray

    2017-11-01

    Oxidative stress and hepatic inflammatory response is primarily implicated in the pathogenesis of LPS induced acute liver injury. Stevioside, a diterpenoidal glycoside isolated from the Stevia rebaudiana leaves, exerts potent anti-oxidant, anti-inflammatory and immunomodulatory activities. The present study was aimed to investigate the hepatoprotective effect of hydroalcoholic extract of Stevia rebaudiana leaves (STE EXT) and its major phytochemical constituent, stevioside (STE) in LPS induced acute liver injury. The hepatoprotective activity of STE EXT (500mg/kg p.o) and STE (250mg/kg p.o) was investigated in lipopolysaccharide (LPS 5mg/kg i.p.) induced acute liver injury in male wistar rats. Our results revealed that both STE EXT and STE treatment ameliorated LPS induced hepatic oxidative stress, evident from altered levels of reduced SOD, Catalase, GSH, MDA, NO. Histopathological observations revealed that both STE EXT and STE attenuated LPS induced structural changes and hepatocellular apoptosis providing additional evidence for its hepatoprotective effect. Further, STE EXT and STE significantly restored the elevated serum and tissue levels of AST and ALT in LPS treated rats. Furthermore, both STE EXT and STE rescued hepatocellular dysfunctions to normal by altering the level of proinflammatory cytokines such as TNF-α, IL-1β and IL-6 exhibiting its anti-inflammatory potential. In conclusion, both STE EXT and STE demonstrated excellent hepatoprotective effects against endotoxemia induced acute liver injury possibly through suppression of hepatic inflammatory response and oxidative stress, attributing to its medicinal importance in treating various liver ailments. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. N-Hydroxylation of 4-Aminobiphenyl by CYP2E1 Produces Oxidative Stress in a Mouse Model of Chemically Induced Liver Cancer

    PubMed Central

    Wang, Shuang; Sugamori, Kim S.; Tung, Aveline; McPherson, J. Peter; Grant, Denis M.

    2015-01-01

    4-Aminobiphenyl (ABP) is a trace component of cigarette smoke and hair dyes, a suspected human carcinogen and a potent rodent liver carcinogen. Postnatal exposure of mice to ABP results in a higher incidence of liver tumors in males than in females, paralleling the sex difference in human liver cancer incidence. A traditional model of ABP tumorigenesis involves initial CYP1A2-mediated N-hydroxylation, which eventually leads to production of mutagenic ABP-DNA adducts that initiate tumor growth. However, several studies have found no correlation between sex or CYP1A2 function and the DNA-damaging, mutagenic, or tumorigenic effects of ABP. Oxidative stress may be an important etiological factor for liver cancer, and it has also been linked to ABP exposure. The goals of this study were to identify novel enzyme(s) that contribute to ABP N-oxidation, and to investigate a potential role for oxidative stress in ABP liver tumorigenicity. Isozyme-selective inhibition experiments using liver microsomes from wild-type and genetically modified mice identified CYP2E1 as a major ABP N-hydroxylating enzyme. The N-hydroxylation of ABP by transiently expressed CYP2E1 produced oxidative stress in cultured mouse hepatoma cells. In vivo postnatal exposure of mice to a tumorigenic dose of ABP also produced oxidative stress in male wild-type mice, but not in male Cyp2e1(−/−) mice or in female mice. However, a stronger NRF2-associated antioxidant response was observed in females. Our results identify CYP2E1 as a novel ABP-N-oxidizing enzyme, and suggest that sex differences in CYP2E1-dependent oxidative stress and antioxidant responses to ABP may contribute to the observed sex difference in tumor incidence. PMID:25601990

  3. Mechanism for Prevention of Alcohol-Induced Liver Injury by Dietary Methyl Donors

    PubMed Central

    Powell, Christine L.; Bradford, Blair U.; Craig, Christopher Patrick; Tsuchiya, Masato; Uehara, Takeki; O’Connell, Thomas M.; Pogribny, Igor P.; Melnyk, Stepan; Koop, Dennis R.; Bleyle, Lisa; Threadgill, David W.; Rusyn, Ivan

    2010-01-01

    Alcohol-induced liver injury (ALI) has been associated with, among other molecular changes, abnormal hepatic methionine metabolism, resulting in decreased levels of S-adenosylmethionine (SAM). Dietary methyl donor supplements such as SAM and betaine mitigate ALI in animal models; however, the mechanisms of protection remain elusive. It has been suggested that methyl donors may act via attenuation of alcohol-induced oxidative stress. We hypothesized that the protective action of methyl donors is mediated by an effect on the oxidative metabolism of alcohol in the liver. Male C57BL/6J mice were administered a control high-fat diet or diet enriched in methyl donors with or without alcohol for 4 weeks using the enteral alcohol feeding model. As expected, attenuation of ALI and an increase in reduced glutathione:oxidized glutathione ratio were achieved with methyl donor supplementation. Interestingly, methyl donors led to a 35% increase in blood alcohol elimination rate, and while there was no effect on alcohol metabolism in the stomach, a profound effect on liver alcohol metabolism was observed. The catalase-dependent pathway of alcohol metabolism was induced, yet the increase in CYP2E1 activity by alcohol was blunted, which may be mitigating production of oxidants. Additional factors contributing to the protective effects of methyl donors in ALI were increased activity of low- and high-Km aldehyde dehydrogenases leading to lower hepatic acetaldehyde, maintenance of the efficient mitochondrial energy metabolism, and promotion of peroxisomal β-oxidation. Profound changes in alcohol metabolism represent additional important mechanism of the protective effect of methyl donors in ALI. PMID:20118189

  4. Loss of 5-lipoxygenase activity protects mice against paracetamol-induced liver toxicity.

    PubMed

    Pu, Shiyun; Ren, Lin; Liu, Qinhui; Kuang, Jiangying; Shen, Jing; Cheng, Shihai; Zhang, Yuwei; Jiang, Wei; Zhang, Zhiyong; Jiang, Changtao; He, Jinhan

    2016-01-01

    Paracetamol (acetaminophen) is the most widely used over-the-counter analgesic and overdosing with paracetamol is the leading cause of hospital admission for acute liver failure. 5-Lipoxygenase (5-LO) catalyses arachidonic acid to form LTs, which lead to inflammation and oxidative stress. In this study, we examined whether deletion or pharmacological inhibition of 5-LO could protect mice against paracetamol-induced hepatic toxicity. Both genetic deletion and pharmacological inhibition of 5-LO in C57BL/6J mice were used to study the role of this enzyme in paracetamol induced liver toxicity. Serum and tissue biochemistry, H&E staining, and real-time PCR were used to assess liver toxicity. Deletion or pharmacological inhibition of 5-LO in mice markedly ameliorated paracetamol-induced hepatic injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and hepatic centrilobular necrosis. The hepatoprotective effect of 5-LO inhibition was associated with induction of the antitoxic phase II conjugating enzyme, sulfotransferase2a1, suppression of the pro-toxic phase I CYP3A11 and reduction of the hepatic transporter MRP3. In 5-LO(-/-) mice, levels of GSH were increased, and oxidative stress decreased. In addition, PPAR α, a nuclear receptor that confers resistance to paracetamol toxicity, was activated in 5-LO(-/-) mice. The activity of 5-LO may play a critical role in paracetamol-induced hepatic toxicity by regulating paracetamol metabolism and oxidative stress. © 2015 The British Pharmacological Society.

  5. Hepatoprotective Effect of Citral on Acetaminophen-Induced Liver Toxicity in Mice

    PubMed Central

    Silva-Filho, Saulo Euclides; Cardia, Gabriel Fernando Esteves; Cremer, Edivaldo; Bersani-Amado, Ciomar Aparecida

    2017-01-01

    High doses of acetaminophen (APAP) lead to acute liver damage. In this study, we evaluated the effects of citral in a murine model of hepatotoxicity induced by APAP. The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) were determined to evaluate the hepatoprotective effects of citral. The livers were used to determine myeloperoxidase (MPO) activity and nitric oxide (NO) production and in histological analysis. The effect of citral on leukocyte migration and antioxidant activity was evaluated in vitro. Citral pretreatment decreased significantly the levels of ALT, AST, ALP, and γGT, MPO activity, and NO production. The histopathological analysis showed an improvement of hepatic lesions in mice after citral pretreatment. Citral inhibited neutrophil migration and exhibited antioxidant activity. Our results suggest that citral protects the liver against liver toxicity induced by APAP. PMID:28717379

  6. Human Umbilical Cord MSC-Derived Exosomes Suppress the Development of CCl4-Induced Liver Injury through Antioxidant Effect.

    PubMed

    Jiang, Wenqian; Tan, Youwen; Cai, Mengjie; Zhao, Ting; Mao, Fei; Zhang, Xu; Xu, Wenrong; Yan, Zhixin; Qian, Hui; Yan, Yongmin

    2018-01-01

    Mesenchymal stem cells (MSCs) have been increasingly applied into clinical therapy. Exosomes are small (30-100 nm in diameter) membrane vesicles released by different cell types and possess the similar functions with their derived cells. Human umbilical cord MSC-derived exosomes (hucMSC-Ex) play important roles in liver repair. However, the effects and mechanisms of hucMSC-Ex on liver injury development remain elusive. Mouse models of acute and chronic liver injury and liver tumor were induced by carbon tetrachloride (CCl 4 ) injection, followed by administration of hucMSC-Ex via the tail vein. Alleviation of liver injury by hucMSC-Ex was determined. We further explored the production of oxidative stress and apoptosis in the development of liver injury and compared the antioxidant effects of hucMSC-Ex with frequently used hepatic protectant, bifendate (DDB) in liver injury. hucMSC-Ex alleviated CCl 4 -induced acute liver injury and liver fibrosis and restrained the growth of liver tumors. Decreased oxidative stress and apoptosis were found in hucMSC-Ex-treated mouse models and liver cells. Compared to bifendate (DDB) treatment, hucMSC-Ex presented more distinct antioxidant and hepatoprotective effects. hucMSC-Ex may suppress CCl 4 -induced liver injury development via antioxidant potentials and could be a more effective antioxidant than DDB in CCl 4 -induced liver tumor development.

  7. Nonacetaminophen Drug-Induced Acute Liver Failure.

    PubMed

    Thomas, Arul M; Lewis, James H

    2018-05-01

    Acute liver failure of all causes is diagnosed in between 2000 and 2500 patients annually in the United States. Drug-induced acute liver failure is the leading cause of acute liver failure, accounting for more than 50% of cases. Nonacetaminophen drug injury represents 11% of all cases in the latest registry from the US Acute Liver Failure Study Group. Although rare, acute liver failure is clinically dramatic when it occurs, and requires a multidisciplinary approach to management. In contrast with acetaminophen-induced acute liver failure, non-acetaminophen-induced acute liver failure has a more ominous prognosis with a lower liver transplant-free survival. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. Cellular and molecular etiology of hepatocyte injury in a murine model of environmentally induced liver abnormality

    PubMed Central

    Al-Griw, M.A.; Alghazeer, R.O.; Al-Azreg, S.A.; Bennour, E.M.

    2016-01-01

    Exposures to a wide variety of environmental substances are negatively associated with many biological cell systems both in humans and rodents. Trichloroethane (TCE), a ubiquitous environmental toxicant, is used in large quantities as a dissolvent, metal degreaser, chemical intermediate, and component of consumer products. This increases the likelihood of human exposure to these compounds through dermal, inhalation and oral routes. The present in vivo study was aimed to investigate the possible cellular and molecular etiology of liver abnormality induced by early exposure to TCE using a murine model. The results showed a significant increase in liver weight. Histopathological examination revealed a TCE-induced hepatotoxicity which appeared as heavily congested central vein and blood sinusoids as well as leukocytic infiltration. Mitotic figures and apoptotic changes such as chromatin condensation and nuclear fragments were also identified. Cell death analysis demonstrates hepatocellular apoptosis was evident in the treated mice compared to control. TCE was also found to induce oxidative stress as indicated by an increase in the levels of lipid peroxidation, an oxidative stress marker. There was also a significant decrease in the DNA content of the hepatocytes of the treated groups compared to control. Agarose gel electrophoresis also provided further biochemical evidence of apoptosis by showing internucleosomal DNA fragmentation in the liver cells, indicating oxidative stress as the cause of DNA damage. These results suggest the need for a complete risk assessment of any new chemical prior to its arrival into the consumer market. PMID:27800299

  9. Hypoxis hemerocallidea Significantly Reduced Hyperglycaemia and Hyperglycaemic-Induced Oxidative Stress in the Liver and Kidney Tissues of Streptozotocin-Induced Diabetic Male Wistar Rats

    PubMed Central

    Oguntibeju, Oluwafemi O.; Meyer, Samantha; Aboua, Yapo G.; Goboza, Mediline

    2016-01-01

    Background. Hypoxis hemerocallidea is a native plant that grows in the Southern African regions and is well known for its beneficial medicinal effects in the treatment of diabetes, cancer, and high blood pressure. Aim. This study evaluated the effects of Hypoxis hemerocallidea on oxidative stress biomarkers, hepatic injury, and other selected biomarkers in the liver and kidneys of healthy nondiabetic and streptozotocin- (STZ-) induced diabetic male Wistar rats. Materials and Methods. Rats were injected intraperitoneally with 50 mg/kg of STZ to induce diabetes. The plant extract-Hypoxis hemerocallidea (200 mg/kg or 800 mg/kg) aqueous solution was administered (daily) orally for 6 weeks. Antioxidant activities were analysed using a Multiskan Spectrum plate reader while other serum biomarkers were measured using the RANDOX chemistry analyser. Results. Both dosages (200 mg/kg and 800 mg/kg) of Hypoxis hemerocallidea significantly reduced the blood glucose levels in STZ-induced diabetic groups. Activities of liver enzymes were increased in the diabetic control and in the diabetic group treated with 800 mg/kg, whereas the 200 mg/kg dosage ameliorated hepatic injury. In the hepatic tissue, the oxygen radical absorbance capacity (ORAC), ferric reducing antioxidant power (FRAP), catalase, and total glutathione were reduced in the diabetic control group. However treatment with both doses improved the antioxidant status. The FRAP and the catalase activities in the kidney were elevated in the STZ-induced diabetic group treated with 800 mg/kg of the extract possibly due to compensatory responses. Conclusion. Hypoxis hemerocallidea demonstrated antihyperglycemic and antioxidant effects especially in the liver tissue. PMID:27403200

  10. Sulforaphane Induces Nrf2 and Protects Against CYP2E1-dependent Binge Alcohol –induced Liver Steatosis

    PubMed Central

    Zhou, Richard; Lin, Jianjun; Wu, Defeng

    2013-01-01

    Background The mechanism(s) by which alcohol causes cell injury are still not clear but a major mechanism appears to be the role of lipid peroxidation and oxidative stress in alcohol toxicity. CYP2E1-generated ROS contributes to the ethanol-induced oxidant stress and inhibition of CYP2E1 activity decreases ethanol-induced fatty liver. The transcription factor Nrf2 regulates the expression of many cytoprotective enzymes which results in cellular protection against a variety of toxins. Method The current study was designed to evaluate the ability of sulforaphane, an activator of Nrf2, to blunt CYP2E1-dependent, ethanol-induced steatosis in vivo and in vitro. Results The sulforaphane treatment activated Nrf2, increased levels of the Nrf2 target heme oxygenase -1 and subsequently lowered oxidant stress as shown by the decline in lipid peroxidation and 3-Nitrotyrosine protein adducts and an increase in GSH levels after the acute ethanol treatment. It decreased ethanol-elevated liver levels of triglycerides and cholesterol and Oil Red O staining. Similar results were found in vitro as addition of sulforaphane to HepG2 E47 cells, which express CYP2E1, elevated Nrf2 levels and decreased the accumulation of lipid in cells cultured with ethanol. Sulforaphane treatment had no effect on levels of or activity of CYP2E1. Conclusions Sulforaphane proved to be an effective in vivo inhibitor of acute ethanol–induced fatty liver in mice. General significance The possible amelioration of liver injury which occurs under these conditions by chemical activators of Nrf2 is of clinical relevance and worthy of further study. PMID:24060752

  11. Role of nicotinamide (vitamin B3) in acetaminophen-induced changes in rat liver: Nicotinamide effect in acetaminophen-damged liver.

    PubMed

    Mahmoud, Yomna I; Mahmoud, Asmaa A

    2016-06-01

    Acetaminophen is a widely used analgesic and antipyretic agent, which is safe at therapeutic doses. However, overdoses of acetaminophen induce severe oxidative stress, which leads to acute liver failure. Nicotinamide has proven effective in ameliorating many pathological conditions that occur due to oxidative stress. This study verifies the prophylactic and therapeutic effects of nicotinamide against the hepatic pathophysiological and ultrastructural alterations induced by acetaminophen. Wistar rats intoxicated with an acute overdose of acetaminophen (5g/kg b.wt) were given a single dose of nicotinamide (500mg/kg b.wt) either before or after intoxication. Acetaminophen caused significant elevation in the liver functions and lipid peroxidation marker, and decline in the activities of the hepatic antioxidant enzymes. This oxidative injury was associated with hepatic centrilobular necrosis, hemorrage, vacuolar degeneration, lipid accumulation and mitochondrial alterations. Treating intoxicated rats with nicotinamide (500mg/kg) significantly ameliorated acetaminophen-induced biochemical changes and pathological injuries. However, administering the same dose of nicotinamide to healthy animals or prior to acetaminophen-intoxication induced hepatotoxicity. Caution should be taken when administering high doses of NAM because of its possible hepatotoxicity. Considering the wide use of nicotinamide, there is an important need for monitoring nicotinamide tolerance, safety and efficacy in healthy and diseased subjects. Copyright © 2016 Elsevier GmbH. All rights reserved.

  12. Baicalin Ameliorates Liver Injury Induced by Chronic plus Binge Ethanol Feeding by Modulating Oxidative Stress and Inflammation via CYP2E1 and NRF2 in Mice

    PubMed Central

    He, Ping; Wu, Yafeng; Shun, Jianchao; Liang, Yaodong; Cheng, Mingliang

    2017-01-01

    Alcoholic liver injury leads to serious complication including death. The potential role of baicalin at the transcription level in mice model of alcohol injury is not known yet. In this study, we examined the effect of baicalin against chronic plus binge ethanol model in mice and understanding the mechanism of protection. Liver function, histology, steatosis, inflammation, NF-κB activity, oxidative stress sources, nuclear translocation of NRF2 transcription factor, and cell death were assessed. Treatment with baicalin ameliorated ethanol-induced oxidative stress, inflammation, and cell death. Baicalin attenuated ethanol-induced proinflammatory molecules such as TNF-α, IL-1β, MIP-2, and MCP-1 and reversed redox-sensitive transcription factor NF-κB activation. Baicalin also modulated Kupffer cell activation in vitro. Baicalin inhibited ethanol-induced expression of reactive oxygen species (ROS) generating enzymes NOX2, p67phox, xanthine oxidase, and iNOS in addition to CYP2E1 activities. Baicalin also enhanced ethanol-induced NRF2 nuclear translocation and increased downstream target gene HO-1 as antioxidant defense. Finally, baicalin reduced significant apoptotic and necrotic cell death. Our study suggests that baicalin ameliorates chronic plus binge ethanol-induced liver injury involving molecular crosstalk of multiple pathways at the transcriptional level and through upregulation of antioxidant defense mechanism. PMID:28951767

  13. Filipendula ulmaria extracts attenuate cisplatin-induced liver and kidney oxidative stress in rats: In vivo investigation and LC-MS analysis.

    PubMed

    Katanić, Jelena; Matić, Sanja; Pferschy-Wenzig, Eva-Maria; Kretschmer, Nadine; Boroja, Tatjana; Mihailović, Vladimir; Stanković, Vesna; Stanković, Nevena; Mladenović, Milan; Stanić, Snežana; Mihailović, Mirjana; Bauer, Rudolf

    2017-01-01

    Filipendula ulmaria, known as meadowsweet, is a perennial herb found in wild and cultivated habitats in Europe and Asia. Usage of F. ulmaria in traditional medicine is based on diuretic, astringent, antirheumatic, and anti-inflammatory properties of this plant. Exposure to cisplatin at a dose of 7.5 mg/kg caused significant increase in serum parameters of liver and kidneys function and tissue oxidative stress markers along with some histopathological changes in liver and kidney tissues of experimental rats, as well as high level of genotoxicity. Administration of F. ulmaria extracts in three different concentrations (100, 200, and 400 mg/kg/day) for 10 days resulted in a reduction of oxidative stress in tissues and decrease of serum parameters. Moreover, tested extracts attenuated the genotoxicity of cisplatin in reverse dose-dependent manner. F. ulmaria extracts had no in vitro cytotoxic activity at all applied concentrations (IC 50  > 50 μg/mL). Tested extracts, rich in polyphenolic compounds, attenuate cisplatin-induced liver and kidney oxidative stress, reduce tissue damage, and enhance the antioxidative status of experimental animals during cisplatin application. Therefore, F. ulmaria extracts may be used as supportive agent for the prevention and amelioration of cisplatin side effects. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. New Insights into the Pathogenesis of Alcohol-Induced ER Stress and Liver Diseases.

    PubMed

    Ji, Cheng

    2014-01-01

    Alcohol-induced liver disease increasingly contributes to human mortality worldwide. Alcohol-induced endoplasmic reticulum (ER) stress and disruption of cellular protein homeostasis have recently been established as a significant mechanism contributing to liver diseases. The alcohol-induced ER stress occurs not only in cultured hepatocytes but also  in vivo  in the livers of several species including mouse, rat, minipigs, zebrafish, and humans. Identified causes for the ER stress include acetaldehyde, oxidative stress, impaired one carbon metabolism, toxic lipid species, insulin resistance, disrupted calcium homeostasis, and aberrant epigenetic modifications. Importance of each of the causes in alcohol-induced liver injury depends on doses, duration and patterns of alcohol exposure, genetic disposition, environmental factors, cross-talks with other pathogenic pathways, and stages of liver disease. The ER stress may occur more or less all the time during alcohol consumption, which interferes with hepatic protein homeostasis, proliferation, and cell cycle progression promoting development of advanced liver diseases. Emerging evidence indicates that long-term alcohol consumption and ER stress may directly be involved in hepatocellular carcinogenesis (HCC). Dissecting ER stress signaling pathways leading to tumorigenesis will uncover potential therapeutic targets for intervention and treatment of human alcoholics with liver cancer.

  15. Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis.

    PubMed

    Dong, Shu; Chen, Qi-Long; Song, Ya-Nan; Sun, Yang; Wei, Bin; Li, Xiao-Yan; Hu, Yi-Yang; Liu, Ping; Su, Shi-Bing

    2016-01-01

    The classic toxicity of carbon tetrachloride (CCl4) is to induce liver lesion and liver fibrosis. Liver fibrosis is a consequence of chronic liver lesion, which can progress into liver cirrhosis even hepatocarcinoma. However, the toxicological mechanisms of CCl4-induced liver fibrosis remain not fully understood. We combined transcriptomic and proteomic analysis and biological network technology, predicted toxicological targets and regulatory networks of CCl4 in liver fibrosis. Wistar rats were treated with CCl4 for 9 weeks. Histopathological changes, hydroxyproline (Hyp) contents, serum ALT and AST in the CCl4-treated group were significantly higher than that of CCl4-untreated group. CCl4-treated and -untreated liver tissues were examined by microarray and iTRAQ. The results showed that 3535 genes (fold change ≥ 1.5, P < 0.05) and 1412 proteins (fold change ≥ 1.2, P < 0.05) were differentially expressed. Moreover, the integrative analysis of transcriptomics and proteomics data showed 523 overlapped proteins, enriched in 182 GO terms including oxidation reduction, response to oxidative stress, inflammatory response, extracellular matrix organization, etc. Furthermore, KEGG pathway analysis showed that 36 pathways including retinol metabolism, PPAR signaling pathway, glycolysis/gluconeogenesis, arachidonic acid metabolism, metabolism of xenobiotics by cytochrome P450 and drug metabolism. Network of protein-protein interaction (PPI) and key function with their related targets were performed and the degree of network was calculated with Cytoscape. The expression of key targets such as CYP4A3, ALDH2 and ALDH7A1 decreased after CCl4 treatment. Therefore, the toxicological mechanisms of CCl4-induced liver fibrosis may be related with multi biological process, pathway and targets which may provide potential protection reaction mechanism for CCl4 detoxication in the liver.

  16. Drug-induced Liver Injury

    PubMed Central

    David, Stefan; Hamilton, James P

    2011-01-01

    Drug-induced liver injury (DILI) is common and nearly all classes of medications can cause liver disease. Most cases of DILI are benign, and improve after drug withdrawal. It is important to recognize and remove the offending agent as quickly as possible to prevent the progression to chronic liver disease and/or acute liver failure. There are no definite risk factors for DILI, but pre-existing liver disease and genetic susceptibility may predispose certain individuals. Although most patients have clinical symptoms that are identical to other liver diseases, some patients may present with symptoms of systemic hypersensitivity. Treatment of drug and herbal-induced liver injury consists of rapid drug discontinuation and supportive care targeted to alleviate unwanted symptoms. PMID:21874146

  17. ARGININOSUCCINATE SYNTHASE CONDITIONS THE RESPONSE TO ACUTE AND CHRONIC ETHANOL-INDUCED LIVER INJURY IN MICE

    PubMed Central

    Yan, Wei; Morón-Concepción, Jose A.; Ward, Stephen C.; Ge, Xiaodong; de la Rosa, Laura Conde; Nieto, Natalia

    2012-01-01

    Background and Aim Argininosuccinate synthase (ASS) is the rate-limiting enzyme in both the urea and the l-citrulline/nitric oxide (NO·) cycles regulating protein catabolism, ammonia levels and NO· generation (1-2). Since a proteomics analysis identified ASS and nitric oxide synthase-2 (NOS2) as co-induced in rat hepatocytes by chronic ethanol consumption, which also occurred in alcoholic liver disease (ALD) and in cirrhotic patients, we hypothesized that ASS could play a role in ethanol binge and chronic ethanol-induced liver damage. Methods To investigate the contribution of ASS to the pathophysiology of ALD, wild-type (WT) and Ass+/− mice (Ass−/− are lethal due to hyperammonemia) were exposed to an ethanol binge or to chronic ethanol drinking. Results Compared with WT, Ass+/− mice given an ethanol binge exhibited decreased steatosis, lower NOS2 induction and less 3-nitrotyrosine (3-NT) protein residues, indicating that reducing nitrosative stress via the l-citrulline/NO· pathway plays a significant role in preventing liver damage. However, chronic ethanol treated Ass+/− mice displayed enhanced liver injury compared with WT mice. This was due to hyperammonemia, lower phosphorylated AMP-activated protein kinase (pAMPKα) to total AMPKα ratio, decreased sirtuin (Sirt-1) and peroxisomal proliferator-activated receptor coactivator-1α (Pgc1α) mRNAs, lower fatty acid β-oxidation due to down-regulation of carnitine palmitoyl transferase-II (CPT-II), decreased antioxidant defense and elevated lipid peroxidation end-products in spite of comparable nitrosative stress but likely reduced NOS3. Conclusion Partial Ass ablation protects only in acute ethanol-induced liver injury by decreasing nitrosative stress but not in a more chronic scenario where oxidative stress and impaired fatty acid β-oxidation are key events. PMID:22213272

  18. Reperfusion does not induce oxidative stress but sustained endoplasmic reticulum stress in livers of rats subjected to traumatic-hemorrhagic shock.

    PubMed

    Duvigneau, Johanna Catharina; Kozlov, Andrey V; Zifko, Clara; Postl, Astrid; Hartl, Romana T; Miller, Ingrid; Gille, Lars; Staniek, Katrin; Moldzio, Rudolf; Gregor, Wolfgang; Haindl, Susanne; Behling, Tricia; Redl, Heinz; Bahrami, Soheyl

    2010-03-01

    Oxidative stress is believed to accompany reperfusion and to mediate dysfunction of the liver after traumatic-hemorrhagic shock (THS). Recently, endoplasmic reticulum (ER) stress has been suggested as an additional factor. This study investigated whether reperfusion after THS leads to increased oxidative and/or ER stress in the liver. In a rat model, including laparotomy, bleeding until decompensation, followed by inadequate or adequate reperfusion phase, three time points were investigated: 40 min, 3 h, and 18 h after shock. The reactive oxygen and nitrogen species and its scavenging capacity (superoxide dismutase 2), the nitrotyrosine formation in proteins, and the lipid peroxidation together with the status of endogenous antioxidants (alpha-tocopherylquinone-alpha-tocopherol ratio) were investigated as markers for oxidative or nitrosylative stress. Mitochondrial function and cytochrome P450 isoform 1A1 activity were analyzed as representatives for hepatocyte function. Activation of the inositol-requiring enzyme 1/X-box binding protein pathway and up-regulation of the 78-kDa glucose-regulated protein were recorded as ER stress markers. Plasma levels of alanine aminotransferase and Bax/Bcl-XL messenger RNA (mRNA) ratio were used as indicators for hepatocyte damage and apoptosis induction. Oxidative or nitrosylative stress markers or representatives of hepatocyte function were unchanged during and short after reperfusion (40 min, 3 h after shock). In contrast, ER stress markers were elevated and paralleled those of hepatocyte damage. Incidence for sustained ER stress and subsequent apoptosis induction were found at 18 h after shock. Thus, THS or reperfusion induces early and persistent ER stress of the liver, independent of oxidative or nitrosylative stress. Although ER stress was not associated with depressed hepatocyte function, it may act as an early trigger of protracted cell death, thereby contributing to delayed organ failure after THS.

  19. Effects of isoquinoline alkaloid berberine on lipid peroxidation, antioxidant defense system, and liver damage induced by lead acetate in rats.

    PubMed

    Hasanein, Parisa; Ghafari-Vahed, Masumeh; Khodadadi, Iraj

    2017-01-01

    Liver is considered a target organ affected by lead toxicity. Oxidative stress is among the mechanisms involved in liver damage. Here we investigated the effects of the natural alkaloid berberine on oxidative stress and hepatotoxicity induced by lead in rats. Animals received an aqueous solution of lead acetate (500 mg Pb/l in the drinking water) and/or daily oral gavage of berberine (50 mg/kg) for 8 weeks. Rats were then weighed and used for the biochemical, molecular, and histological evaluations. Lead-induced oxidative stress, shown by increasing lipid peroxidation along with a concomitant decrease in hepatic levels of thiol groups, total antioxidant capacity, the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase, and reduced versus oxidized glutathione ratio. Berberine corrected all the disturbances in oxidative stress markers induced by lead administration. Berberine also prevented the elevated levels of enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) and the decrease in body weight and albumin. The protective effects of berberine were comparable with silymarin. Furthermore, berberine attenuated liver damage, shown by decreased necrosis and inflammatory cell infiltration. Berberine represents a potential therapeutic option against lead-induced hepatotoxicity through inhibiting lipid peroxidation and enhancing antioxidant defenses. Berberine exerted protective effects on lead-induced oxidative stress and hepatotoxicity in rats.

  20. Cannabidiol attenuates alcohol-induced liver steatosis, metabolic dysregulation, inflammation and neutrophil-mediated injury.

    PubMed

    Wang, Yuping; Mukhopadhyay, Partha; Cao, Zongxian; Wang, Hua; Feng, Dechun; Haskó, György; Mechoulam, Raphael; Gao, Bin; Pacher, Pal

    2017-09-21

    Cannabidiol (CBD) is a non-psychoactive component of marijuana, which has anti-inflammatory effects. It has also been approved by FDA for various orphan diseases for exploratory trials. Herein, we investigated the effects of CBD on liver injury induced by chronic plus binge alcohol feeding in mice. CBD or vehicle was administered daily throughout the alcohol feeding study. At the conclusion of the feeding protocol, serums samples, livers or isolated neutrophils were utilized for molecular biology, biochemistry and pathology analysis. CBD significantly attenuated the alcohol feeding-induced serum transaminase elevations, hepatic inflammation (mRNA expressions of TNFα, MCP1, IL1β, MIP2 and E-Selectin, and neutrophil accumulation), oxidative/nitrative stress (lipid peroxidation, 3-nitrotyrosine formation, and expression of reactive oxygen species generating enzyme NOX2). CBD treatment also attenuated the respiratory burst of neutrophils isolated from chronic plus binge alcohol fed mice or from human blood, and decreased the alcohol-induced increased liver triglyceride and fat droplet accumulation. Furthermore, CBD improved alcohol-induced hepatic metabolic dysregulation and steatosis by restoring changes in hepatic mRNA or protein expression of ACC-1, FASN, PPARα, MCAD, ADIPOR-1, and mCPT-1. Thus, CBD may have therapeutic potential in the treatment of alcoholic liver diseases associated with inflammation, oxidative stress and steatosis, which deserves exploration in human trials.

  1. 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

  2. Preventive effects of indole-3-carbinol against alcohol-induced liver injury in mice via antioxidant, anti-inflammatory, and anti-apoptotic mechanisms: Role of gut-liver-adipose tissue axis.

    PubMed

    Choi, Youngshim; Abdelmegeed, Mohamed A; Song, Byoung-Joon

    2018-05-01

    Indole-3-carbinol (I3C), found in Brassica family vegetables, exhibits antioxidant, anti-inflammatory, and anti-cancerous properties. Here, we aimed to evaluate the preventive effects of I3C against ethanol (EtOH)-induced liver injury and study the protective mechanism(s) by using the well-established chronic-plus-binge alcohol exposure model. The preventive effects of I3C were evaluated by conducting various histological, biochemical, and real-time PCR analyses in mouse liver, adipose tissue, and colon, since functional alterations of adipose tissue and intestine can also participate in promoting EtOH-induced liver damage. Daily treatment with I3C alleviated EtOH-induced liver injury and hepatocyte apoptosis, but not steatosis, by attenuating elevated oxidative stress, as evidenced by the decreased levels of hepatic lipid peroxidation, hydrogen peroxide, CYP2E1, NADPH-oxidase, and protein acetylation with maintenance of mitochondrial complex I, II, and III protein levels and activities. I3C also restored the hepatic antioxidant capacity by preventing EtOH-induced suppression of glutathione contents and mitochondrial aldehyde dehydrogenase-2 activity. I3C preventive effects were also achieved by attenuating the increased levels of hepatic proinflammatory cytokines, including IL1β, and neutrophil infiltration. I3C also attenuated EtOH-induced gut leakiness with decreased serum endotoxin levels through preventing EtOH-induced oxidative stress, apoptosis of enterocytes, and alteration of tight junction protein claudin-1. Furthermore, I3C alleviated adipose tissue inflammation and decreased free fatty acid release. Collectively, I3C prevented EtOH-induced liver injury via attenuating the damaging effect of ethanol on the gut-liver-adipose tissue axis. Therefore, I3C may also have a high potential for translational research in treating or preventing other types of hepatic injury associated with oxidative stress and inflammation. Copyright © 2017 Elsevier Inc. All

  3. Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction.

    PubMed

    La Mura, Vincenzo; Pasarín, Marcos; Meireles, Cintia Z; Miquel, Rosa; Rodríguez-Vilarrupla, Aina; Hide, Diana; Gracia-Sancho, Jorge; García-Pagán, Juan Carlos; Bosch, Jaime; Abraldes, Juan G

    2013-03-01

    Endothelial dysfunction drives vascular derangement and organ failure associated with sepsis. However, the consequences of sepsis on liver sinusoidal endothelial function are largely unknown. Statins might improve microvascular dysfunction in sepsis. The present study explores liver vascular abnormalities and the effects of statins in a rat model of endotoxemia. For this purpose, lipopolysaccharide (LPS) or saline was given to: (1) rats treated with placebo; (2) rats treated with simvastatin (25 mg/kg, orally), given at 3 and 23 hours after LPS/saline challenge; (3) rats treated with simvastatin (25 mg/kg/24 h, orally) from 3 days before LPS/saline injection. Livers were isolated and perfused and sinusoidal endothelial function was explored by testing the vasodilation of the liver circulation to increasing concentrations of acetylcholine. The phosphorylated endothelial nitric oxide synthase (PeNOS)/endothelial nitric oxide synthase (eNOS) ratio was measured as a marker of eNOS activation. LPS administration induced an increase in baseline portal perfusion pressure and a decrease in vasodilation to acetylcholine (sinusoidal endothelial dysfunction). This was associated with reduced eNOS phosphorylation and liver inflammation. Simvastatin after LPS challenge did not prevent the increase in baseline portal perfusion pressure, but attenuated the development of sinusoidal endothelial dysfunction. Treatment with simvastatin from 3 days before LPS prevented the increase in baseline perfusion pressure and totally normalized the vasodilating response of the liver vasculature to acetylcholine and reduced liver inflammation. Both protocols of treatment restored a physiologic PeNOS/eNOS ratio. LPS administration induces intrahepatic endothelial dysfunction that might be prevented by simvastatin, suggesting that statins might have potential for liver protection during endotoxemia. Copyright © 2012 American Association for the Study of Liver Diseases.

  4. Fish oil prevents sucrose-induced fatty liver but exacerbates high-safflower oil-induced fatty liver in ddy mice.

    PubMed

    Yamazaki, Tomomi; Nakamori, Akiko; Sasaki, Eriko; Wada, Satoshi; Ezaki, Osamu

    2007-12-01

    Diets high in sucrose/fructose or fat can result in hepatic steatosis (fatty liver). We analyzed the effects of dietary fish oil on fatty liver induced by sucrose, safflower oil, and butter in ddY mice. In experiment I, mice were fed a high-starch diet [70 energy% (en%) starch] plus 20% (wt/wt) sucrose in the drinking water or fed a high-safflower oil diet (60 en%) for 11 weeks. As a control, mice were fed a high-starch diet with drinking water. Fish oil (10 en%) was either supplemented or not. Mice supplemented with sucrose or fed safflower oil showed a 1.7-fold or 2.2-fold increased liver triglyceride content, respectively, compared with that of control mice. Fish oil completely prevented sucrose-induced fatty liver, whereas it exacerbated safflower oil-induced fatty liver. Sucrose increased SREBP-1c and target gene messenger RNAs (mRNAs), and fish oil completely inhibited these increases. In experiment II, mice were fed a high-safflower oil or a high-butter diet, with or without fish oil supplementation. Fish oil exacerbated safflower oil-induced fatty liver but did not affect butter-induced fatty liver. Fish oil increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and target CD36 mRNA in safflower oil-fed mice. These increases were not observed in sucrose-supplemented or butter-fed mice. The effects of dietary fish oil on fatty liver differ according to the cause of fatty liver; fish oil prevents sucrose-induced fatty liver but exacerbates safflower oil-induced fatty liver. The exacerbation of fatty liver may be due, at least in part, to increased expression of liver PPARgamma.

  5. Ellagic and ferulic acids alleviate gamma radiation and aluminium chloride-induced oxidative damage.

    PubMed

    Salem, Ahmed M; Mohammaden, Tarek F; Ali, Mohamed A M; Mohamed, Enas A; Hasan, Hesham F

    2016-09-01

    Ionizing radiation interacts with biological systems through the generation of free radicals, which induce oxidative stress. Aluminium (Al) can negatively impact human health by direct interaction with antioxidant enzymes. Ellagic acid (EA) and Ferulic acid (FA) are plant polyphenolic compounds, have gained attention due to their multiple biological activities. To date, no studies investigating the antioxidant effect of EA/FA in a model involving both γ radiation and aluminium chloride (AlCl3) have been reported. Herein, we investigated the protective effect of EA and FA against oxidative stress induced by γ radiation and AlCl3 in rats. Rats were divided into thirteen groups: a negative control group, 3 positive control groups (γ-irradiated, AlCl3-treated and γ-irradiated+AlCl3-treated) and 9 groups (3 γ-irradiated, 3 AlCl3-treated and 3 γ-irradiated+AlCl3-treated) treated with EA and/or FA. Liver function and lipid profile were assessed. Levels of lipid peroxidation, protein oxidation and endogenous antioxidants as well as the concentrations of copper, iron and zinc were estimated in liver tissue homogenate. Furthermore, liver tissue sections were histologically examined. Oral administration of EA and/or FA resulted in 1) amelioration of AlCl3 and/or γ-radiation-induced hepatic function impairment, dyslipidemia and hepatic histological alterations; 2) reduction in liver MDA and PCC levels; 3) elevation of liver CAT, GPx and SOD activity as well as GSH level; 4) elevation in liver Cu concentrations which was accompanied by a reduction in Fe and Zn concentrations. Oral administration of EA and/or FA may be useful for ameliorating γ radiation and/or AlCl3-induced oxidative damage. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Ethanol and liver: Recent insights into the mechanisms of ethanol-induced fatty liver

    PubMed Central

    Liu, Jinyao

    2014-01-01

    Alcoholic fatty liver disease (AFLD), a potentially pathologic condition, can progress to steatohepatitis, fibrosis, and cirrhosis, leading to an increased probability of hepatic failure and death. Alcohol induces fatty liver by increasing the ratio of reduced form of nicotinamide adenine dinucleotide to oxidized form of nicotinamide adenine dinucleotide in hepatocytes; increasing hepatic sterol regulatory element-binding protein (SREBP)-1, plasminogen activator inhibitor (PAI)-1, and early growth response-1 activity; and decreasing hepatic peroxisome proliferator-activated receptor-α activity. Alcohol activates the innate immune system and induces an imbalance of the immune response, which is followed by activated Kupffer cell-derived tumor necrosis factor (TNF)-α overproduction, which is in turn responsible for the changes in the hepatic SREBP-1 and PAI-1 activity. Alcohol abuse promotes the migration of bone marrow-derived cells (BMDCs) to the liver and then reprograms TNF-α expression from BMDCs. Chronic alcohol intake triggers the sympathetic hyperactivity-activated hepatic stellate cell (HSC) feedback loop that in turn activates the HSCs, resulting in HSC-derived TNF-α overproduction. Carvedilol may block this feedback loop by suppressing sympathetic activity, which attenuates the progression of AFLD. Clinical studies evaluating combination therapy of carvedilol with a TNF-α inhibitor to treat patients with AFLD are warranted to prevent the development of alcoholic liver disease. PMID:25356030

  7. 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

  8. 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.

  9. Inhibition of EGFR attenuates fibrosis and stellate cell activation in diet-induced model of nonalcoholic fatty liver disease.

    PubMed

    Liang, Dandan; Chen, Hongjin; Zhao, Leping; Zhang, Wenxin; Hu, Jie; Liu, Zhiguo; Zhong, Peng; Wang, Wei; Wang, Jingying; Liang, Guang

    2018-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD begins with steatosis and advances to nonalcoholic steatohepatitis (NASH) and cirrhosis. The molecular mechanisms involved in NAFLD progression are not understood. Based on recent studies showing dysregulation of epidermal growth factor receptor (EGFR) in animal models of liver injury, we sought to determine if inhibition of EGFR mitigates liver fibrosis and HSC activation in NAFLD. We utilized the high fat diet (HFD)-induced murine model of liver injury to study the role of EGFR in NAFLD. The lipid accumulation, oxidative stress, hepatic stellate cell (HSC) activation and matrix deposition were examined in the liver tissues. We also evaluated the EGFR signaling pathway, ROS activation and pro-fibrogenic phenotype in oxidized low density lipoproteins (ox-LDL) challenged cultured HSCs. We demonstrate that EGFR was phosphorylated in liver tissues of HFD murine model of NAFLD. Inhibition of EGFR prevented diet-induced lipid accumulation, oxidative stress, and HSC activation and matrix deposition. In cultured HSCs, we show that ox-LDL caused rapid activation of the EGFR signaling pathway and induce the production of reactive oxygen species. EGFR also mediated HSC activation and promoted a pro-fibrogenic phenotype. In conclusion, our data demonstrate that EGFR plays an important role in NAFLD and is an attractive target for NAFLD therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Protective effect of oligomeric proanthocyanidins against alcohol-induced liver steatosis and injury in mice.

    PubMed

    Wang, Zhiguo; Su, Bo; Fan, Sumei; Fei, Haixia; Zhao, Wei

    2015-03-20

    The long-term consumption of alcohol has been associated with multiple pathologies at all levels, such as alcoholism, chronic pancreatitis, malnutrition, alcoholic liver disease (ALD) and cancer. In the current study, we investigated the protective effect of oligomeric proanthocyanidins (OPC) against alcohol-induced liver steatosis and injury and the possible mechanisms using ethanol-induced chronic liver damage mouse models. The results showed that OPC significantly improved alcohol-induced dyslipidemia and alleviated liver steatosis by reducing levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total triglyceride (TG), total cholesterol (TC), low-density cholesterol (LDL-c) and liver malondialdehyde (MDA), and increasing levels of serum high-density lipoprotein (HDL-c), liver superoxide dismutase (SOD). Further investigation indicated that OPC markedly decreased the expressions of lipid synthesis genes and inflammation genes such as sterol regulatory element-binding protein-1c (Srebp-1c), protein-2 (Srebp2), interleukin IL-1β, IL-6 and TNF-α. Furthermore, AML-12 cells line was used to investigate the possible mechanisms which indicated that OPC might alleviate liver steatosis and damage through AMP-activated protein kinase (AMPK) activation involving oxidative stress. In conclusion, our study demonstrated excellent protective effect of OPC against alcohol-induced liver steatosis and injury, which could a potential drug for the treatment of alcohol-induced liver injury in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Cajanus cajan Linn. (Leguminosae) prevents alcohol-induced rat liver damage and augments cytoprotective function.

    PubMed

    Kundu, Rakesh; Dasgupta, Suman; Biswas, Anindita; Bhattacharya, Anirban; Pal, Bikas C; Bandyopadhyay, Debashis; Bhattacharya, Shelley; Bhattacharya, Samir

    2008-08-13

    Cajanus cajan Linn. (Leguminosae) is a nontoxic edible herb, widely used in Indian folk medicine for the prevention of various liver disorders. In the present study we have demonstrated that methanol-aqueous fraction (MAF2) of Cajanus cajan leaf extract could prevent the chronically treated alcohol induced rat liver damage. Chronic doses of alcohol (3.7 g/ kg) orally administered to rats for 28 days and liver function marker enzymes such as GPT, GOT, ALP and anti-oxidant enzyme activities were determined. Effect of MAF2 at a dose of 50mg/kg body weight on alcohol treated rats was noted. Alcohol effected significant increase in liver marker enzyme activities and reduced the activities of anti-oxidant enzymes. Co-administration of MAF2 reversed the liver damage due to alcohol; it decreased the activities of liver marker enzymes and augmented antioxidant enzyme activities. We also demonstrate significant decrease of the phase II detoxifying enzyme, UDP-glucuronosyl transferase (UGT) activity along with a three- and two-fold decrease of UGT2B gene and protein expression respectively. MAF2 co-administration normalized UGT activity and revived the expression of UGT2B with a concomitant expression and nuclear translocation of Nrf2, a transcription factor that regulates the expression of many cytoprotective genes. Cajanus cajan extract therefore shows a promise in therapeutic use in alcohol induced liver dysfunction.

  12. Coconut water vinegar ameliorates recovery of acetaminophen induced liver damage in mice.

    PubMed

    Mohamad, Nurul Elyani; Yeap, Swee Keong; Beh, Boon-Kee; Ky, Huynh; Lim, Kian Lam; Ho, Wan Yong; Sharifuddin, Shaiful Adzni; Long, Kamariah; Alitheen, Noorjahan Banu

    2018-06-25

    Coconut water has been commonly consumed as a beverage for its multiple health benefits while vinegar has been used as common seasoning and a traditional Chinese medicine. The present study investigates the potential of coconut water vinegar in promoting recovery on acetaminophen induced liver damage. Mice were injected with 250 mg/kg body weight acetaminophen for 7 days and were treated with distilled water (untreated), Silybin (positive control) and coconut water vinegar (0.08 mL/kg and 2 mL/kg body weight). Level of oxidation stress and inflammation among treated and untreated mice were compared. Untreated mice oral administrated with acetaminophen were observed with elevation of serum liver profiles, liver histological changes, high level of cytochrome P450 2E1, reduced level of liver antioxidant and increased level of inflammatory related markers indicating liver damage. On the other hand, acetaminophen challenged mice treated with 14 days of coconut water vinegar were recorded with reduction of serum liver profiles, improved liver histology, restored liver antioxidant, reduction of liver inflammation and decreased level of liver cytochrome P450 2E1 in dosage dependent level. Coconut water vinegar has helped to attenuate acetaminophen-induced liver damage by restoring antioxidant activity and suppression of inflammation.

  13. Metoprolol induces oxidative damage in common carp (Cyprinus carpio).

    PubMed

    Martínez-Rodríguez, Héctor; Donkor, Kingsley; Brewer, Sharon; Galar-Martínez, Marcela; SanJuan-Reyes, Nely; Islas-Flores, Hariz; Sánchez-Aceves, Livier; Elizalde-Velázquez, Armando; Gómez-Oliván, Leobardo Manuel

    2018-04-01

    During the last decade, β-blockers such as metoprolol (MTP) have been frequently detected in surface water, aquatic systems and municipal water at concentrations of ng/L to μg/L. Only a small number of studies exist on the toxic effects induced by this group of pharmaceuticals on aquatic organisms. Therefore, the present study aimed to evaluate the oxidative damage induced by MTP in the common carp Cyprinus carpio, using oxidative stress biomarkers. To this end, indicators of cellular oxidation such as hydroperoxide content (HPC), lipid peroxidation (LPX) and protein carbonyl content (PCC) were determined, as well as the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Also, concentrations of MTP and its metabolite O-desmethyl metoprolol were determined in water as well as carp gill, liver, kidney, brain and blood, along with the partial uptake pattern of these compounds. Results show that carp takes up MTP and its metabolite in the different organs evaluated, particularly liver and gill. The oxidative stress biomarkers, HPC, LPX, and PCC, as well as SOD and CAT activity all increased significantly at most exposure times in all organs evaluated. Results indicate that MTP and its metabolite induce oxidative stress on the teleost C. carpio and that the presence of these compounds may constitute a risk in water bodies for aquatic species. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. Environmentally toxicant exposures induced intragenerational transmission of liver abnormalities in mice

    PubMed Central

    Al-Griw, Mohamed A.; Treesh, Soad A.; Alghazeer, Rabia O.; Regeai, Sassia O.

    2017-01-01

    Environmental toxicants such as chemicals, heavy metals, and pesticides have been shown to promote transgenerational inheritance of abnormal phenotypes and/or diseases to multiple subsequent generations following parental and/or ancestral exposures. This study was designed to examine the potential transgenerational action of the environmental toxicant trichloroethane (TCE) on transmission of liver abnormality, and to elucidate the molecular etiology of hepatocyte cell damage. A total of thirty two healthy immature female albino mice were randomly divided into three equal groups as follows: a sham group, which did not receive any treatment; a vehicle group, which received corn oil alone, and TCE treated group (3 weeks, 100 μg/kg i.p., every 4th day). The F0 and F1 generation control and TCE populations were sacrificed at the age of four months, and various abnormalities histpathologically investigated. Cell death and oxidative stress indices were also measured. The present study provides experimental evidence for the inheritance of environmentally induced liver abnormalities in mice. The results of this study show that exposure to the TCE promoted adult onset liver abnormalities in F0 female mice as well as unexposed F1 generation offspring. It is the first study to report a transgenerational liver abnormalities in the F1 generation mice through maternal line prior to gestation. This finding was based on careful evaluation of liver histopathological abnormalities, apoptosis of hepatocytes, and measurements of oxidative stress biomarkers (lipid peroxidation, protein carbonylation, and nitric oxide) in control and TCE populations. There was an increase in liver histopathological abnormalities, cell death, and oxidative lipid damage in F0 and F1 hepatic tissues of TCE treated group. In conclusion, this study showed that the biological and health impacts of environmental toxicant TCE do not end in maternal adults, but are passed on to offspring generations. Hence

  15. Argininosuccinate synthase conditions the response to acute and chronic ethanol-induced liver injury in mice.

    PubMed

    Leung, Tung Ming; Lu, Yongke; Yan, Wei; Morón-Concepción, Jose A; Ward, Stephen C; Ge, Xiaodong; Conde de la Rosa, Laura; Nieto, Natalia

    2012-05-01

    Argininosuccinate synthase (ASS) is the rate-limiting enzyme in both the urea and the L-citrulline/nitric oxide (NO·) cycles regulating protein catabolism, ammonia levels, and NO· generation. Because a proteomics analysis identified ASS and nitric oxide synthase-2 (NOS2) as coinduced in rat hepatocytes by chronic ethanol consumption, which also occurred in alcoholic liver disease (ALD) and in cirrhosis patients, we hypothesized that ASS could play a role in ethanol binge and chronic ethanol-induced liver damage. To investigate the contribution of ASS to the pathophysiology of ALD, wildtype (WT) and Ass(+/-) mice (Ass(-/-) are lethal due to hyperammonemia) were exposed to an ethanol binge or to chronic ethanol drinking. Compared with WT, Ass(+/-) mice given an ethanol binge exhibited decreased steatosis, lower NOS2 induction, and less 3-nitrotyrosine (3-NT) protein residues, indicating that reducing nitrosative stress by way of the L-citrulline/NO· pathway plays a significant role in preventing liver damage. However, chronic ethanol-treated Ass(+/-) mice displayed enhanced liver injury compared with WT mice. This was due to hyperammonemia, lower phosphorylated AMP-activated protein kinase alpha (pAMPKα) to total AMPKα ratio, decreased sirtuin-1 (Sirt-1) and peroxisomal proliferator-activated receptor coactivator-1α (Pgc1α) messenger RNAs (mRNAs), lower fatty acid β-oxidation due to down-regulation of carnitine palmitoyl transferase-II (CPT-II), decreased antioxidant defense, and elevated lipid peroxidation end-products in spite of comparable nitrosative stress but likely reduced NOS3. Partial Ass ablation protects only in acute ethanol-induced liver injury by decreasing nitrosative stress but not in a more chronic scenario where oxidative stress and impaired fatty acid β-oxidation are key events. Copyright © 2011 American Association for the Study of Liver Diseases.

  16. Hepatoprotective effect of electrolyzed reduced water against carbon tetrachloride-induced liver damage in mice.

    PubMed

    Tsai, Chia-Fang; Hsu, Yu-Wen; Chen, Wen-Kang; Chang, Wen-Huei; Yen, Cheng-Chieh; Ho, Yung-Chyuan; Lu, Fung-Jou

    2009-08-01

    The study investigated the protective effect of electrolyzed reduced water (ERW) against carbon tetrachloride (CCl(4))-induced liver damage. Male ICR mice were randomly divided into control, CCl(4), CCl(4)+silymarin, and CCl(4)+ERW groups. CCl(4)-induced liver lesions include leukocytes infiltration, hepatocyte necrosis, ballooning degeneration, mitosis, calcification, fibrosis and an increase of serum alanine aminotransferase (ALT), and aminotransferase (AST) activity. In addition, CCl(4) also significantly decreased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). By contrast, ERW or silymarin supplement significantly ameliorated the CCl(4)-induced liver lesions, lowered the serum levels of hepatic enzyme markers (ALT and AST) and increased the activities of SOD, catalase, and GSH-Px in liver. Therefore, the results of this study show that ERW can be proposed to protect the liver against CCl(4)-induced oxidative damage in mice, and the hepatoprotective effect might be correlated with its antioxidant and free radical scavenging effect.

  17. Turmeric extract and its active compound, curcumin, protect against chronic CCl4-induced liver damage by enhancing antioxidation.

    PubMed

    Lee, Hwa-Young; Kim, Seung-Wook; Lee, Geum-Hwa; Choi, Min-Kyung; Jung, Han-Wool; Kim, Young-Jun; Kwon, Ho-Jeong; Chae, Han-Jung

    2016-08-26

    Curcumin, a major active component of turmeric, has previously been reported to alleviate liver damage. Here, we investigated the mechanism by which turmeric and curcumin protect the liver against carbon tetrachloride (CCl4)-induced injury in rats. We hypothesized that turmeric extract and curcumin protect the liver from CCl4-induced liver injury by reducing oxidative stress, inhibiting lipid peroxidation, and increasing glutathione peroxidase activation. Chronic hepatic stress was induced by a single intraperitoneal injection of CCl4 (0.1 ml/kg body weight) into rats. Turmeric extracts and curcumin were administered once a day for 4 weeks at three dose levels (100, 200, and 300 mg/kg/day). We performed ALT and AST also measured of total lipid, triglyceride, cholesterol levels, and lipid peroxidation. We found that turmeric extract and curcumin significantly protect against liver injury by decreasing the activities of serum aspartate aminotransferase and alanine aminotransferase and by improving the hepatic glutathione content, leading to a reduced level of lipid peroxidase. Our data suggest that turmeric extract and curcumin protect the liver from chronic CCl4-induced injury in rats by suppressing hepatic oxidative stress. Therefore, turmeric extract and curcumin are potential therapeutic antioxidant agents for the treatment of hepatic disease.

  18. Hepatoprotective Effect of Essential Oils from Hyptis crenata in Sepsis-Induced Liver Dysfunction.

    PubMed

    Lima, Glauber Cruz; Vasconcelos, Yuri de Abreu Gomes; de Santana Souza, Marilia Trindade; Oliveira, Alan Santos; Bomfim, Rangel Rodrigues; de Albuquerque Júnior, Ricardo Luiz Cavalcanti; Camargo, Enilton Aparecido; Portella, Viviane Gomes; Coelho-de-Souza, Andrelina Noronha; Diniz, Lúcio Ricardo Leite

    2018-02-28

    No specific therapeutics are available for the treatment of sepsis-induced liver dysfunction, a clinical complication strongly associated with the high mortality rate of septic patients. This study investigated the effect of the essential oil of Hyptis crenata (EOHc), a lamiaceae plant used to treat liver disturbances in Brazilian folk medicine, on liver function during early sepsis. Sepsis was induced by the cecal ligation and puncture (CLP) model. Rats were divided into four groups: Sham, Sham+EOHc, CLP, and CLP+EOHc. EOHc (300 mg/kg) was orally administered 12 and 24 h after surgery. The animals were sacrificed for blood collection and liver tissue samples 48 h after surgery. Hepatic function was evaluated by measuring serum bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase, and alanine aminotransferase (ALT) levels. The levels of malondialdehyde and the activity of superoxide dismutase, catalase, and GSH peroxidase (GSH-Px) were measured for assessment of oxidative stress. Liver morphology was analyzed by hematoxylin and eosin staining. EOHc normalized serum ALP, ALT, and bilirubin levels and inhibited morphological changes. In addition, we observed that EOHc inhibited elevation in hepatic lipid peroxidation and reduction of the glutathione peroxidase activity induced by sepsis. Our data show that EOHc plays a protective effect against liver injury induced by sepsis.

  19. Betanin attenuates carbon tetrachloride (CCl4)-induced liver injury in common carp (Cyprinus carpio L.).

    PubMed

    Han, Junyan; Gao, Cheng; Yang, Shaobin; Wang, Jun; Tan, Dehong

    2014-06-01

    This study investigates the protective effect of betanin against liver injury induced by carbon tetrachloride (CCl4) in common carp (Cyprinus carpio L.). The fish were treated with 1, 2, and 4 % betanin in fodder throughout the experiment. After 20 days of treatment, the fish were intraperitoneally injected with 20 % (v/v in peanut oil) CCl4 at a volume of 0.5 mL/kg body weight. The fish were killed 3 days after CCl4 intoxication, and then, histological and biochemical assays were performed. Results showed that CCl4-induced liver CYP2E1 activity, oxidative stress, and injury, as indicated by the depleted glycogen storage, increased serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) activities and liver histological damage. Compared with the CCl4 control group, the betanin-treated groups exhibited reduced CYP2E1 activity, decreased malondialdehyde level, increased liver antioxidative capacity (increased glutathione level and superoxide dismutase and catalase activities), increased liver glycogen storage, and reduced serum AST/ALT activities, with significant differences in the 2 and 4 % groups (p < 0.05). Histological assay further confirmed the protective effect of betanin. In conclusion, betanin attenuates CCl4-induced liver damage in common carp. Moreover, the inhibition of CYP2E1 activity and oxidative stress may have significant roles in the protective effect of betanin.

  20. A review of drug-induced liver injury databases.

    PubMed

    Luo, Guangwen; Shen, Yiting; Yang, Lizhu; Lu, Aiping; Xiang, Zheng

    2017-09-01

    Drug-induced liver injuries have been a major focus of current research in drug development, and are also one of the major reasons for the failure and withdrawal of drugs in development. Drug-induced liver injuries have been systematically recorded in many public databases, which have become valuable resources in this field. In this study, we provide an overview of these databases, including the liver injury-specific databases LiverTox, LTKB, Open TG-GATEs, LTMap and Hepatox, and the general databases, T3DB, DrugBank, DITOP, DART, CTD and HSDB. The features and limitations of these databases are summarized and discussed in detail. Apart from their powerful functions, we believe that these databases can be improved in several ways: by providing the data about the molecular targets involved in liver toxicity, by incorporating information regarding liver injuries caused by drug interactions, and by regularly updating the data.

  1. The Virtual Liver: Modeling Chemical-Induced Liver Toxicity

    EPA Science Inventory

    The US EPA Virtual Liver (v-Liver) project is aimed at modeling chemical-induced processes in hepatotoxicity and simulating their dose-dependent perturbations. The v-Liver embodies an emerging field of research in computational tissue modeling that integrates molecular and cellul...

  2. Hepatoprotective effect of Taraxacum officinale leaf extract on sodium dichromate-induced liver injury in rats.

    PubMed

    Hfaiedh, Mbarka; Brahmi, Dalel; Zourgui, Lazhar

    2016-03-01

    Taraxacum officinale (L.) Weber, commonly known as Dandelion, has been widely used as a folkloric medicine for the treatment of liver and kidney disorders and some women diseases such as breast and uterus cancers. The main objective of the present study was to assess the efficiency of T. officinale leaf extract (TOE) in treating sodium dichromate hazards; it is a major environmental pollutant known for its wide toxic manifestations witch induced liver injury. TOE at a dose of 500 mg/kg b.w was orally administered once per day for 30 days consecutively, followed by 10 mg/kg b.w sodium dichromate was injected (intraperitoneal) for 10 days. Our results using Wistar rats showed that sodium dichromate significantly increased serum biochemical parameters. In the liver, it was found to induce an oxidative stress, evidenced from increase in lipid peroxidation and changes in antioxidative activities. In addition, histopathological observation revealed that sodium dichromate causes acute liver damage, necrosis of hepatocytes, as well as DNA fragmentation. Interestingly, animals that were pretreated with TOE, prior to sodium dichromate administration, showed a significant hepatoprotection, revealed by a significant reduction of sodium dichromate-induced oxidative damage for all tested markers. These finding powerfully supports that TOE was effective in the protection against sodium dichromate-induced hepatotoxicity and genotoxicity and, therefore, suggest a potential therapeutic use of this plant as an alternative medicine for patients with acute liver diseases. © 2014 Wiley Periodicals, Inc.

  3. Protective effects from Houttuynia cordata aqueous extract against acetaminophen-induced liver injury.

    PubMed

    Chen, Wei-Ting; Yang, Chieh-Ling; Yin, Mei-Chin

    2014-01-01

    Protective effects of Houttuynia cordata aqueous extract (HCAE) against acetaminophen-induced hepatotoxicity in Balb/cA mice were examined. HCAE, at 1 or 2 g/L, was added into the drinking water for 4 weeks. Acute liver injury was induced by acetaminophen treatment intraperitoneally (350 mg/kg body weight). Acetaminophen treatment significantly depleted hepatic glutathione (GSH) content, increased hepatic malonyldialdehyde (MDA), reactive oxygen species (ROS) and oxidized glutathione (GSSG) levels, and decreased hepatic activity of glutathione peroxidase (GPX), catalase and superoxide dismutase (SOD) ( p <0.05). The pre-intake of HCAE alleviated acetaminophen-induced oxidative stress by retaining GSH content, decreasing MDA, ROS and GSSG production, and maintaining activity of GPX, catalase and SOD in liver ( p <0.05). The pre-intake of HCAE also significantly lowered acetaminophen-induced increase in cytochrome P450 2E1 activity ( p <0.05). Acetaminophen treatment increased hepatic release of interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein-1 ( p <0.05). HCAE intake significantly diminished acetaminophen-induced elevation of these cytokines ( p <0.05). These results support that HCAE could provide hepato-protection.

  4. Loss of 5‐lipoxygenase activity protects mice against paracetamol‐induced liver toxicity

    PubMed Central

    Pu, Shiyun; Ren, Lin; Liu, Qinhui; Kuang, Jiangying; Shen, Jing; Cheng, Shihai; Zhang, Yuwei; Jiang, Wei; Zhang, Zhiyong; Jiang, Changtao

    2015-01-01

    Background and Purpose Paracetamol (acetaminophen) is the most widely used over‐the‐counter analgesic and overdosing with paracetamol is the leading cause of hospital admission for acute liver failure. 5‐Lipoxygenase (5‐LO) catalyses arachidonic acid to form LTs, which lead to inflammation and oxidative stress. In this study, we examined whether deletion or pharmacological inhibition of 5‐LO could protect mice against paracetamol‐induced hepatic toxicity. Experimental Approach Both genetic deletion and pharmacological inhibition of 5‐LO in C57BL/6J mice were used to study the role of this enzyme in paracetamol induced liver toxicity. Serum and tissue biochemistry, H&E staining, and real‐time PCR were used to assess liver toxicity. Key Results Deletion or pharmacological inhibition of 5‐LO in mice markedly ameliorated paracetamol‐induced hepatic injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and hepatic centrilobular necrosis. The hepatoprotective effect of 5‐LO inhibition was associated with induction of the antitoxic phase II conjugating enzyme, sulfotransferase2a1, suppression of the pro‐toxic phase I CYP3A11 and reduction of the hepatic transporter MRP3. In 5‐LO−/− mice, levels of GSH were increased, and oxidative stress decreased. In addition, PPAR α, a nuclear receptor that confers resistance to paracetamol toxicity, was activated in 5‐LO−/− mice. Conclusions and Implications The activity of 5‐LO may play a critical role in paracetamol‐induced hepatic toxicity by regulating paracetamol metabolism and oxidative stress. PMID:26398229

  5. Baicalin Ameliorates Experimental Liver Cholestasis in Mice by Modulation of Oxidative Stress, Inflammation, and NRF2 Transcription Factor

    PubMed Central

    Feng, Xiaowen; Zhang, Feng; Xie, Haiyang

    2017-01-01

    Experimental cholestatic liver fibrosis was performed by bile duct ligation (BDL) in mice, and significant liver injury was observed in 15 days. Administration of baicalin in mice significantly ameliorates liver fibrosis. Experimental cholestatic liver fibrosis was associated with induced gene expression of fibrotic markers such as collagen I, fibronectin, alpha smooth muscle actin (SMA), and connective tissue growth factor (CTGF); increased inflammatory cytokines (TNFα, MIP1α, IL1β, and MIP2); increased oxidative stress and reactive oxygen species- (ROS-) inducing enzymes (NOX2 and iNOS); dysfunctional mitochondrial electron chain complexes; and apoptotic/necrotic cell death markers (DNA fragmentation, caspase 3 activity, and PARP activity). Baicalin administration on alternate day reduced fibrosis along with profibrotic gene expression, proinflammatory cytokines, oxidative stress, and cell death whereas improving the function of mitochondrial electron transport chain. We observed baicalin enhanced NRF2 activation by nuclear translocation and induced its target genes HO-1 and GCLM, thus enhancing antioxidant defense. Interplay of oxidative stress/inflammation and NRF2 were key players for baicalin-mediated protection. Stellate cell activation is crucial for initiation of fibrosis. Baicalin alleviated stellate cell activation and modulated TIMP1, SMA, collagen 1, and fibronectin in vitro. This study indicates that baicalin might be beneficial for reducing inflammation and fibrosis in liver injury models. PMID:28757911

  6. Protective effects of Nano-elemental selenium against chromium-vi-induced oxidative stress in broiler liver.

    PubMed

    Xueting, L; Rehman, M U; Zhang, H; Tian, X; Wu, X; Shixue; Mehmood, K; Zhou, D

    2018-01-01

    The valuable role of selenium in mitigation of oxidative stress and heavy metal toxicity is well-known. Thus, the aim of the current study on broiler chickens was to examine whether nano elemental selenium (Nano-Se) supplementation can reduce the effects of chromium VI (K2Cr2O7) toxicity. For this purpose, a total of 150, one-day-old broiler chickens were allotted to five groups with three replicates: control group (standard diet), poisoned group (K2Cr2O7 via drinking water), protection group (K2Cr2O7 + Nano- Se), cure group (K2Cr2O7 for initial 2 weeks and then Nano-Se), and prevention group (opposite to the cure group). The broilers were detected by the activities of marker enzymes and oxidative stress markers including, aspartate aminotransferase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT) and superoxide dismutase (SOD), glutathione peroxidase (GSH-px), malondialdehyde (MDA), respectively. The (K2Cr2O7 administration caused histopathological damage in the liver of the chickens. Moreover, changes in serum biochemical indicators and oxidative stress parameters were also observed. Nano-Se supplementation increased the levels of GSH-px but reduced the activities of SOD, MDA, GGT, ALT and AST in the experimental groups (P less than 0.05). Our results showed that Nano-Se plays a protective role by preventing the oxidative stress induced by the chromium VI in broiler chickens.

  7. Acetaminophen-induced liver injury in rats and mice: Comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    McGill, Mitchell R.; Williams, C. David; Xie, Yuchao

    2012-11-01

    Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites amore » reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity. Highlights: ► Acetaminophen overdose causes severe liver injury only in mice but not in rats. ► APAP causes hepatic GSH depletion and protein adduct formation in rats and mice. ► Less protein adducts were measured in rat liver mitochondria compared to mouse. ► No oxidant stress, peroxynitrite formation or JNK activation was present in rats

  8. Silibinin Capsules improves high fat diet-induced nonalcoholic fatty liver disease in hamsters through modifying hepatic de novo lipogenesis and fatty acid oxidation.

    PubMed

    Cui, Chun-Xue; Deng, Jing-Na; Yan, Li; Liu, Yu-Ying; Fan, Jing-Yu; Mu, Hong-Na; Sun, Hao-Yu; Wang, Ying-Hong; Han, Jing-Yan

    2017-08-17

    Silibinin Capsules (SC) is a silybin-phospholipid complex with silybin as the bioactive component. Silybin accounts for 50-70% of the seed extract of Silybum marianum (L.) Gaertn.. As a traditional medicine, silybin has been used for treatment of liver diseases and is known to provide a wide range of hepatoprotective effects. High fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) is a worldwide health problem. This study was to investigate the role of SC in NAFLD with focusing on its underlying mechanism and likely target. Male hamsters (Cricetidae) received HFD for 10 weeks to establish NAFLD model. NAFLD was assessed by biochemical assays, histology and immunohistochemistry. Proton nuclear magnetic resonance spectroscopy and western blot were conducted to gain insight into the mechanism. Hamsters fed HFD for 10 weeks developed fatty liver accompanying with increased triglyceride (TG) accumulation, enhancing de novo lipogenesis, increase in fatty acid (FA) uptake and reducing FA oxidation and TG lipolysis, as well as a decrease in the expression of phospho-adenosine monophosphate activated protein kinase α (p-AMPKα) and Sirt 1. SC treatment at 50mg/kg silybin and 100mg/kg silybin for 8 weeks protected hamsters from development of fatty liver, reducing de novo lipogenesis and increasing FA oxidation and p-AMPKα expression, while having no effect on FA uptake and TG lipolysis. SC protected against NAFLD in hamsters by inhibition of de novo lipogenesis and promotion of FA oxidation, which was likely mediated by activation of AMPKα. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  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. The potential antifibrotic impact of apocynin and alpha-lipoic acid in concanavalin A-induced liver fibrosis in rats: Role of NADPH oxidases 1 and 4.

    PubMed

    Fayed, Mostafa R; El-Naga, Reem N; Akool, El-Sayed; El-Demerdash, Ebtehal

    2018-01-01

    Liver fibrosis results from chronic inflammation that precipitates excessive accumulation of extracellular matrix. Oxidative stress is involved in its pathogenesis. This study aimed to elucidate the potential antifibrotic effect of the NADPH oxidase (NOX) inhibitor, apocynin against concanavalin A (ConA)-induced immunological model of liver fibrosis, and to investigate the ability of the antioxidant, alpha-lipoic acid (α-LA) to potentiate this effect. Rats were treated with apocynin and/or α-LA for six weeks. Hepatotoxicity indices, oxidative stress, insulin, NOXs, inflammatory and liver fibrosis markers were assessed. Treatment of animals with apocynin and α-LA significantly ameliorated the changes in liver functions and histopathological architecture induced by ConA. Liver fibrosis induced by ConA was evident where alpha-smooth muscle actin and transforming growth factor- beta1 were elevated, which was further confirmed by Masson's trichrome stain and increased hydroxyproline. Co-treatment with apocynin and α-LA significantly reduced their expression. Besides, apocynin and α-LA significantly ameliorated oxidative stress injury evoked by ConA, as evidenced by enhancing reduced glutathione content, antioxidant enzymes activities and decreasing lipid peroxides. ConA induced a significant elevation in serum insulin level and inflammatory markers; tumor necrosis factor-alpha, interleukin-6 and nuclear factor kappa b. Furthermore, the mRNA tissue expression of NOXs 1 and 4 was found to be elevated in the ConA group. All these elevations were significantly reduced by apocynin and α-LA co-treatment. These findings indicate that using apocynin and α-LA in combination possess marked antifibrotic effects, and that NOX enzymes are partially involved in the pathogenesis of ConA-induced liver fibrosis.

  11. Silymarin modulates doxorubicin-induced oxidative stress, Bcl-xL and p53 expression while preventing apoptotic and necrotic cell death in the liver

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Patel, Nirav; Joseph, Cecil; Corcoran, George B.

    2010-06-01

    The emergence of silymarin (SMN) as a natural remedy for liver diseases, coupled with its entry into NIH clinical trial, signifies its hepatoprotective potential. SMN is noted for its ability to interfere with apoptotic signaling while acting as an antioxidant. This in vivo study was designed to explore the hepatotoxic potential of Doxorubicin (Dox), the well-known cardiotoxin, and in particular whether pre-exposures to SMN can prevent hepatotoxicity by reducing Dox-induced free radical mediated oxidative stress, by modulating expression of apoptotic signaling proteins like Bcl-xL, and by minimizing liver cell death occurring by apoptosis or necrosis. Groups of male ICR micemore » included Control, Dox alone, SMN alone, and Dox with SMN pre/co-treatment. Control and Dox groups received saline i.p. for 14 days. SMN was administered p.o. for 14 days at 16 mg/kg/day. An approximate LD{sub 50} dose of Dox, 60 mg/kg, was administered i.p. on day 12 to animals receiving saline or SMN. Animals were euthanized 48 h later. Dox alone induced frank liver injury (> 50-fold increase in serum ALT) and oxidative stress (> 20-fold increase in malondialdehyde [MDA]), as well as direct damage to DNA (> 15-fold increase in DNA fragmentation). Coincident genomic damage and oxidative stress influenced genomic stability, reflected in increased PARP activity and p53 expression. Decreases in Bcl-xL protein coupled with enhanced accumulation of cytochrome c in the cytosol accompanied elevated indexes of apoptotic and necrotic cell death. Significantly, SMN exposure reduced Dox hepatotoxicity and associated apoptotic and necrotic cell death. The effects of SMN on Dox were broad, including the ability to modulate changes in both Bcl-xL and p53 expression. In animals treated with SMN, tissue Bcl-xL expression exceeded control values after Dox treatment. Taken together, these results demonstrated that SMN (i) reduced, delayed onset, or prevented toxic effects of Dox which are typically

  12. Boron attenuates malathion-induced oxidative stress and acetylcholinesterase inhibition in rats.

    PubMed

    Coban, Funda Karabag; Ince, Sinan; Kucukkurt, Ismail; Demirel, Hasan Huseyin; Hazman, Omer

    2015-10-01

    Organophosphorus compounds cause oxidative stress and lead to alterations in antioxidant status in organisms. In this study, the effects of subchronic exposure to malathion and the protective effects of boron (B) were evaluated in 48 Wistar rats, which were divided equally into six groups. For 28 d, the control group received a normal diet and tap water, the corn oil group received a normal diet and 0.5 mL of corn oil by gastric gavage and the malathion group received a normal diet and malathion (100 mg/kg/d) by gastric gavage. During the same period, each of the three other groups received a different dosage of B (5, 10 and 20 mg/kg/d, respectively) and malathion (100 mg/kg/d) by gastric gavage. Malathion administration during the period increased malondialdehyde, nitric oxide and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, as well as markers of liver function, yet decreased acetylcholinesterase, reduced glutathione, superoxide dismutase, and catalase activities in blood, liver, kidney and brain tissues. Administration of B in a dose-dependent manner also reversed malathion-induced oxidative stress, lipid peroxidation (LPO) and antioxidant enzyme activity. Moreover, B exhibited protective action against malathion-induced histopathological changes in liver, kidney and brain tissues. These results demonstrate that, if used in a dose-dependent manner, B decreases malathion-induced oxidative stress, enhances the antioxidant defense mechanism and regenerates tissues in rats.

  13. Chronic high fat, high cholesterol supplementation decreases 18 kDa Translocator Protein binding capacity in association with increased oxidative stress in rat liver and aorta.

    PubMed

    Dimitrova-Shumkovska, Jasmina; Veenman, Leo; Ristoski, Trpe; Leschiner, Svetlana; Gavish, Moshe

    2010-03-01

    It is well known that high fat and high cholesterol levels present a contributing factor to pathologies including fatty liver and atherosclerosis. Oxidative stress is also considered to play a role in these pathologies. The 18 kDa Translocator Protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, is known to be involved in cholesterol metabolism, oxidative stress, and cardiovascular pathology. We applied a high fat high cholesterol atherogenic (HFHC) diet to rats to study correlations between cardiovascular and liver pathology, oxidative stress, and TSPO expression in the liver and the cardiovascular system. This study corroborates the presence of increased oxidative stress markers and decreased anti-oxidants in liver and aorta. In addition, it appeared that induction of oxidative stress in the liver and aorta by atherogenic HFHC diet was accompanied by a reduction in TSPO binding density in both these tissues. Our data suggest that involvement of TSPO in oxidative stress and ROS generation, as reported in other studies, may also take part in atherogenesis as induced by HFHC diet. Presently, it is not clear whether this TSPO response is compensatory for the stress induced by HFHC diet or is a participant in the induction of oxidative stress. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  14. Effects of ovariectomy and resistance training on oxidative stress markers in the rat liver

    PubMed Central

    Rodrigues, Maria Fernanda Cury; Stotzer, Uliana Sbeguen; Domingos, Mateus Moraes; Deminice, Rafael; Shiguemoto, Gilberto Eiji; Tomaz, Luciane Magri; de Sousa, Nuno Manuel Frade; Ferreira, Fabiano Candido; Leite, Richard Diego; Selistre-de-Araújo, Heloisa Sobreiro; Jordão-Júnior, Alceu Afonso; Baldissera, Vilmar; de Andrade Perez, Sérgio Eduardo

    2013-01-01

    OBJECTIVE: The objective of this study was to assess the effects of resistance training on oxidative stress markers in the livers of ovariectomized rats. METHOD: Adult Sprague-Dawley rats were divided into the following four groups (n = 8 per group): sham-operated sedentary, ovariectomized sedentary, sham-operated resistance training, and ovariectomized resistance training. During the resistance training period, the animals climbed a 1.1-m vertical ladder with weights attached to their tails; the sessions were conducted 3 times per week, with 4-9 climbs and 8-12 dynamic movements per climb. The oxidative stress was assessed by measuring the levels of reduced glutathione and oxidized glutathione, the enzymatic activity of catalase and superoxide dismutase, lipid peroxidation, vitamin E concentrations, and the gene expression of glutathione peroxidase. RESULTS: The results showed significant reductions in the reduced glutathione/oxidized glutathione ratio (4.11±0.65 nmol/g tec), vitamin E concentration (55.36±11.11 nmol/g), and gene expression of glutathione peroxidase (0.49±0.16 arbitrary units) in the livers of ovariectomized rats compared with the livers of unovariectomized animals (5.71±0.71 nmol/g tec, 100.14±10.99 nmol/g, and 1.09±0.54 arbitrary units, respectively). Moreover, resistance training for 10 weeks was not able to reduce the oxidative stress in the livers of ovariectomized rats and induced negative changes in the hepatic anti-oxidative/oxidative balance. CONCLUSION: Our findings indicate that the resistance training program used in this study was not able to attenuate the hepatic oxidative damage caused by ovariectomy and increased the hepatic oxidative stress. PMID:24141842

  15. Effects of ovariectomy and resistance training on oxidative stress markers in the rat liver.

    PubMed

    Rodrigues, Maria Fernanda Cury; Stotzer, Uliana Sbeguen; Domingos, Mateus Moraes; Deminice, Rafael; Shiguemoto, Gilberto Eiji; Tomaz, Luciane Magri; Sousa, Nuno Manuel Frade de; Ferreira, Fabiano Candido; Leite, Richard Diego; Selistre-de-Araújo, Heloisa Sobreiro; Jordão-Júnior, Alceu Afonso; Baldissera, Vilmar; Perez, Sérgio Eduardo de Andrade

    2013-09-01

    The objective of this study was to assess the effects of resistance training on oxidative stress markers in the livers of ovariectomized rats. Adult Sprague-Dawley rats were divided into the following four groups (n = 8 per group): sham-operated sedentary, ovariectomized sedentary, sham-operated resistance training, and ovariectomized resistance training. During the resistance training period, the animals climbed a 1.1-m vertical ladder with weights attached to their tails; the sessions were conducted 3 times per week, with 4-9 climbs and 8-12 dynamic movements per climb. The oxidative stress was assessed by measuring the levels of reduced glutathione and oxidized glutathione, the enzymatic activity of catalase and superoxide dismutase, lipid peroxidation, vitamin E concentrations, and the gene expression of glutathione peroxidase. The results showed significant reductions in the reduced glutathione/oxidized glutathione ratio (4.11±0.65 nmol/g tec), vitamin E concentration (55.36±11.11 nmol/g), and gene expression of glutathione peroxidase (0.49±0.16 arbitrary units) in the livers of ovariectomized rats compared with the livers of unovariectomized animals (5.71±0.71 nmol/g tec, 100.14±10.99 nmol/g, and 1.09±0.54 arbitrary units, respectively). Moreover, resistance training for 10 weeks was not able to reduce the oxidative stress in the livers of ovariectomized rats and induced negative changes in the hepatic anti-oxidative/oxidative balance. Our findings indicate that the resistance training program used in this study was not able to attenuate the hepatic oxidative damage caused by ovariectomy and increased the hepatic oxidative stress.

  16. Effects of ozone oxidative preconditioning on radiation-induced organ damage in rats

    PubMed Central

    Gultekin, Fatma Ayca; Bakkal, Bekir Hakan; Guven, Berrak; Tasdoven, Ilhan; Bektas, Sibel; Can, Murat; Comert, Mustafa

    2013-01-01

    Because radiation-induced cellular damage is attributed primarily to harmful effects of free radicals, molecules with direct free radical scavenging properties are particularly promising as radioprotectors. It has been demonstrated that controlled ozone administration may promote an adaptation to oxidative stress, preventing the damage induced by reactive oxygen species. Thus, we hypothesized that ozone would ameliorate oxidative damage caused by total body irradiation (TBI) with a single dose of 6 Gy in rat liver and ileum tissues. Rats were randomly divided into groups as follows: control group; saline-treated and irradiated (IR) groups; and ozone oxidative preconditioning (OOP) and IR groups. Animals were exposed to TBI after a 5-day intraperitoneal pretreatment with either saline or ozone (1 mg/kg/day). They were decapitated at either 6 h or 72 h after TBI. Plasma, liver and ileum samples were obtained. Serum AST, ALT and TNF-α levels were elevated in the IR groups compared with the control group and were decreased after treatment with OOP. TBI resulted in a significant increase in the levels of MDA in the liver and ileal tissues and a decrease of SOD activities. The results demonstrated that the levels of MDA liver and ileal tissues in irradiated rats that were pretreated with ozone were significantly decreased, while SOD activities were significantly increased. OOP reversed all histopathological alterations induced by irradiation. In conclusion, data obtained from this study indicated that ozone could increase the endogenous antioxidant defense mechanism in rats and there by protect the animals from radiation-induced organ toxicity. PMID:22915786

  17. Hepatoprotective activity of bacoside A against N-nitrosodiethylamine-induced liver toxicity in adult rats.

    PubMed

    Janani, Panneerselvam; Sivakumari, Kanakarajan; Parthasarathy, Chandrakesan

    2009-10-01

    N-Nitrosodiethylamine (DEN) is a notorious carcinogen, present in many environmental factors. DEN induces oxidative stress and cellular injury due to enhanced generation of reactive oxygen species; free radical scavengers protect the membranes from DEN-induced damage. The present study was designed to evaluate the protective effect of bacoside A (the active principle isolated from Bacopa monniera Linn.) on carcinogen-induced damage in rat liver. Adult male albino rats were pretreated with 15 mg/kg body weight/day of bacoside A orally (for 14 days) and then intoxicated with single necrogenic dose of N-nitrosodiethylamine (200 mg/kg bodyweight, intraperitonially) and maintained for 7 days. The liver weight, lipid peroxidation (LPO), and activity of serum marker enzymes (aspartate transaminases, alanine transaminases, lactate dehydrogenase, alkaline phosphatase, and gamma-glutamyl transpeptidase) were markedly increased in carcinogen-administered rats, whereas the activities of marker enzymes were near normal in bacoside A-pretreated rats. Activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutatione-S-transferase, and reduced glutathione) in liver also decreased in carcinogen-administered rats, which were significantly elevated in bacoside A-pretreated rats. It is concluded that pretreatment of bacoside A prevents the elevation of LPO and activity of serum marker enzymes and maintains the antioxidant system and thus protects the rats from DEN-induced hepatotoxicity.

  18. Curcumin Attenuates N-Nitrosodiethylamine-Induced Liver Injury in Mice by Utilizing the Method of Metabonomics.

    PubMed

    Qiu, Peiyu; Sun, Jiachen; Man, Shuli; Yang, He; Ma, Long; Yu, Peng; Gao, Wenyuan

    2017-03-08

    N-Nitrosodiethylamine (DEN) exists as a food additive in cheddar cheese, processed meats, beer, water, and so forth. It is a potent hepatocarcinogen in animals and humans. Curcumin as a natural dietary compound decreased DEN-induced hepatocarcinogenesis in this research. According to the histopathological examination of liver tissues and biomarker detection in serum and livers, it was demonstrated that curcumin attenuated DEN-induced hepatocarcinogenesis through parts of regulating the oxidant stress enzymes (T-SOD and CAT), liver function (ALT and AST) and LDHA, AFP level, and COX-2/PGE2 pathway. Furthermore, curcumin attenuated metabolic disorders via increasing concentration of glucose and fructose, and decreasing levels of glycine and proline, and mRNA expression of GLUT1, PKM and FASN. Docking study indicated that curcumin presented strong affinity with key metabolism enzymes such as GLUT1, PKM, FASN and LDHA. There were a number of amino acid residues involved in curcumin-targeting enzymes of hydrogen bonds and hydrophobic interactions. All in all, curcumin exhibited a potent liver protective agent inhibiting chemically induced liver injury through suppressing liver cellular metabolism in the prospective application.

  19. Identification of Plants That Inhibit Lipid Droplet Formation in Liver Cells: Rubus suavissimus Leaf Extract Protects Mice from High-Fat Diet-Induced Fatty Liver by Directly Affecting Liver Cells

    PubMed Central

    Takahashi, Tomohiro; Sugawara, Wataru; Takiguchi, Yuya; Takizawa, Kento; Nakabayashi, Ami; Nakamura, Mitsuo; Nagano-Ito, Michiyo; Ichikawa, Shinichi

    2016-01-01

    Fatty liver disease is a condition in which abnormally large numbers of lipid droplets accumulate in liver cells. Fatty liver disease induces inflammation under conditions of oxidative stress and may result in cancer. To identify plants that protect against fatty liver disease, we examined the inhibitory effects of plant extracts on lipid droplet formation in mouse hepatoma cells. A screen of 98 water extracts of plants revealed 4 extracts with inhibitory effects. One of these extracts, Rubus suavissimus S. Lee (Tien-cha or Chinese sweet tea) leaf extract, which showed strong inhibitory effects, was tested in a mouse fatty liver model. In these mouse experiments, intake of the plant extract significantly protected mice against fatty liver disease without affecting body weight gain. Our results suggest that RSE directly affects liver cells and protects them from fatty liver disease. PMID:27429636

  20. Scavenging and antioxidant properties of different grape cultivars against ionizing radiation-induced liver damage ex vivo.

    PubMed

    Singha, Indrani; Das, Subir Kumar

    2016-04-01

    higher concentration (10 mg extract/g liver tissue) showed stronger antioxidant potential against lower dose (6 Gy) of ionizing radiation. Our results suggest that grape extracts could serve as a potential source of natural antioxidant against lower doses of IR-induced oxidative stress in liver extracts ex vivo.

  1. Propylthiouracil-Induced Acute Liver Failure: Role of Liver Transplantation

    PubMed Central

    Carrion, Andres F.; Czul, Frank; Arosemena, Leopoldo R.; Selvaggi, Gennaro; Garcia, Monica T.; Tekin, Akin; Tzakis, Andreas G.; Martin, Paul; Ghanta, Ravi K.

    2010-01-01

    Propylthiouracil- (PTU-) induced hepatotoxicity is rare but potentially lethal with a spectrum of liver injury ranging from asymptomatic elevation of transaminases to fulminant hepatic failure and death. We describe two cases of acute hepatic failure due to PTU that required liver transplantation. Differences in the clinical presentation, histological characteristics, and posttransplant management are described as well as alternative therapeutic options. Frequent monitoring for PTU-induced hepatic dysfunction is strongly advised because timely discontinuation of this drug and implementation of noninvasive therapeutic interventions may prevent progression to liver failure or even death. PMID:21234410

  2. Bazhen Decoction Protects against Acetaminophen Induced Acute Liver Injury by Inhibiting Oxidative Stress, Inflammation and Apoptosis in Mice

    PubMed Central

    Song, Erqun; Fu, Juanli; Xia, Xiaomin; Su, Chuanyang; Song, Yang

    2014-01-01

    Bazhen decoction is a widely used traditional Chinese medicinal decoction, but the scientific validation of its therapeutic potential is lacking. The objective of this study was to investigate corresponding anti-oxidative, anti-inflammatory and anti-apoptosis activities of Bazhen decoction, using acetaminophen-treated mice as a model system. A total of 48 mice were divided into four groups. Group I, negative control, treated with vehicle only. Group II, fed with 500 mg/kg/day Bazhen decoction for 10 continuous days. Group III, received a single dose of 900 mg/kg acetaminophen. Group IV, fed with 500 mg/kg/day Bazhen decoction for 10 continuous days and a single dose of 900 mg/kg acetaminophen 30 min before last Bazhen decoction administration. Bazhen decoction administration significantly decrease acetaminophen-induced serum ALT, AST, ALP, LDH, TNF-α, IL-1β, ROS, TBARS and protein carbonyl group levels, as well as GSH depletion and loss of MMP. Bazhen decoction restore SOD, CAT, GR and GPx activities and depress the expression of pro-inflammatory factors, such as iNOS, COX-2, TNF-α, NF-κB, IL-1β and IL-6, respectively. Moreover, Bazhen decoction down-regulate acetaminophen-induced Bax/Bcl-2 ratio, caspase 3, caspase 8 and caspase 9. These results suggest the anti-oxidative, anti-inflammatory and anti-apoptosis properties of Bazhen decoction towards acetaminophen-induced liver injury in mice. PMID:25222049

  3. Protective Effect of Cymbopogon citratus Essential Oil in Experimental Model of Acetaminophen-Induced Liver Injury.

    PubMed

    Uchida, Nancy Sayuri; Silva-Filho, Saulo Euclides; Aguiar, Rafael Pazinatto; Wiirzler, Luiz Alexandre Marques; Cardia, Gabriel Fernando Esteves; Cavalcante, Heitor Augusto Otaviano; Silva-Comar, Francielli Maria de Souza; Becker, Tânia Cristina Alexandrino; Silva, Expedito Leite; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

    2017-01-01

    To investigate the hepatoprotective effect of Cymbopogon citratus or lemongrass essential oil (LGO), it was used in an animal model of acute liver injury induced by acetaminophen (APAP). Swiss mice were pretreated with LGO (125, 250 and 500[Formula: see text]mg/kg) and SLM (standard drug, 200[Formula: see text]mg/kg) for a duration of seven days, followed by the induction of hepatotoxicity of APAP (single dose, 250[Formula: see text]mg/kg). The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase were determined to evaluate the hepatoprotective effects of the LGO. The livers were used to determine myeloperoxidase (MPO) activity, nitric oxide (NO) production and histological analysis. The effect of LGO on leukocyte migration was evaluated in vitro. Anti-oxidant activity was performed by assessing the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) in vitro. LGO pretreatment decreased significantly the levels of ALT, AST and ALP compared with APAP group. MPO activity and NO production were decreased. The histopathological analysis showed an improved of hepatic lesions in mice after LGO pretreatment. LGO inhibited neutrophil migration and exhibited anti-oxidant activity. Our results suggest that LGO has protective activity against liver toxicity induced by paracetamol.

  4. Effects of curcumin on angiotensin-converting enzyme gene expression, oxidative stress and anti-oxidant status in thioacetamide-induced hepatotoxicity.

    PubMed

    Fazal, Yumna; Fatima, Syeda Nuzhat; Shahid, Syed Muhammad; Mahboob, Tabassum

    2015-12-01

    This study aimed to evaluate the protective effects of curcumin on angiotensin-converting enzyme (ACE) gene expression, oxidative stress and anti-oxidant status in thioacetamide (TAA)-induced hepatotoxicity in rats. Total 32 albino Wistar rats (male, 200-250 g) were divided into six groups (n=8). Group 1: untreated controls; Group 2: received TAA (200 mg/kg body weight (b.w.); i.p.) for 12 weeks; Group 3: received curcumin (75 mg/kg b.w.) for 24 weeks; Group 4: received TAA (200 mg/kg b.w.; i.p.) for 12 weeks+curcumin (75 mg/kg b.w.) for 12 weeks. A significantly higher ACE gene expression was observed in TAA-induced groups as compared with control, indicating more synthesis of ACE proteins. Treatment with curcumin suppressed ACE expression in TAA liver and reversed the toxicity produced. TAA treatment results in higher lipid peroxidation and lower GSH, SOD and CAT than the normal, and this produces oxidative stress in the liver. Cirrhotic conditions were confirmed by serum enzymes (ALT, AST and ALP) as well as histopathological observations. Curcumin treatment reduced oxidative stress in animals by scavenging reactive oxygen species, protecting the anti-oxidant enzymes from being denatured and reducing the oxidative stress marker lipid peroxidation. Curcumin treatment restores hepatocytes, damaged by TAA, and protects liver tissue approaching cirrhosis. © The Author(s) 2014.

  5. Cafeteria diet induces obesity and insulin resistance associated with oxidative stress but not with inflammation: improvement by dietary supplementation with a melon superoxide dismutase.

    PubMed

    Carillon, Julie; Romain, Cindy; Bardy, Guillaume; Fouret, Gilles; Feillet-Coudray, Christine; Gaillet, Sylvie; Lacan, Dominique; Cristol, Jean-Paul; Rouanet, Jean-Max

    2013-12-01

    Oxidative stress is involved in obesity. However, dietary antioxidants could prevent oxidative stress-induced damage. We have previously shown the preventive effects of a melon superoxide dismutase (SODB) on oxidative stress. However, the mechanism of action of SODB is still unknown. Here, we evaluated the effects of a 1-month curative supplementation with SODB on the liver of obese hamsters. Golden Syrian hamsters received either a standard diet or a cafeteria diet composed of high-fat, high-sugar, and high-salt supermarket products, for 15 weeks. This diet resulted in insulin resistance and in increased oxidative stress in the liver. However, inflammatory markers (IL-6, TNF-α, and NF-κB) were not enhanced and no liver steatosis was detected, although these are usually described in obesity-induced insulin resistance models. After the 1-month supplementation with SODB, body weight and insulin resistance induced by the cafeteria diet were reduced and hepatic oxidative stress was corrected. This could be due to the increased expression of the liver antioxidant defense proteins (manganese and copper/zinc superoxide dismutase, catalase, and glutathione peroxidase). Even though no inflammation was detected in the obese hamsters, inflammatory markers were decreased after SODB supplementation, probably through the reduction of oxidative stress. These findings suggest for the first time that SODB could exert its antioxidant properties by inducing the endogenous antioxidant defense. The mechanisms underlying this induction need to be further investigated. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Sesquiterpenoids from the root of Panax Ginseng protect CCl4-induced acute liver injury by anti-inflammatory and anti-oxidative capabilities in mice.

    PubMed

    Wang, Weidong; Wang, Shijie; Liu, Jinping; Cai, Enbo; Zhu, Hongyan; He, Zhongmei; Gao, Yugang; Li, Pingya; Zhao, Yan

    2018-06-01

    The oxidative stress and inflammatory response play an important role in carbon tetracholoride (CCl 4 )-induced acute liver injury. In this work, sesquiterpenoids from the root of Panax Ginseng (SPG) were prepared, and then the hepatoprotective effects of SPG against CCl 4 -induced acute liver injury were investigated and the underlying mechanism was explored in mice. All mice were divided into four groups: the control, CCl 4 and SPG (2.5 and 10 mg/kg, dissolved in soybean oil, i.g.) groups. All mice were given continuous administration for 7 days, and injected with CCl 4 (0.1 mL/10 g body weight 0.2% CCl 4 solution in soybean oil, i.p.) 1 h after the end of the administration except the control group. Mice were sacrificed 24 h post-CCl 4 injection. The results indicated that SPG significantly reduced the increasement of serum AST and ALT levels induced by CCl 4 -treatment. And the histopathological analysis revealed that SPG treated mice had normal liver architecture and no necrosis. The decreased activities of SOD, GSH and CAT, and increased MDA level were inhibited by SPG treatment. At the same time, the levels of TNF-α, IL-1β and IL-6 were significantly decreased by SPG treatment. SPG treatment also reduced the heptic protein expressions of NF-κB p65, COX-2, MAPK p38, ERK and JNK in the liver. These fingdings demonstrated that SPG exhibited strong hepatoprective effect on the CCl 4 -induced acute liver injury, which was related to anti-oxidantive and anti-inflammatory capabilities; and the anti-inflammatory effect of SPG might mediated by the NF-κB and MAPKs signaling pathways. Taken together, SPG might be a potential material for drug and functional food development against chemical hepatic injury. Copyright © 2018. Published by Elsevier Masson SAS.

  7. Mobile phone radiation-induced free radical damage in the liver is inhibited by the antioxidants N-acetyl cysteine and epigallocatechin-gallate.

    PubMed

    Ozgur, Elcin; Güler, Göknur; Seyhan, Nesrin

    2010-11-01

    To investigate oxidative damage and antioxidant enzyme status in the liver of guinea pigs exposed to mobile phone-like radiofrequency radiation (RFR) and the potential protective effects of N-acetyl cysteine (NAC) and epigallocatechin-gallate (EGCG) on the oxidative damage. Nine groups of guinea pigs were used to study the effects of exposure to an 1800-MHz Global System for Mobile Communications (GSM)-modulated signal (average whole body Specific Absorption Rate (SAR) of 0.38 W/kg, 10 or 20 min per day for seven days) and treatment with antioxidants. Significant increases in malondialdehyde (MDA) and total nitric oxide (NO(x)) levels and decreases in activities of superoxide dismutase (SOD), myeloperoxidase (MPO) and glutathione peroxidase (GSH-Px) were observed in the liver of guinea pigs after RFR exposure. Only NAC treatment induces increase in hepatic GSH-Px activities, whereas EGCG treatment alone attenuated MDA level. Extent of oxidative damage was found to be proportional to the duration of exposure (P < 0.05). Mobile phone-like radiation induces oxidative damage and changes the activities of antioxidant enzymes in the liver. The adverse effect of RFR may be related to the duration of mobile phone use. NAC and EGCG protect the liver tissue against the RFR-induced oxidative damage and enhance antioxidant enzyme activities.

  8. Plumbagin, a vitamin K3 analogue, abrogates lipopolysaccharide-induced oxidative stress, inflammation and endotoxic shock via NF-κB suppression.

    PubMed

    Checker, Rahul; Patwardhan, Raghavendra S; Sharma, Deepak; Menon, Jisha; Thoh, Maikho; Sandur, Santosh K; Sainis, Krishna B; Poduval, T B

    2014-04-01

    Plumbagin has been reported to modulate cellular redox status and suppress NF-κB. In the present study, we investigated the effect of plumbagin on lipopolysaccharide (LPS)-induced endotoxic shock, oxidative stress and inflammatory parameters in vitro and in vivo. Plumbagin inhibited LPS-induced nitric oxide, TNF-α, IL-6 and prostaglandin-E2 production in a concentration-dependent manner in RAW 264.7 cells without inducing any cell death. Plumbagin modulated cellular redox status in RAW cells. Plumbagin treatment significantly reduced MAPkinase and NF-κB activation in macrophages. Plumbagin prevented mice from endotoxic shock-associated mortality and decreased serum levels of pro-inflammatory markers. Plumbagin administration ameliorated LPS-induced oxidative stress in peritoneal macrophages and splenocytes. Plumbagin also attenuated endotoxic shock-associated changes in liver and lung histopathology and decreased the activation of ERK and NF-κB in liver. These findings demonstrate the efficacy of plumbagin in preventing LPS-induced endotoxemia and also provide mechanistic insights into the anti-inflammatory effects of plumbagin.

  9. Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice

    PubMed Central

    Williams, Jessica A.; Ni, Hong-Min; Ding, Yifeng

    2015-01-01

    Alcoholic liver disease claims two million lives per year. We previously reported that autophagy protected against alcohol-induced liver injury and steatosis by removing damaged mitochondria. However, the mechanisms for removal of these mitochondria are unknown. Parkin is an evolutionarily conserved E3 ligase that is recruited to damaged mitochondria to initiate ubiquitination of mitochondrial outer membrane proteins and subsequent mitochondrial degradation by mitophagy. In addition to its role in mitophagy, Parkin has been shown to have other roles in maintaining mitochondrial function. We investigated whether Parkin protected against alcohol-induced liver injury and steatosis using wild-type (WT) and Parkin knockout (KO) mice treated with alcohol by the acute-binge and Gao-binge (chronic plus acute-binge) models. We found that Parkin protected against liver injury in both alcohol models, likely because of Parkin's role in maintaining a population of healthy mitochondria. Alcohol caused greater mitochondrial damage and oxidative stress in Parkin KO livers compared with WT livers. After alcohol treatment, Parkin KO mice had severely swollen and damaged mitochondria that lacked cristae, which were not seen in WT mice. Furthermore, Parkin KO mice had decreased mitophagy, β-oxidation, mitochondrial respiration, and cytochrome c oxidase activity after acute alcohol treatment compared with WT mice. Interestingly, liver mitochondria seemed able to adapt to alcohol treatment, but Parkin KO mouse liver mitochondria had less capacity to adapt to Gao-binge treatment compared with WT mouse liver mitochondria. Overall, our findings indicate that Parkin is an important mediator of protection against alcohol-induced mitochondrial damage, steatosis, and liver injury. PMID:26159696

  10. Chronic Intermittent Hypoxia and Acetaminophen Induce Synergistic Liver Injury

    PubMed Central

    Savransky, Vladimir; Reinke, Christian; Jun, Jonathan; Bevans-Fonti, Shannon; Nanayakkara, Ashika; Li, Jianguo; Myers, Allen C.; Torbenson, Michael S.; Polotsky, Vsevolod Y.

    2010-01-01

    Obstructive sleep apnea (OSA) leads to chronic intermittent hypoxia (CIH) during sleep. OSA has been associated with liver injury. Acetaminophen (APAP) is one of the most commonly used drugs, which has known hepatotoxicity. The goal of the present study was to examine whether CIH increases liver injury, hepatic oxidative stress and inflammation induced by chronic APAP treatment. C57BL/6J mice were exposed to CIH or intermittent air (IA) for 4 weeks. Mice in both groups were treated with intraperitoneal injections of either APAP (200 mg/kg) or normal saline daily. A combination of CIH and APAP caused liver injury with marked increases in serum alanine aminotransferase, aspartate aminotransferase (AST), gamma glutamyl transferase and total bilirubin levels, whereas CIH alone induced only elevation in serum AST levels. APAP alone did not affect serum levels of liver enzymes. Histopathology revealed hepatic necrosis and increased apoptosis in mice exposed to CIH and APAP, whereas the liver remained intact in all other groups. Mice exposed to CIH and APAP exhibited decreased hepatic glutathione in conjunction with a five-fold increase in nitrotyrosine levels, suggesting formation of toxic peroxynitrite in hepatocytes. APAP or CIH alone had no effect on either glutathione or nitrotyrosine. A combination of CIH and APAP caused marked increases in pro-inflammatory chemokines, monocyte chemoattractant protein-1 and macrophage inflammatory protein-2, which were not observed in mice exposed to CIH or APAP alone. We conclude that CIH and chronic APAP treatment lead to synergistic liver injury, which may have clinical implications for patients with OSA. PMID:19028810

  11. Dietary α-lactalbumin induced fatty liver by enhancing nuclear liver X receptor αβ/sterol regulatory element-binding protein-1c/PPARγ expression and minimising PPARα/carnitine palmitoyltransferase-1 expression and AMP-activated protein kinase α phosphorylation associated with atherogenic dyslipidaemia, insulin resistance and oxidative stress in Balb/c mice.

    PubMed

    López-Oliva, María Elvira; Garcimartin, Alba; Muñoz-Martínez, Emilia

    2017-12-01

    The effect and the role played by dietary α-lactalbumin (α-LAC) on hepatic fat metabolism are yet to be fully elucidated. We reported previously that α-LAC intake induced atherogenic dyslipidaemia in Balb/c mice. The aim of the present study was to investigate if this atherogenic effect could be due to a possible α-LAC-induced hepatic steatosis. We examine the ability of dietary α-LAC to induce liver steatosis, identifying the molecular mechanisms underlying hepatic lipid metabolism in association with the lipid profile, peripheral insulin resistance (IR) and changes in the hepatic oxidative environment. Male Balb/c mice (n 6) were fed with diets containing either chow or 14 % α-LAC for 4 weeks. The α-LAC-fed mice developed abdominal adiposity and IR. Moderate liver steatosis with increased TAG and NEFA contents was correlated with atherogenic dyslipidaemia. There was increased nuclear expression of liver X receptor αβ (LXRαβ), sterol regulatory element-binding protein-1c (SREBP-1c) and PPARγ transcription factors and of the cytosolic enzymes acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase involved in the hepatic de novo lipogenesis. The opposite was found for the nuclear receptor PPARα and the mitochondrial enzyme carnitine palmitoyltransferase-1 (CPT-1), leading to reduced fatty acid β-oxidation (FAO). These changes were associated with a significant decrease in both p-Thr172-AMP-activated protein kinase α (AMPKα) (inactivation) and p-Ser79-ACC1 (activation) and with a more oxidative liver environment increasing lipid peroxidation and protein oxidation and reducing GSH:GSSG ratio in the α-LAC-fed mice. In conclusion, 4 weeks of 14 % α-LAC feeding induced liver steatosis associated with atherogenic dyslipidaemia, IR and oxidative stress by enhancing nuclear LXRαβ/SREBP-1c/PPARγ expression and diminishing PPARα/CPT-1 expression and AMPKα phosphorylation shifting the hepatic FAO toward fatty acid synthesis in Balb/c mice.

  12. Preexposure to Olive Oil Polyphenols Extract Increases Oxidative Load and Improves Liver Mass Restoration after Hepatectomy in Mice via Stress-Sensitive Genes

    PubMed Central

    Marinić, Jelena; Broznić, Dalibor; Milin, Čedomila

    2016-01-01

    Polyphenols can act as oxidants in some conditions, inducing redox-sensitive genes. We investigated the effect of preexposure to the olive oil polyphenols extract (PFE) on time-dependent changes in the hepatic oxidative state in a model of liver regeneration—a process in which oxidative stress associated with the metabolic overload accounts for the early events that contribute to the onset of liver self-repair. Liver regeneration was induced by one-third hepatectomy in mice. Prior to hepatectomy, mice were intraperitoneally given either PFE (50 mg/kg body weight) or saline for seven consecutive days, while respective controls received vehicle alone. Redox state-regulating enzymes and thiol proteins along with the mRNA levels of Nrf2 gene and its targets γ-glutamylcysteine synthetase and heme oxygenase-1 were determined at different time intervals after hepatectomy. The liver mass restoration was calculated to assess hepatic regeneration. The resulting data demonstrate the effectiveness of preexposure to PFE in stimulating liver regeneration in a model of a small tissue loss which may be ascribed to the transient increase in oxidant load during the first hours after hepatectomy and associated induction of stress response gene-profiles under the control of Nrf2. PMID:26925195

  13. 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

  14. Hepatoprotective effect of grape seed oil against carbon tetrachloride induced oxidative stress in liver of γ-irradiated rat.

    PubMed

    Ismail, Amel F M; Salem, Asmaa A M; Eassawy, Mamdouh M T

    2016-07-01

    Carbon tetrachloride (CCl4) and ionizing radiation are well known environmental pollutants that generate free radicals and induce oxidative stress. The liver is the primary and major target organ responsible for the metabolism of drugs, toxic chemicals and affected by irradiation. This study investigated the effect of grape seed oil (GSO) on acute liver injury induced by carbon tetrachloride (CCl4) in γ-irradiated rats (7Gy). CCl4-intoxicated rats exhibited an elevation of ALT, AST activities, IL-6 and TNF-α level in the serum. Further, the levels of MDA, NO, NF-κB and the gene expression of CYP2E1, iNOS and Caspase-3 were increased, and SOD, CAT, GSH-Px, GST activities and GSH content were decreased. Furthermore, silent information regulator protein 1 (SIRT1) gene expression was markedly down-regulated. Additionally, alterations of the trace elements; copper, manganese, zinc and DNA fragmentation was observed in the hepatic tissues of the intoxicated group. These effects were augmented in CCl4-intoxicated-γ-irradiated rats. However, the administration of GSO ameliorated these parameters. GSO exhibit protective effects on CCl4 induced acute liver injury in γ-irradiated rats that could be attributed to its potent antioxidant, anti-inflammatory and anti-apoptotic activities. The induction of the antioxidant enzymes activities, down-regulation of the CYP2E1, iNOS, Caspase-3 and NF-κB expression, up-regulation of the trace elements concentration levels and activation of SIRT1 gene expression are responsible for the improvement of the antioxidant and anti-inflammatory status in the hepatic tissues and could be claimed to be the hepatoprotective mechanism of GSO. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Protective effect of Allium neapolitanum Cyr. versus Allium sativum L. on acute ethanol-induced oxidative stress in rat liver.

    PubMed

    Nencini, Cristina; Franchi, Gian Gabriele; Cavallo, Federica; Micheli, Lucia

    2010-04-01

    This study investigated the protective effect of Allium neapolitanum Cyr., a spontaneous species of the Italian flora, compared with garlic (Allium sativum L.) on liver injury induced by ethanol in rats. Male albino Wistar rats were orally treated with fresh Allium homogenates (leaves or bulbs, 250 mg/kg) daily for 5 days, whereas controls received vehicle only. At the end of the experimental 5-day period, the animals received an acute ethanol dose (6 mL/kg, i.p.) 2 hours before the last Allium administration and were sacrificed 6 hours after ethanol administration. The activities of catalase (CAT), superoxide dismutase (SOD), and glutathione reductase (GR) and the levels of malondialdehyde (MDA), ascorbic acid (AA), and reduced (GSH) and oxidized glutathione in liver tissue were determined. Administration of both Allium species for 5 days (leaves or bulbs) led to no statistical variation of nonenzymatic parameters versus the control group; otherwise Allium treatment caused an increase of GSH and AA levels compared with the ethanol group and a diminution of MDA levels, showing in addition that A. neapolitanum bulb had the best protective effect. Regarding to enzymatic parameters, GR and CAT activities were enhanced significantly compared with the ethanol group, whereas SOD activity showed a trend different from other parameters estimated. However, the treatment with both Allium species followed by acute ethanol administration reestablished the nonenzymatic parameters similar to control values and enhanced the activities of the enzymes measured. These results suggest that fresh Allium homogenates (leaves or bulbs) possess antioxidant properties and provide protection against ethanol-induced liver injury.

  16. Antioxidant and antiapoptotic effects of green tea polyphenols against azathioprine-induced liver injury in rats.

    PubMed

    El-Beshbishy, Hesham A; Tork, Ola M; El-Bab, Mohamed F; Autifi, Mohamed A

    2011-04-01

    Green tea polyphenols (GTP) is considered to have protective effects against several diseases. The hepatotoxicity of azathioprine (AZA) has been reported and was found to be associated with oxidative damage. This study was conducted to evaluate the role of GTP to protect against AZA-induced liver injury in rats. AZA was administered i.p. in a single dose (50mgkg(-1)) to adult male rats. AZA-intoxicated rats were orally administered GTP (either 100mgkg(-1)day(-1) or 300mgkg(-1)day(-1), for 21 consecutive days, started 7 days prior AZA injection). AZA administration to rats resulted in significant elevation of serum transaminases (sALT and sAST), alkaline phosphatase (sALP), depletion of hepatic reduced glutathione (GSH), catalase (CAT) and glutathione peroxidase (GPx), accumulation of oxidized glutathione (GSSG), elevation of lipid peroxides (LPO) expressed as malondialdehyde (MDA), reduction of the hepatic total antioxidant activity (TAA), decrease serum total proteins and elevation of liver protein carbonyl content. Significant rises in liver tumor necrosis factor-alpha (TNF-α) and caspase-3 levels were noticed in AZA-intoxicated rats. Treatment of the AZA-intoxicated rats with GTP significantly prevented the elevations of sALT, sAST and sALP, inhibited depletion of hepatic GSH, GPx, CAT and GSSG and inhibited MDA accumulation. Furthermore, GTP had normalized serum total proteins and hepatic TAA, CAT, TNF-α and caspase-3 levels of AZA-intoxicated rats. In addition, GTP prevented the AZA-induced apoptosis and liver injury as indicated by the liver histopathological analysis. The linear regression analysis showed significant correlation in either AZA-GTP100 or AZA-GTP300 groups between TNF-α and each of serum ALT, AST, ALP and total proteins and liver TAA, GPX, CAT, GSH, GSSG, MDA and caspase-3 levels. However, liver TNF-α produced non-significant correlation with the serum total proteins in both AZA-GTP100 and AZA-GTP300 groups. In conclusion, our data indicate

  17. Evidence That the Capacity of Nongenotoxic Carcinogens to Induce Oxidative Stress Is Subject to Marked Variability

    PubMed Central

    Henderson, Colin J.; Cameron, Amy R.; Chatham, Lynsey; Stanley, Lesley A.; Wolf, Charles Roland

    2015-01-01

    Many drugs and environmental chemicals which are not directly mutagenic have the capacity to increase the incidence of tumors in the liver and other tissues. For this reason, such compounds are known as nongenotoxic carcinogens. The mechanisms underlying their effects remain unclear; however, their capacity to induce oxidative stress is considered to be a critical step in the carcinogenic process, although the evidence that this is actually the case remains equivocal and sparse. We have exploited a novel heme oxygenase-1 reporter mouse to evaluate the capacity of nongenotoxic carcinogens with different mechanisms of action to induce oxidative stress in the liver in vivo. When these compounds were administered at doses reported to cause liver tumors, marked differences in activation of the reporter were observed. 1,4-Dichlorobenzene and nafenopin were strong inducers of oxidative stress, whereas phenobarbital, piperonyl butoxide, cyproterone acetate, and WY14,643 were, at best, only very weak inducers. In the case of phenobarbital and thioacetamide, the number of LacZ-positive hepatocytes increased with time, and for the latter also with dose. The data obtained demonstrate that although some nongenotoxic carcinogens can induce oxidative stress, it is not a dominant feature of the response to these compounds. Therefore in contrast to the current models, these data suggest that oxidative stress is not a key determinant in the mechanism of nongenotoxic carcinogenesis but may contribute to the effects in a compound-specific manner. PMID:25690736

  18. Antioxidant and hepatoprotective effects of A. cerana honey against acute alcohol-induced liver damage in mice.

    PubMed

    Zhao, Haoan; Cheng, Ni; He, Liangliang; Peng, Guoxia; Xue, Xiaofeng; Wu, Liming; Cao, Wei

    2017-11-01

    A. cerana honey, gathered from Apis cerana Fabricius (A. cerana), has not been fully studied. Samples of honey originating from six geographical regions (mainly in the Qinling Mountains of China) were investigated to determine their antioxidant and hepatoprotective effects against acute alcohol-induced liver damage. The results showed that A. cerana honeys from the Qinling Mountains had high total phenolic contents (345.1-502.1mgGAkg -1 ), ascorbic acid contents (153.8-368.4mgkg -1 ), and strong antioxidant activities in DPPH radical scavenging activity assays (87.5-136.2IC50mgmL -1 ), ferric reducing antioxidant powers (191.8-317.4mgTroloxkg -1 ), and ferrous ion-chelating activities (27.5-35.5mgNa 2 EDTAkg -1 ). Pretreatment with A. cerana honey (Qinling Mountains) at 5, 10, or 20gkg -1 twice daily for 12weeks significantly inhibited serum lipoprotein oxidation and increased serum radical absorbance capacity (ORAC) (P<0.05). Moreover, A. cerana honey inhibited acute alcohol-induced increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum (P<0.05), reduced the production of hepatic malondialdehyde (MDA) (P<0.05), and promoted superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities (P<0.05). More importantly, it also remarkably inhibited the level of TGF-β1 in the serum and liver (P<0.05). The results of this study indicate that administration of A. cerana honey prevents acute alcohol-induced liver damage likely because of its antioxidant properties and ability to prevent oxidative stress. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Uridine prevents tamoxifen-induced liver lipid droplet accumulation

    PubMed Central

    2014-01-01

    Background Tamoxifen, an agonist of estrogen receptor, is widely prescribed for the prevention and long-term treatment of breast cancer. A side effect of tamoxifen is fatty liver, which increases the risk for non-alcoholic fatty liver disease. Prevention of tamoxifen-induced fatty liver has the potential to improve the safety of long-term tamoxifen usage. Methods Uridine, a pyrimidine nucleoside with reported protective effects against drug-induced fatty liver, was co-administered with tamoxifen in C57BL/6J mice. Liver lipid levels were evaluated with lipid visualization using coherent anti-Stokes Raman scatting (CARS) microscopy, biochemical assay measurement of triacylglyceride (TAG), and liquid chromatography coupled with mass spectrometry (LC-MS) measurement of membrane phospholipid. Blood TAG and cholesterol levels were measured. Mitochondrial respiration of primary hepatocytes in the presence of tamoxifen and/or uridine was evaluated by measuring oxygen consumption rate with an extracellular flux analyzer. Liver protein lysine acetylation profiles were evaluated with 1D and 2D Western blots. In addition, the relationship between endogenous uridine levels, fatty liver, and tamoxifen administration was evaluated in transgenic mice UPase1−/−and UPase1-TG. Results Uridine co-administration prevented tamoxifen-induced liver lipid droplet accumulation in mice. The most prominent effect of uridine co-administration with tamoxifen was the stimulation of liver membrane phospholipid biosynthesis. Uridine had no protective effect against tamoxifen-induced impairment to mitochondrial respiration of primary hepatocytes or liver TAG and cholesterol export. Uridine had no effect on tamoxifen-induced changes to liver protein acetylation profile. Transgenic mice UPase1−/−with increased pyrimidine salvage activity were protected against tamoxifen-induced liver lipid droplet accumulation. In contrast, UPase1-TG mice with increased pyrimidine catabolism activity had

  20. Uridine prevents tamoxifen-induced liver lipid droplet accumulation.

    PubMed

    Le, Thuc T; Urasaki, Yasuyo; Pizzorno, Giuseppe

    2014-05-23

    Tamoxifen, an agonist of estrogen receptor, is widely prescribed for the prevention and long-term treatment of breast cancer. A side effect of tamoxifen is fatty liver, which increases the risk for non-alcoholic fatty liver disease. Prevention of tamoxifen-induced fatty liver has the potential to improve the safety of long-term tamoxifen usage. Uridine, a pyrimidine nucleoside with reported protective effects against drug-induced fatty liver, was co-administered with tamoxifen in C57BL/6J mice. Liver lipid levels were evaluated with lipid visualization using coherent anti-Stokes Raman scatting (CARS) microscopy, biochemical assay measurement of triacylglyceride (TAG), and liquid chromatography coupled with mass spectrometry (LC-MS) measurement of membrane phospholipid. Blood TAG and cholesterol levels were measured. Mitochondrial respiration of primary hepatocytes in the presence of tamoxifen and/or uridine was evaluated by measuring oxygen consumption rate with an extracellular flux analyzer. Liver protein lysine acetylation profiles were evaluated with 1D and 2D Western blots. In addition, the relationship between endogenous uridine levels, fatty liver, and tamoxifen administration was evaluated in transgenic mice UPase1-/-and UPase1-TG. Uridine co-administration prevented tamoxifen-induced liver lipid droplet accumulation in mice. The most prominent effect of uridine co-administration with tamoxifen was the stimulation of liver membrane phospholipid biosynthesis. Uridine had no protective effect against tamoxifen-induced impairment to mitochondrial respiration of primary hepatocytes or liver TAG and cholesterol export. Uridine had no effect on tamoxifen-induced changes to liver protein acetylation profile. Transgenic mice UPase1-/-with increased pyrimidine salvage activity were protected against tamoxifen-induced liver lipid droplet accumulation. In contrast, UPase1-TG mice with increased pyrimidine catabolism activity had intrinsic liver lipid droplet

  1. The pathogenesis of diclofenac induced immunoallergic hepatitis in a canine model of liver injury

    PubMed Central

    Selvaraj, Saravanakumar; Oh, Jung-Hwa; Spanel, Reinhard; Länger, Florian; Han, Hyoung-Yun; Lee, Eun-Hee; Yoon, Seokjoo; Borlak, Jürgen

    2017-01-01

    Hypersensitivity to non-steroidal anti-inflammatory drugs is a common adverse drug reaction and may result in serious inflammatory reactions of the liver. To investigate mechanism of immunoallergic hepatitis beagle dogs were given 1 or 3 mg/kg/day (HD) oral diclofenac for 28 days. HD diclofenac treatment caused liver function test abnormalities, reduced haematocrit and haemoglobin but induced reticulocyte, WBC, platelet, neutrophil and eosinophil counts. Histopathology evidenced hepatic steatosis and glycogen depletion, apoptosis, acute lobular hepatitis, granulomas and mastocytosis. Whole genome scans revealed 663 significantly regulated genes of which 82, 47 and 25 code for stress, immune response and inflammation. Immunopathology confirmed strong induction of IgM, the complement factors C3&B, SAA, SERPING1 and others of the classical and alternate pathway. Alike, marked expression of CD205 and CD74 in Kupffer cells and lymphocytes facilitate antigen presentation and B-cell differentiation. The highly induced HIF1A and KLF6 protein expression in mast cells and macrophages sustain inflammation. Furthermore, immunogenomics discovered 24, 17, 6 and 11 significantly regulated marker genes to hallmark M1/M2 polarized macrophages, lymphocytic and granulocytic infiltrates; note, the latter was confirmed by CAE staining. Other highly regulated genes included alpha-2-macroglobulin, CRP, hepcidin, IL1R1, S100A8 and CCL20. Diclofenac treatment caused unprecedented induction of myeloperoxidase in macrophages and oxidative stress as shown by SOD1/SOD2 immunohistochemistry. Lastly, bioinformatics defined molecular circuits of inflammation and consisted of 161 regulated genes. Altogether, the mechanism of diclofenac induced liver hypersensitivity reactions involved oxidative stress, macrophage polarization, mastocytosis, complement activation and an erroneous programming of the innate and adaptive immune system. PMID:29296203

  2. Forsythia suspensa extract attenuates lipopolysaccharide-induced inflammatory liver injury in rats via promoting antioxidant defense mechanisms.

    PubMed

    Zhao, Panfeng; Piao, Xiangshu; Pan, Long; Zeng, Zhikai; Li, Qingyun; Xu, Xiao; Wang, Hongliang

    2017-06-01

    Reactive oxygen species (ROS) have been shown to have a role in inflammation. We investigated whether Forsythia suspensa extract (FSE) could exert its antioxidant potential against lipopolysaccharide (LPS)-induced inflammatory liver injury in rats. Rats were orally fed FSE once daily for 7 consecutive days prior to LPS (Escherichia coli, serotype O55:B5) injection. LPS treatment caused liver dysfunction as evidenced by massive histopathological changes and increased serum alanine aminotransferase and aspartate aminotransferase activities which were ameliorated by FSE pretreatment. FSE attenuated LPS-induced depletion of cytosolic nuclear factor-erythroid 2-related factor 2 (Nrf2) and suppression of Nrf2 nuclear translocation in liver, and the generation of ROS and malondialdehyde in serum and liver. FSE increased the Nrf2-mediated induction of heme oxygenase-1 in liver, as well as superoxide dismutase and glutathione peroxidase activities in serum and liver. Importantly, FSE attenuated LPS-induced nuclear factor-кB (NF-кB) nuclear translocation in liver, and subsequently decreased tumor necrosis factor-α, interleukin (IL)-1β and IL-6 levels in serum and liver, which were associated with FSE-induced activation of Nrf2 in liver. These results indicate that the protective mechanisms of FSE may be involved in the attenuation of oxidative stress and the inhibition of the NF-кB-mediated inflammatory response by modulating the Nrf2-mediated antioxidant response against LPS-induced inflammatory liver injury. © 2016 Japanese Society of Animal Science.

  3. Virgin coconut oil supplementation attenuates acute chemotherapy hepatotoxicity induced by anticancer drug methotrexate via inhibition of oxidative stress in rats.

    PubMed

    Famurewa, Ademola C; Ufebe, Odomero G; Egedigwe, Chima A; Nwankwo, Onyebuchi E; Obaje, Godwin S

    2017-03-01

    The emerging health benefit of virgin coconut oil (VCO) has been associated with its potent natural antioxidants; however, the antioxidant and hepatoprotective effect of VCO against methotrexate-induced liver damage and oxidative stress remains unexplored. The study explored the antioxidant and hepatoprotective effects of VCO against oxidative stress and liver damage induced by anticancer drug methotrexate (MTX) in rats. Liver damage was induced in Wistar rats pretreated with dietary supplementation of VCO (5% and 15%) by intraperitoneal administration of MTX (20mg/kg bw) on day 10 only. After 12days of treatment, assays for serum liver biomarkers (aminotransferases), alkaline phosphatase, albumin and total protein as well as hepatic content of malondialdehyde, reduced glutathione and antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) were carried out. Liver was used to examine histopathological changes. MTX administration induced significant increase in serum liver enzymes along with marked decrease in albumin and total protein compared to control group. Hepatic activities of antioxidant enzymes were significantly decreased, while malondialdehyde increased significantly. Treatment with VCO supplemented diet prior to MTX administration attenuated MTX-induced liver injury and oxidative stress evidenced by significant improvements in serum liver markers, hepatic antioxidant enzymes and malondialdehyde comparable to control group. Histopathological alterations were prevented and correlated well with the biochemical indices. The study suggests antioxidant and hepatoprotective effects of VCO supplementation against hepatotoxicity and oxidative damage via improving antioxidant defense system in rats. Our findings may have beneficial application in the management of hepatotoxicity associated with MTX cancer chemotherapy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  4. Protective effects of extracts from Pomegranate peels and seeds on liver fibrosis induced by carbon tetrachloride in rats.

    PubMed

    Wei, Xiang-Lan; Fang, Ru-Tang; Yang, Yong-Hua; Bi, Xue-Yuan; Ren, Guo-Xia; Luo, A-Li; Zhao, Ming; Zang, Wei-Jin

    2015-10-27

    Liver fibrosis is a feature in the majority of chronic liver diseases and oxidative stress is considered to be its main pathogenic mechanism. Antioxidants including vitamin E, are effective in preventing liver fibrogenesis. Several plant-drived antioxidants, such as silymarin, baicalin, beicalein, quercetin, apigenin, were shown to interfere with liver fibrogenesis. The antioxidans above are polyphenols, flavonoids or structurally related compounds which are the main chemical components of Pomegranate peels and seeds, and the antioxidant activity of Pomegranate peels and seeds have been verified. Here we investigated whether the extracts of pomegranate peels (EPP) and seeds (EPS) have preventive efficacy on liver fibrosis induced by carbon tetrachloride (CCl4) in rats and explored its possible mechanisms. The animal model was established by injection with 50 % CCl4 subcutaneously in male wistar rats twice a week for four weeks. Meanwhile, EPP and EPS were administered orally every day for 4 weeks, respectively. The protective effects of EPP and EPS on biochemical metabolic parameters, liver function, oxidative markers, activities of antioxidant enzymes and liver fibrosis were determined in CCl4-induced liver toxicity in rats. Compared with the sham group, the liver function was worse in CCl4 group, manifested as increased levels of serum alanine aminotransferase, aspartate aminotransferase and total bilirubin. EPP and EPS treatment significantly ameliorated these effects of CCl4. EPP and EPS attenuated CCl4-induced increase in the levels of TGF-β1, hydroxyproline, hyaluronic acid laminin and procollagen type III. They also restored the decreased superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities and inhibited the formation of lipid peroxidized products in rats treated with CCl4. The EPP and EPS have protective effects against liver fibrosis induced by CCl4, and its mechanisms might be associated with their antioxidant activity, the ability of

  5. Olive oil and leaf extract prevent fluoxetine-induced hepatotoxicity by attenuating oxidative stress, inflammation and apoptosis.

    PubMed

    Elgebaly, Hassan A; Mosa, Nermeen M; Allach, Mariam; El-Massry, Khaled F; El-Ghorab, Ahmed H; Al Hroob, Amir M; Mahmoud, Ayman M

    2018-02-01

    Olive oil and leaf extract have several health benefits; however, their beneficial effect against fluoxetine-induced liver injury has not been investigated. The present study aimed to scrutinize the impact of fluoxetine on the liver of rats and to evaluate the protective effects of olive oil and leaf extract. Rats received fluoxetine orally at dose of 10 mg/kg body weight for 7 consecutive days. The fluoxetine-induced rats were concurrently treated with olive oil or leaf extract. At the end of the experiment, blood and liver samples were collected for analysis. Fluoxetine administration significantly increased circulating ALT, AST, ALP and the pro-inflammatory cytokines TNF-α and IL-1β levels in rats. Histological analysis showed several alterations, such as inflammatory cells infiltration, hepatocyte vacuolation and dilated sinusoids in the liver of fluoxetine-induced rats. Concurrent supplementation of olive oil and olive leaf extract significantly reduced circulating liver function marker enzymes and pro-inflammatory cytokines, and prevented fluoxetine-induced histological alterations. Both olive oil and leaf extract significantly decreased liver lipid peroxidation and nitric oxide, and ameliorated liver glutathione, superoxide dismutase, catalase and glutathione peroxidase. In addition, olive oil and leaf extract prevented fluoxetine-induced apoptosis in the liver of rats as evidenced by decreased expression of Bax and caspase-3, and up-regulated expression of Bcl-2. In conclusion, olive oil and leaf extract protect against fluoxetine-induced liver injury in rats through attenuation of oxidative stress, inflammation and apoptosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Dietary fructose augments ethanol-induced liver pathology.

    PubMed

    Thomes, Paul G; Benbow, Jennifer H; Brandon-Warner, Elizabeth; Thompson, Kyle J; Jacobs, Carl; Donohue, Terrence M; Schrum, Laura W

    2017-05-01

    Certain dietary components when combined with alcohol exacerbate alcohol-induced liver injury (ALI). Here, we tested whether fructose, a major ingredient of the western diet, enhances the severity of ALI. We fed mice ethanol for 8 weeks in the following Lieber-DeCarli diets: (a) Regular (contains olive oil); (b) corn oil (contains corn oil); (c) fructose (contains fructose and olive oil) and (d) corn+fructose (contains fructose and corn oil). We compared indices of metabolic function and liver pathology among the different groups. Mice fed fructose-free and fructose-containing ethanol diets exhibited similar levels of blood alcohol, blood glucose and signs of disrupted hepatic insulin signaling. However, only mice given fructose-ethanol diets showed lower insulin levels than their respective controls. Compared with their respective pair-fed controls, all ethanol-fed mice exhibited elevated levels of serum ALT; the inflammatory cytokines TNF-α, MCP-1 and MIP-2; hepatic lipid peroxides and triglycerides. All the latter parameters were significantly higher in mice given fructose-ethanol diets than those fed fructose-free ethanol diets. Mice given fructose-free or fructose-containing ethanol diets each had higher levels of hepatic lipogenic enzymes than controls. However, the level of the lipogenic enzyme fatty acid synthase (FAS) was significantly higher in livers of mice given fructose control and fructose-ethanol diets than in all other groups. Our findings indicate that dietary fructose exacerbates ethanol-induced steatosis, oxidant stress, inflammation and liver injury, irrespective of the dietary fat source, to suggest that inclusion of fructose in or along with alcoholic beverages increases the risk of more severe ALI in heavy drinkers. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Synergistic hepatoprotective potential of ethanolic extract of Solanum xanthocarpum and Juniperus communis against paracetamol and azithromycin induced liver injury in rats.

    PubMed

    Singh, Hem; Prakash, Atish; Kalia, A N; Majeed, Abu Bakar Abdul

    2016-10-01

    Previously explored combination therapies mostly involved the use of bioactive molecules. It is believed that herbal compounds containing multiple plant products have synergistic hepatoprotective effects and could enhance the desired actions. To investigate the combination of ethanolic fruits extract of Solanum xanthocarpum (SX) and Juniperus communis (JC) against Paracetamol (PCM) and Azithromycin (AZM) induced liver toxicity in rats. Liver toxicity was induced by combine oral administration of PCM (250 mg/kg) and AZM (200 mg/kg) for 7 days in Wistar rats. Fruit extract of SX (200 and 400 mg/kg) and JC (200 and 400 mg/kg) were administered daily for 14 days. The hepatoprotective activity was assessed using liver functional test, oxidative parameters and histopathological examination. The results demonstrated that combine administration of AZM and PCM significantly produced liver toxicity by increasing the serum level of hepatic enzymes and oxidative parameters in liver of rats. Histopathological examination also indicated that AZM and PCM produced liver damage in rats. Chronic treatment of SX and JC extract significantly and dose-dependently attenuated the liver toxicity by normalizing the biochemical factors and no gross histopathological changes were observed in liver of rats. Furthermore, combine administration of lower dose of SX and JC significantly potentiated their hepatoprotective effect which was significant as compared to their effect per se. The results clearly indicated that SX and JC extract has hepatoprotective potential against AZM and PCM induced liver toxicity due to their synergistic anti-oxidant properties.

  8. Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice.

    PubMed

    Williams, Jessica A; Ni, Hong-Min; Ding, Yifeng; Ding, Wen-Xing

    2015-09-01

    Alcoholic liver disease claims two million lives per year. We previously reported that autophagy protected against alcohol-induced liver injury and steatosis by removing damaged mitochondria. However, the mechanisms for removal of these mitochondria are unknown. Parkin is an evolutionarily conserved E3 ligase that is recruited to damaged mitochondria to initiate ubiquitination of mitochondrial outer membrane proteins and subsequent mitochondrial degradation by mitophagy. In addition to its role in mitophagy, Parkin has been shown to have other roles in maintaining mitochondrial function. We investigated whether Parkin protected against alcohol-induced liver injury and steatosis using wild-type (WT) and Parkin knockout (KO) mice treated with alcohol by the acute-binge and Gao-binge (chronic plus acute-binge) models. We found that Parkin protected against liver injury in both alcohol models, likely because of Parkin's role in maintaining a population of healthy mitochondria. Alcohol caused greater mitochondrial damage and oxidative stress in Parkin KO livers compared with WT livers. After alcohol treatment, Parkin KO mice had severely swollen and damaged mitochondria that lacked cristae, which were not seen in WT mice. Furthermore, Parkin KO mice had decreased mitophagy, β-oxidation, mitochondrial respiration, and cytochrome c oxidase activity after acute alcohol treatment compared with WT mice. Interestingly, liver mitochondria seemed able to adapt to alcohol treatment, but Parkin KO mouse liver mitochondria had less capacity to adapt to Gao-binge treatment compared with WT mouse liver mitochondria. Overall, our findings indicate that Parkin is an important mediator of protection against alcohol-induced mitochondrial damage, steatosis, and liver injury. Copyright © 2015 the American Physiological Society.

  9. Establishment of the Tree Shrew as an Alcohol-Induced Fatty Liver Model for the Study of Alcoholic Liver Diseases

    PubMed Central

    Xing, Huijie; Jia, Kun; He, Jun; Shi, Changzheng; Fang, Meixia; Song, Linliang; Zhang, Pu; Zhao, Yue; Fu, Jiangnan; Li, Shoujun

    2015-01-01

    Currently, the pathogenesis of alcoholic liver diseases (ALDs) is not clear. As a result, there is no effective treatment for ALDs. One limitation is the lack of a suitable animal model for use in studying ALDs. The tree shrew is a lower primate animal, characterized by a high-alcohol diet. This work aimed to establish a fatty liver model using tree shrews and to assess the animals’ suitability for the study of ALDs. Tree shrews were treated with alcohol solutions (10% and 20%) for two weeks. Hemophysiology, blood alcohol concentrations (BACs), oxidative stress factors, alcohol metabolic enzymes and hepatic pathology were checked and assayed with an automatic biochemical analyzer, enzyme-linked immunosorbent assay (ELISA), western blot, hematoxylin-eosin (HE) staining and oil red O staining, and magnetic resonance imaging (MRI). Compared with the normal group, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), total cholesterol (TC), triglyceride (TG), reactive oxygen species (ROS), and malondialdehyde (MDA) were significantly enhanced in alcohol-treated tree shrews. However, the activity of reduced glutathione hormone (GSH) and superoxide dismutase (SOD) declined. Notable changes in alcohol dehydrogenase(ADH1), aldehyde dehydrogenase(ALDH2), CYP2E1, UDP-glucuronosyl transferase 1A1 (UGT1A1) and nuclear factor erythroid-related factor 2 (Nrf2) were observed. HE and oil red O staining showed that hepatocyte swelling, hydropic degeneration, and adipohepatic syndrome occurred in the tree shrews. Alcohol can induce fatty liver-like pathological changes and result in alterations in liver function, oxidative stress factors, alcohol metabolism enzymes and Nrf2. Therefore, the established fatty liver model of tree shrews induced by alcohol should be a promising tool for the study of ALDs. PMID:26030870

  10. 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. © 2015 by the Association of Clinical Scientists, Inc.

  11. Polyenylphosphatidylcholine attenuates alcohol-induced fatty liver and hyperlipemia in rats.

    PubMed

    Navder, K P; Baraona, E; Lieber, C S

    1997-09-01

    Chronic administration of a soybean-derived polyenylphosphatidylcholine (PPC) extract prevents the development of cirrhosis in alcohol-fed baboons. To assess whether this phospholipid also affects earlier changes induced by alcohol consumption (such as fatty liver and hyperlipemia), 28 male rat littermates were pair-fed liquid diets containing 36% of energy either as ethanol or as additional carbohydrate for 21 d, and killed 90 min after intragastric administration of the corresponding diets. Half of the rats were given PPC (3 g/l), whereas the other half received the same amount of linoleate (as safflower oil) and choline (as bitartrate salt). PPC did not affect diet or alcohol consumption [15.4 +/- 0.5 G/(kg.d)], but the ethanol-induced hepatomegaly and the hepatic accumulation of lipids (principally triglycerides and cholesterol esters) and proteins were about half those in rats not given PPC. The ethanol-induced postprandial hyperlipemia was lower with PPC than without, despite an enhanced fat absorption and no difference in the level of plasma free fatty acids. The attenuation of fatty liver and hyperlipemia was associated with correction of the ethanol-induced inhibition of mitochondrial oxidation of palmitoyl-1-carnitine and the depression of cytochrome oxidase activity, as well as the increases in activity of serum glutamate dehydrogenase and aminotransferases. Thus, PPC attenuates early manifestations of alcohol toxicity, at least in part, by improving mitochondrial injury. These beneficial effects of PPC at the initial stages of alcoholic liver injury may prevent or delay the progression to more advanced forms of alcoholic liver disease.

  12. Dietary Fisetin Supplementation Protects Against Alcohol-Induced Liver Injury in Mice.

    PubMed

    Sun, Qian; Zhang, Wenliang; Zhong, Wei; Sun, Xinguo; Zhou, Zhanxiang

    2016-10-01

    Overproduction of reactive oxygen species is associated with the development of alcoholic liver disease (ALD). Plant polyphenols have been used as dietary interventions for multiple diseases including ALD. The objective of this study was to determine whether dietary supplementation with fisetin, a novel flavonoid, exerts beneficial effect on alcohol-induced liver injury. C57BL/6J mice were pair-fed with the Lieber-DeCarli control or ethanol (EtOH) diet for 4 weeks with or without fisetin supplementation at 10 mg/kg/d. Alcohol feeding induced lipid accumulation in the liver and increased plasma alanine aminotransferase and aspartate aminotransferase activities, which were attenuated by fisetin supplementation. The EtOH concentrations in the plasma and liver were significantly elevated by alcohol exposure but were reduced by fisetin supplementation. Although fisetin did not affect the protein expression of alcohol metabolism enzymes, the aldehyde dehydrogenase activities were significantly increased by fisetin compared to the alcohol alone group. In addition, fisetin supplementation remarkably reduced hepatic NADPH oxidase 4 levels along with decreased plasma hydrogen peroxide and hepatic superoxide and 4-hydroxynonenal levels after alcohol exposure. Alcohol-induced apoptosis and up-regulation of Fas and cleaved caspase-3 in the liver were prevented by fisetin. Moreover, fisetin supplementation attenuated alcohol-induced hepatic steatosis through increasing plasma adiponectin levels and hepatic protein levels of p-AMPK, ACOX1, CYP4A, and MTTP. This study demonstrated that the protective effect of fisetin on ALD is achieved by accelerating EtOH clearance and inhibition of oxidative stress. The data suggest that fisetin has a therapeutical potential for treating ALD. Copyright © 2016 by the Research Society on Alcoholism.

  13. Dietary fisetin supplementation protects against alcohol-induced liver injury in mice

    PubMed Central

    Sun, Qian; Zhang, Wenliang; Zhong, Wei; Sun, Xinguo; Zhou, Zhanxiang

    2016-01-01

    Background Overproduction of reactive oxygen species (ROS) is associated with the development of alcoholic liver disease (ALD). Plant polyphenols have been used as dietary inverventions for multiple diseases including ALD. The objective of the present study was to determine whether dietary supplementation with fisetin, a novel flavonoid, exerts beneficial effect on alcohol-induced liver injury. Methods C57BL/6J mice were pair-fed with the Lieber-DeCarli control or ethanol diet for four weeks with or without fisetin supplementation at 10 mg/kg/d. Results Alcohol feeding induced lipid accumulation in the liver and increased plasma ALT and AST activities, which were attenuated by fisetin suplementation. The ethanol concentrations in the plasma and liver were significantly elevated by alcohol exposure but were reduced by fisetin suplementation. Although fisetin did not affect the protein expression of alcohol metabolism enzymes, the aldehyde dehydrogenase activities were significantly increased by fisetin compared to the alcohol alone group. In addition, fisetin suplementation remarkably reduced hepatic NADPH oxidase 4 (NOX4) levels along with decreased plasma hydrogen peroxide and hepatic superoxide and 4-hydroxynonenal (4HNE) levels after alcohol exposure. Alcohol-induced apoptosis and upregulation of Fas and cleaved caspase-3 in the liver were prevented by fisetin. Moreover, fisetin suplementation attenuated alcohol-induced hepatic streatosis through increasing plasma adiponectin levels and hepatic protein levels of p-AMPK, ACOX1, CYP4A, and MTTP. Conclusion The present study demonstrated that the protective effect of fisetin on ALD is achieved by accelerating ethanol clearance and inhibition of oxidative stress. The data suggest that fisetin has a therapeutical potential for treating ALD. PMID:27575873

  14. Protective effect of Chlorogenic acid against methotrexate induced oxidative stress, inflammation and apoptosis in rat liver: An experimental approach.

    PubMed

    Ali, Nemat; Rashid, Summya; Nafees, Sana; Hasan, Syed Kazim; Shahid, Ayaz; Majed, Ferial; Sultana, Sarwat

    2017-06-25

    Methotrexate (MTX) is a drug which is used to treat different types of cancers but hepatotoxicity limits its clinical use. Chlorogenic acid (CGA) is one of the most abundant naturally occurring polyphenols in the human diet. Here, we assessed the effect of CGA against MTX-induced hepatotoxicity and investigated the underlying possible mechanisms in Wistar Rats. Rats were pre-treated with CGA (50 or 100 mg kg/b.w) and administered a single dose of MTX (20 mg/kg, b.w.). MTX caused hepatotoxicity as evidenced by significant increase in serum toxicity markers, histopathological changes. decreased activities of anti-oxidant armory (SOD, CAT, GPx, GR) and GSH content. MTX significantly causes upregulation of iNOS, Cox-2, Bax and downregulation of Bcl-2 expressions, it causes higher caspase 3, 9 activities. However CGA pretreatment alleviates the hepatotoxicity by decreasing the oxidative stress. CGA inhibited Cox-2, iNOS, Bax, Bcl-2 and Caspases 3, 9 mediated inflammation and apoptosis, and improve the histology induced by MTX. Thus, these findings demonstrated the hepatoprotective nature of CGA by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in hepatic tissue. These results imply that CGA has perfective effect against MTX-induced liver injury. Hence CGA supplementation might be helpful in abrogation of MTX toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Isofuranodiene, the main volatile constituent of wild celery (Smyrnium olusatrum L.), protects d-galactosamin/lipopolysacchride-induced liver injury in rats.

    PubMed

    Li, Wenping; Shi, Jingshan; Papa, Fabrizio; Maggi, Filippo; Chen, Xiuping

    2016-01-01

    Isofuranodiene is a natural sesquiterpene rich occurring in Smyrnium olusatrum, a forgotten culinary herb which was marginalised after the domestication of the improved form of celery. Our recent data showed that isofuranodiene inhibited the proliferation and induced apoptosis in cancer cells. In this study, we investigated its protective effect on d-galactosamine/lipopolysacchride (GalN/LPS)-induced liver injury in SD rats. Oral administration of isofuranodiene (20 and 50 mg/kg) dramatically inhibited GalN/LPS-induced serum elevation of aspartate aminotransferase, alanine aminotransferase and malondialdehyde levels, and significantly ameliorated liver injury as evidenced by the histological improvement in H&E staining. Furthermore, isofuranodiene treatment significantly inhibited GalN/LPS-induced mRNA expression of IL-1β, IL-6 and inducible nitric oxide synthase in liver tissues. The results from this study showed that isofuranodiene protects GalN/LPS-induced liver injury in SD rats and suggested that it may be a potential functional food ingredient for the prevention and treatment of liver diseases.

  16. Abacavir-induced liver toxicity.

    PubMed

    Pezzani, Maria Diletta; Resnati, Chiara; Di Cristo, Valentina; Riva, Agostino; Gervasoni, Cristina

    2016-01-01

    Abacavir-induced liver toxicity is a rare event almost exclusively occurring in HLA B*5701-positive patients. Herein, we report one case of abnormal liver function tests occurring in a young HLA B*5701-negative woman on a stable nevirapine-based regimen with no history of liver problems or alcohol abuse after switching to abacavir from tenofovir. We also investigated the reasons for abacavir discontinuation in a cohort of patients treated with abacavir-lamivudine-nevirapine. Copyright © 2016 Elsevier Editora Ltda. All rights reserved.

  17. Amelioration of CCl4-induced liver injury in rats by selenizing Astragalus polysaccharides: Role of proinflammatory cytokines, oxidative stress and hepatic stellate cells.

    PubMed

    Hamid, Mohammed; Liu, Dandan; Abdulrahim, Yassin; Liu, Yunhuan; Qian, Gang; Khan, Alamzeb; Gan, Fang; Huang, Kehe

    2017-10-01

    Selenizing Astragalus polysaccharides (sAPS) were prepared by nitric acid-sodium selenite method. Effect of sAPS on carbon tetrachloride (CCl4)-induced liver injury and the underlying mechanisms were investigated in the rat. Forty male Wistar rats were divided into five equal groups as follows: control group; CCl 4 group; CCl 4 +Astragalus polysaccharides group; CCl 4 +sodium selenite group and CCl 4 +selenizing Astragalus polysaccharides group. The results showed that sAPS significantly decreased the levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase in the serum, malondialdehyde and hydroxyproline content in liver (P<0.01), and increased the levels of total protein, total antioxidant capacity, glutathione peroxidase, and superoxide dismutase in liver of rats induced by CCl 4. In addition, expression levels of antioxidant-related genes (GPX1, SOD1, and Nrf2) were significantly increased following supplementation of the sAPS (P<0.01). Furthermore, sAPS effectively ameliorated CCl 4 induced hepatic necrosis and inflammation, and it also reduced the expression levels of proinflammatory cytokines including TNF-α, IL-6, COX-2 and NFκB (P<0.01) . Moreover, sAPS significantly decreased the expression levels of α-smooth muscle actin, collagen 1, TGF-β1, but increased the Bcl-2/Bax mRNA ratio in rats administered CCl 4 (P<0.01). Taken together, it could be concluded that sAPS could increase the activities of Astragalus polysaccharides and sodium selenite to protect the liver from damage by attenuating hepatic inflammation, oxidative stress, fibrogenesis, and induces apoptosis and cell cycle arrest in hepatic stellate cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Autophagy in alcohol-induced liver diseases

    PubMed Central

    Dolganiuc, Angela; Thomes, Paul G.; Ding, Wen-Xing; Lemasters, John J.; Donohue, Terrence M.

    2013-01-01

    Alcohol is the most abused substance worldwide and a significant source of liver injury; the mechanisms of alcohol-induced liver disease are not fully understood. Significant cellular toxicity and impairment of protein synthesis and degradation occur in alcohol-exposed liver cells, along with changes in energy balance and modified responses to pathogens. Autophagy is the process of cellular catabolism through the lysosomal-dependent machinery, which maintains a balance among protein synthesis, degradation, and recycling of self. Autophagy is part of normal homeostasis and it can be triggered by multiple factors that threaten cell integrity including starvation, toxins, or pathogens. Multiple factors regulate autophagy; survival and preservation of cellular integrity at the expense of inadequately-folded proteins and damaged high energy-generating intracellular organelles are prominent targets of autophagy in pathologic conditions. Coincidentally, inadequately-folded proteins accumulate and high energy-generating intracellular organelles, such as mitochondria, are damaged by alcohol abuse; these alcohol-induced pathological findings prompted investigation of the role of autophagy in the pathogenesis of alcohol-induced liver damage. Our review summarizes the current knowledge about the role and implications of autophagy in alcohol-induced liver disease. PMID:22551004

  19. High fat diet-induced oxidative stress blocks hepatocyte nuclear factor 4α and leads to hepatic steatosis in mice.

    PubMed

    Yu, Dongsheng; Chen, Gang; Pan, Minglin; Zhang, Jia; He, Wenping; Liu, Yang; Nian, Xue; Sheng, Liang; Xu, Bin

    2018-06-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease with manifestation of over-accumulation of fat in liver. Increasing evidences indicate that NAFLD may be in part caused by malfunction of very low density lipoprotein (VLDL) secretion. Hepatocyte nuclear factor 4α (HNF4α), a nuclear receptor protein, plays an important role in sustain hepatic lipid homeostasis via transcriptional regulation of genes involved in secretion of VLDL, such as apolipoprotein B (ApoB). However, the exact functional change of HNF4α in NAFLD remains to be elucidated. In the present study, we found that high fat diet (HFD) induced cytoplasmic retention of HNF4α in hepatocytes, which led to down-regulation of hepatic ApoB expression and its protein level in serum, as well as reduced secretion of VLDL. We further revealed that oxidative stress, elevated in fatty liver, was the key factor inducing the cytoplasmic retention of HNF4α in hepatocytes by activating protein kinase C (PKC)-mediated phosphorylation in HNF4α. Thus, our findings reveal a novel mechanism underlying HFD-induced fatty liver that oxidative stress impairs function of HNF4α on ApoB expression and VLDL secretion via PKC activation, eventually promoting fat accumulation in the liver. Therefore, oxidative stress/PKC/HNF4α pathway may be a novel target to treat diet-induced fatty liver. © 2017 Wiley Periodicals, Inc.

  20. Geraniol attenuates hydrogen peroxide-induced liver fatty acid alterations in male rats.

    PubMed

    Ozkaya, Ahmet; Sahin, Zafer; Gorgulu, Ahmet Orhan; Yuce, Abdurrauf; Celik, Sait

    2017-01-01

    Hydrogen peroxide (H 2 O 2 ) is an oxidant agent and this molecule naturally occurs in the body as a product of aerobic metabolism. Geraniol is a plant-derived natural antioxidant. The aim of this study was to determine the role of geraniol on hepatic fatty acids alterations following H 2 O 2 -induced oxidative stress in male rats. After randomization, male Wistar rats were divided into four groups ( n = 7 each group). Geraniol (50 mg/kg, dissolved in corn oil) and H 2 O 2 (16 mg/kg, dissolved in distilled water) were administered by an intraperitoneal injection. Administrations were performed during 30 days with 1-day interval. Administration of H 2 O 2 resulted with a significant increase in malondialdehyde (MDA) and a significant decrease in glutathione (GSH) peroxidase glutathione level; geraniol restored its effects on liver. However, hepatic catalase (CAT) activities were significantly higher in H 2 O 2 , geraniol, and geraniol+H 2 O 2 groups than control group. The ratio of hepatic total saturated fatty acids increased in H 2 O 2 -treated animals compared with control. In addition, hepatic total unsaturated fatty acids reduced in H 2 O 2 group compared with control. The percentages of both hepatic total saturated and unsaturated fatty acids were not different between geraniol+H 2 O 2 and control groups. H 2 O 2 -induced oxidative stress may affect fatty acid composition in liver and body. Geraniol can partly restore oxidative hepatic damage because it cannot completely reverse the H 2 O 2 -induced increase in hepatic CAT activities. Moreover, this natural compound can regulate hepatic total saturated and unsaturated fatty acids percentages against H 2 O 2 -induced alterations.

  1. Imatinib-induced fulminant liver failure in chronic myeloid leukemia: role of liver transplant and second-generation tyrosine kinase inhibitors: a case report.

    PubMed

    Nacif, Lucas Souto; Waisberg, Daniel R; Pinheiro, Rafael Soares; Lima, Fabiana Roberto; Rocha-Santos, Vinicius; Andraus, Wellington; D'Albuquerque, Luiz Carneiro

    2018-03-10

    There is a worldwide problem of acute liver failure and mortality associated with remaining on the waiting for a liver transplant. In this study, we highlight results published in recent years by leading transplant centers in evaluating imatinib-induced acute liver failure in chronic myeloid leukemia and follow-up in liver transplantation. A 36-year-old brown-skinned woman (mixed Brazilian race) diagnosed 1 year earlier with chronic myeloid leukemia was started after delivery of a baby and continued for 6 months with imatinib mesylate (selective inhibitor of Bcr-Abl tyrosine kinase), which induced liver failure. We conducted a literature review using the PubMed database for articles published through September 2017, and we demonstrate a role of liver transplant in this situation for imatinib-induced liver failure. We report previously published results and a successful liver transplant after acute liver failure due to imatinib-induced in chronic myeloid leukemia treatment. We report a case of a successful liver transplant after acute liver failure resulting from imatinib-induced chronic myeloid leukemia treatment. The literature reveals the importance of prompt acute liver failure diagnosis and treatment with liver transplant in selected cases.

  2. Glycyrrhizin ameliorates metabolic syndrome-induced liver damage in experimental rat model.

    PubMed

    Sil, Rajarshi; Ray, Doel; Chakraborti, Abhay Sankar

    2015-11-01

    Glycyrrhizin, a major constituent of licorice (Glycyrrhiza glabra) root, has been reported to ameliorate insulin resistance, hyperglycemia, dyslipidemia, and obesity in rats with metabolic syndrome. Liver dysfunction is associated with this syndrome. The objective of this study is to investigate the effect of glycyrrhizin treatment on metabolic syndrome-induced liver damage. After induction of metabolic syndrome in rats by high fructose (60%) diet for 6 weeks, the rats were treated with glycyrrhizin (50 mg/kg body weight, single intra-peritoneal injection). After 2 weeks of treatment, rats were sacrificed to collect blood samples and liver tissues. Compared to normal, elevated activities of serum alanine transaminase, alkaline phosphatase and aspartate transaminase, increased levels of liver advanced glycation end products, reactive oxygen species, lipid peroxidation, protein carbonyl, protein kinase Cα, NADPH oxidase-2, and decreased glutathione cycle components established liver damage and oxidative stress in fructose-fed rats. Activation of nuclear factor κB, mitogen-activated protein kinase pathways as well as signals from mitochondria were found to be involved in liver cell apoptosis. Increased levels of cyclooxygenase-2, tumor necrosis factor, and interleukin-12 proteins suggested hepatic inflammation. Metabolic syndrome caused hepatic DNA damage and poly-ADP ribose polymerase cleavage. Fluorescence-activated cell sorting using annexin V/propidium iodide staining confirmed the apoptotic hepatic cell death. Histology of liver tissue also supported the experimental findings. Treatment with glycyrrhizin reduced oxidative stress, hepatic inflammation, and apoptotic cell death in fructose-fed rats. The results suggest that glycyrrhizin possesses therapeutic potential against hepatocellular damage in metabolic syndrome.

  3. Anti-inflammatory and ameliorative effects of gallic acid on fluoxetine-induced oxidative stress and liver damage in rats.

    PubMed

    Karimi-Khouzani, Omid; Heidarian, Esfandiar; Amini, Sayed Asadollah

    2017-08-01

    Fluoxetine-induced liver damage is a cause of chronic liver disease. In the present study the hepatoprotective effects of gallic acid against fluoxetine-induced liver damage were examined. Forty-eight male rats were divided into six groups as follow: group 1, the control group; group 2, rats receiving fluoxetine (24mg/kg bw daily, po) without treatment; group 3, rats receiving 24mg/kg bw fluoxetine, treated with 50mg/kg bw silymarin and groups 4, 5, and 6 in which gallic acid (50, 100, and 200mg/kg bw, po, respectively) was prescribed after the consumption of fluoxetine. The histopathological changes of hepatic tissues were checked out. Fluoxetine caused a significant increase in the levels of serum glutamate oxaloacetate transaminase (GOT), serum glutamate pyruvate transaminase (GPT), lipid profiles, urea, fasting blood sugar (FBS), creatinine (Cr), protein carbonyl (PC) content, malondialdehyde (MDA), and liver TNF-α as an inflammatory element. Also, the obtained results of group 2 revealed a significant decline in ferric reducing ability of plasma (FRAP), liver catalase (CAT), superoxide dismutase (SOD), and vitamin C levels. The treatment with gallic acid showed significant ameliorations in abnormalities of fluoxetine-induced liver injury as represented by the improvement of hepatic CAT, SOD activities, vitamin C levels, serum biochemical parameters, and histopathological changes, in addition to the recovery of antioxidant defense system status. Gallic acid has inhibitory effects on fluoxetine-induced liver damage. The effect of gallic acid is derived from free radical scavenging properties and the anti-inflammatory effect related to TNF-α. Copyright © 2017. Published by Elsevier Urban & Partner Sp. z o.o.

  4. An iso-α-acid-rich extract from hops (Humulus lupulus) attenuates acute alcohol-induced liver steatosis in mice.

    PubMed

    Hege, Marianne; Jung, Finn; Sellmann, Cathrin; Jin, Chengjun; Ziegenhardt, Doreen; Hellerbrand, Claus; Bergheim, Ina

    2018-01-01

    Results of in vitro and in vivo studies suggest that consumption of beer is less harmful for the liver than consumption of spirits. It also has been suggested that secondary plant compounds derived from hops such as xanthohumol or iso-α-acids may have beneficial effects on the development of liver diseases of various etiologies. The aim of this study was to determine whether iso-α-acids consumed in doses achieved by "normal" beer consumption have beneficial effects on health. Female C57 Bl/6 J mice, pretreated for 4 d with an iso-α-acid-rich extract (∼30% iso-α-acids from hops, 0.75 mg/kg body weight), were fed one bolus of ethanol (6 g/kg body weight intragastric) or an iso-caloric maltodextrin solution. Markers of liver damage, toll-like receptor-4 signaling, and lipid peroxidation were determined. Furthermore, the effect of isohumulone on the lipopolysaccharide-dependent activation of J774 A.1 macrophages, used as a model of Kupffer cells, was determined. In the liver, acute ethanol administration led to a significant accumulation of fat (∼10-fold), which was accompanied by significantly higher inducible nitric oxide synthase protein level, elevated nitric oxide production, and increased plasminogen activator inhibitor 1 protein concentration when compared to controls. In mice pretreated with iso-α-acids, these effects of alcohol were markedly attenuated. Pretreatment of J774 A.1 macrophages with isohumulone significantly attenuated lipopolysaccharide-induced mRNA expression of inducible nitric oxide synthase and interleukin-6 as well as the release of nitric oxide. Taken together, iso-α-acids markedly attenuated the development of acute alcohol-induced damage in mice. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Pomegranate protects against arsenic-induced p53-dependent ROS-mediated inflammation and apoptosis in liver cells.

    PubMed

    Choudhury, Sreetama; Ghosh, Sayan; Mukherjee, Sudeshna; Gupta, Payal; Bhattacharya, Saurav; Adhikary, Arghya; Chattopadhyay, Sreya

    2016-12-01

    Molecular mechanisms involved in arsenic-induced toxicity are complex and elusive. Liver is one of the most favored organs for arsenic toxicity as methylation of arsenic occurs mostly in the liver. In this study, we have selected a range of environmentally relevant doses of arsenic to examine the basis of arsenic toxicity and the role of pomegranate fruit extract (PFE) in combating it. Male Swiss albino mice exposed to different doses of arsenic presented marked hepatic injury as evident from histological and electron microscopic studies. Increased activities of enzymes alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase corroborated extensive liver damage. It was further noted that arsenic exposure initiated reactive oxygen species (ROS)-dependent apoptosis in the hepatocytes involving loss of mitochondrial membrane potential. Arsenic significantly increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB), coupled with increase in phosphorylated Iκ-B, possibly as adaptive cellular survival strategies. Arsenic-induced oxidative DNA damage to liver cells culminated in p53 activation and increased expression of p53 targets like miR-34a and Bax. Pomegranate polyphenols are known to possess remarkable antioxidant properties and are capable of protecting normal cells from various stimuli-induced oxidative stress and toxicities. We explored the protective role of PFE in ameliorating arsenic-induced hepatic damage. PFE was shown to reduce ROS generation in hepatocytes, thereby reducing arsenic-induced Nrf2 activation. PFE also inhibited arsenic-induced NF-κB-inflammatory pathway. Data revealed that PFE reversed arsenic-induced hepatotoxicity and apoptosis by modulating the ROS/Nrf2/p53-miR-34a axis. For the first time, we have mapped the possible signaling pathways associated with arsenic-induced hepatotoxicity and its rescue by pomegranate polyphenols. Copyright

  6. Chlorogenic acid protects D-galactose-induced liver and kidney injury via antioxidation and anti-inflammation effects in mice.

    PubMed

    Feng, Yan; Yu, Ying-Hua; Wang, Shu-Ting; Ren, Jing; Camer, Danielle; Hua, Yu-Zhou; Zhang, Qian; Huang, Jie; Xue, Dan-Lu; Zhang, Xiao-Fei; Huang, Xu-Feng; Liu, Yi

    2016-01-01

    Oxidative stress and inflammation are implicated in the aging process and its related hepatic and renal function decline. Chlorogenic acid (CGA) is one of the most abundant polyphenol compounds in the human diet. Recently, CGA has shown in vivo and in vitro antioxidant properties. The current study investigates the effects of protective effects of chlorogenic acid (CGA) on D-galactose-induced liver and kidney injury. Hepatic and renal injuries were induced in a mouse model by subcutaneously injection of D-galactose (D-gal; 100 mg/kg) once a day for 8 consecutive weeks and orally administered simultaneously with CGA included in the food (200 mg/kg of diet). The liver and renal functions were examined. Histological analyses of liver and kidney were done by haematoxylin and eosin staining. The oxidative stress markers and pro-inflammatory cytokines in the liver and the kidney were measured. Results CGA significantly reduced the serum aminotransferase, serum creatinine (SCr) and blood urea nitrogen (BUN) levels in D-gal mice (p <0.05). CGA also restored superoxide dismutase, catalase, and malondialdehyde levels and decreased glutathione content in the liver and kidney in D-gal mice (p <0.05). Improvements in liver and kidney were also noted in histopathological studies. CGA reduced tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) protein levels in the liver and kidney in D-gal mice (p <0.05). These findings suggest that CGA attenuates D-gal-induced chronic liver and kidney injury and that this protection may be due to its antioxidative and anti-inflammatory activities.

  7. 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.

  8. Hepatoprotective effects of Vaccinium arctostaphylos against CCl4-induced acute liver injury in rats.

    PubMed

    Ravan, Alireza Pouyandeh; Bahmani, Mahdi; Ghasemi Basir, Hamid Reza; Salehi, Iraj; Oshaghi, Ebrahim Abbasi

    2017-09-26

    This study was carried out to evaluate the antioxidant and hepatoprotective effects of Vaccinium arctostaphylos (V.a) methanolic extract on carbon tetrachloride (CCl4)-induced acute liver injury in Wistar rats. Total phenolic and total flavonoid contents as well as antioxidant activity of V.a were determined. Extracts of V.a at doses of 200 and 400 mg/kg were administered by oral gavage to rats once per day for 7 days and then were given an intraperitoneal injection of 1 mL/kg CCl4 (1:1 in olive oil) for 3 consecutive days. Serum biochemical markers of liver injury, oxidative markers, as well as hydroxyproline (HP) content and histopathology of liver were evaluated. The obtained results showed that V.a had strong antioxidant activity. Treatment of rats with V.a blocked the CCl4-induced elevation of serum markers of liver function and enhanced albumin and total protein levels. The level of hepatic HP content was also reduced by the administration of V.a treatment. Histological examination of the liver section revealed that V.a prevented the occurrence of pathological changes in CCl4-treated rats. These findings suggested that V.a may be useful in the treatment and prevention of hepatic injury induced by CCl4.

  9. Oxidative stress and hepatic stellate cell activation are key events in arsenic induced liver fibrosis in mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ghatak, Subhadip; Biswas, Ayan; Dhali, Gopal Krishna

    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 ofmore » 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.« less

  10. Hepatoprotective effect of collagen peptides from cod skin against liver oxidative damage in vitro and in vivo.

    PubMed

    Han, Yantao; Xie, Jing; Gao, Hui; Xia, Yunqiu; Chen, Xuehong; Wang, Chunbo

    2015-03-01

    The objective of this study was to investigate the hepatoprotective effect of cod skin collagen peptides (CSCP), isolated from fishing industrial by-products, in vitro and in vivo. Effect of CSCP on cell proliferation of normal and H2O2-damaged Chang liver cells was determined by MTT assay in vitro. Two animal models, CCl4-induced and acetaminophenum-induced acute hepatotoxicity, were established to assess the hepatoprotective effect of CSCP. Liver weight index, serum ALT and AST, antioxidant enzymes, and lipid peroxidation product were used as the markers of liver toxicity. The cell viability in the H2O2-treated Chang liver cells was remarkably increased when pretreated with CSCP from 100 to 1,000 µg/ml in a dose-dependent manner. CSCP pretreatment also alleviated the CCL4-induced liver index loss, while no marked changes were found in acetaminophenum-treated mice. Furthermore, CSCP pulled down serum ALT and AST level, increased the activities of SOD and CAT, and decreased MDA in both murine models of acute liver toxicity. Pretreatment with CSCP protected liver tissue against oxidative injure in vivo and in vitro. The underlying mechanism might involve enhancement in the activities of antioxidant enzymes and reduction in the lipid peroxidation.

  11. GGPPS deficiency aggravates CCl4-induced liver injury by inducing hepatocyte apoptosis.

    PubMed

    Chen, Wei-Bo; Lai, Shan-Shan; Yu, De-Cai; Liu, Jia; Jiang, Shan; Zhao, Dan-Dan; Ding, Yi-Tao; Li, Chao-Jun; Xue, Bin

    2015-04-28

    GGPPS catalyses the expression of GGPP, a key protein in the mevalonate metabolic pathway. HMG-CoA reductase inhibitor statins can induce liver injury by inhibiting GGPP. However, the function of GGPPS in liver injury has not yet been revealed. In this study, we found that GGPPS increased in liver injury and that GGPPS deletion augmented liver injury and fibrosis. GGPPS inhibition induced hepatocyte apoptosis, inflammation and TGF-β1 secretion, which activated hepatic stellate cells. Our findings imply that GGPPS deletion induces hepatocyte apoptosis, which makes the liver vulnerable to hepatotoxicity. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  12. An in vivo analysis of Cr6+ induced biochemical, genotoxicological and transcriptional profiling of genes related to oxidative stress, DNA damage and apoptosis in liver of fish, Channa punctatus (Bloch, 1793).

    PubMed

    Awasthi, Yashika; Ratn, Arun; Prasad, Rajesh; Kumar, Manoj; Trivedi, Sunil P

    2018-07-01

    Present study was designed to assess the hexavalent chromium (Cr 6+ ) mediated oxidative stress that induces DNA damage and apoptosis in adult fish, Channa punctatus (35 ± 3.0 g; 14.5 ± 1.0 cm; Actinopterygii). Fishes were maintained in three groups for 15, 30 and 45 d of exposure periods. They were treated with 5% (Group T1) and 10% (Group T2) of 96 h-LC 50 of chromium trioxide (Cr 6+ ). Controls were run for the similar duration. A significant (p < 0.05) increment in the activities of antioxidant enzymes, SOD and CAT in liver tissues of the exposed fish evinces the persistence of oxidative stress. A significant (p < 0.05) increase in induction of micronuclei (MN) coupled with transcriptional responses of target genes related to antioxidant enzymes, DNA damage and apoptosis (sod, cat, gsr, nox-1, p53, bax, bcl-2, apaf-1 and casp3a) establishes the impact of oxidative stress due to in vivo, Cr 6+ accumulation in liver as compared to control (0 mg/L), in a dose and exposure-dependent manner. Initially, the increased level of reactive oxygen species (ROS) in liver coincided with that of enhanced mRNA expression of antioxidant enzymes, sod, cat, gsr and nox-1 but, later, the overproduction of ROS, after 45 d of exposure of Cr 6+ , resulted in a significant (p < 0.05) up-regulation of p53. Our findings also unveil that the up-regulation of bax, apaf-1 and casp3a and down-regulation of bcl-2 are associated with Cr 6+ -induced oxidative stress mediated-apoptosis in liver of test fish. Aforesaid molecular markers can, thus, be efficiently utilized for bio-monitoring of aquatic regimes and conservation of fish biodiversity. Copyright © 2018 Elsevier B.V. All rights reserved.

  13. Tetrachloro-p-benzoquinone induces hepatic oxidative damage and inflammatory response, but not apoptosis in mouse: The prevention of curcumin

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Xu, Demei; Hu, Lihua; Su, Chuanyang

    2014-10-15

    This study investigated the protective effects of curcumin on tetrachloro-p-benzoquinone (TCBQ)-induced hepatotoxicity in mice. TCBQ-treatment causes significant liver injury (the elevation of serum AST and ALT activities, histopathological changes in liver section including centrilobular necrosis and inflammatory cells), oxidative stress (the elevation of TBAR level and the inhibition of SOD and catalase activities) and inflammation (up-regulation of iNOS, COX-2, IL-1β, IL-6, TNF-α and NF-κB). However, these changes were alleviated upon pretreatment with curcumin. Interestingly, TCBQ has no effect on caspase family genes or B-cell lymphoma 2 (Bcl-2)/Bcl-2 associated X (Bax) protein expressions, which implied that TCBQ-induced hepatotoxicity is independent ofmore » apoptosis. Moreover, curcumin was shown to induce phase II detoxifying/antioxidant enzymes HO-1 and NQO1 through the activation of nuclear factor erythroid-derived 2-like 2 (Nrf2). In summary, the protective mechanisms of curcumin against TCBQ-induced hepatoxicity may be related to the attenuation of oxidative stress, along with the inhibition of inflammatory response via the activation of Nrf2 signaling. - Highlights: • TCBQ-intoxication significantly increased AST and ALT activities. • TCBQ-intoxication induced oxidative stress in mice liver. • TCBQ-intoxication induced inflammatory response in mice liver. • TCBQ-intoxication induced hepatotoxicity is independent of apoptosis. • Curcumin relieved TCBQ-induced liver damage remarkably.« less

  14. Glutamine Supplementation Attenuates Ethanol-Induced Disruption of Apical Junctional Complexes in Colonic Epithelium and Ameliorates Gut Barrier Dysfunction and Fatty Liver in Mice

    PubMed Central

    Chaudhry, Kamaljit K.; Shukla, Pradeep K.; Mir, Hina; Manda, Bhargavi; Gangwar, Ruchika; Yadav, Nikki; McMullen, Megan; Nagy, Laura E.; Rao, RadhaKrishna

    2015-01-01

    Previous in vitro studies showed that glutamine (Gln) prevents acetaldehyde-induced disruption of tight junctions and adherens junctions in Caco-2 cell monolayers and human colonic mucosa. In the present study, we evaluated the effect of Gln supplementation on ethanol-induced gut barrier dysfunction and liver injury in mice in vivo. Ethanol feeding caused a significant increase in inulin permeability in distal colon. Elevated permeability was associated with a redistribution of tight junction and adherens junction proteins and depletion of detergent-insoluble fractions of these proteins, suggesting that ethanol disrupts apical junctional complexes in colonic epithelium and increases paracellular permeability. Ethanol-induced increase in colonic mucosal permeability and disruption of junctional complexes were most severe in mice fed Gln-free diet. Gln supplementation attenuated ethanol-induced mucosal permeability and disruption of tight junctions and adherens junctions in a dose-dependent manner, indicating the potential role of glutamine in nutritional intervention to alcoholic tissue injury. Gln supplementation dose-dependently elevated reduced-protein thiols in colon without affecting the level of oxidized-protein thiols. Ethanol feeding depleted reduced protein thiols and elevated oxidized protein thiols. Ethanol-induced protein thiol oxidation was most severe in mice fed Gln-free diet and absent in mice fed Gln-supplemented diet, suggesting that antioxidant effect is one of the likely mechanisms involved in Gln-mediated amelioration of ethanol-induced gut barrier dysfunction. Ethanol feeding elevated plasma transaminase and liver triglyceride, which was accompanied by histopathologic lesions in the liver; ethanol-induced liver damage was attenuated by Gln supplementation. These results indicate that Gln supplementation ameliorates alcohol-induced gut and liver injury. PMID:26365579

  15. Free Radical Scavenging Properties of Skin and Pulp Extracts of Different Grape Cultivars In Vitro and Attenuation of H2O2-Induced Oxidative Stress in Liver Tissue Ex Vivo.

    PubMed

    Singha, Indrani; Das, Subir Kumar

    2015-07-01

    Grapes are the richest source of antioxidants due to the presence of potent bioactive phytochemicals. In this study, the phytochemical contents, scavenging activities and protective role against H2O2-induced oxidative stress in liver tissue ex vivo of four grape (Vitis vinifera) cultivars extracts, namely Flame seedless (black), Kishmish chorni (black with reddish brown), Red globe (red) and Thompson seedless mutant (green), were evaluated. The total phenolics and flavonoids content in pulp or skin fractions of different grape cultivars were in the range of 47.6-310 mg gallic acid equivalent/g fresh weight (fw), and 46.6-733.3 µg catechin equivalent/g fw respectively. The scavenging activities in skin of different grape varieties against 2,2-diphenyl-1-picrylhydrazyl (44-58 %), hydrogen peroxide (15.3-18.6 %), and hydroxyl radicals (50-85 %), were higher than pulp of the corresponding cultivars. These scavenging activities of grape extracts were found to be significantly (p < 0.01) correlated with the levels of total phenols, flavonoids and ascorbic acid. Liver tissues from goat treated with H2O2 (500 μM) showed significantly decreased GSH content by 42.9 % and activities of catalase by 50 % and glutathione reductase by 66.6 %; while increased thiobarbituric acid reactive substances and nitric oxide level by 2.53- and 0.86-fold, respectively, and activity of glutathione S-transferase by 0.96-fold. Grape skin extracts showed the stronger protective activity against H2O2-induced oxidative stress in liver tissue ex vivo, than its pulp of any cultivar; and the Flame seedless (black) cultivar showed the highest potential. In conclusion, our study suggested that the higher antioxidant potential, phytochemical contents and significant scavenging capacities in pulp and skin of grape extracts showed the protective action of grape extracts against H2O2-induced oxidative stress in liver tissue ex vivo.

  16. Effects of olive leave extract on metabolic disorders and oxidative stress induced by 2.45 GHz WIFI signals.

    PubMed

    Salah, Myriam Ben; Abdelmelek, Hafedh; Abderraba, Manef

    2013-11-01

    We investigated the effect of olive leaves extract administration on glucose metabolism and oxidative response in liver and kidneys of rats exposed to radio frequency (RF). The exposure of rats to RF (2.45 GHz, 1h/day during 21 consecutive days) induced a diabetes-like status. Moreover, RF decreased the activities of glutathione peroxidase (GPx, -33.33% and -49.40%) catalase (CAT, -43.39% and -39.62%) and the superoxide dismutase (SOD, -59.29% and -68.53%) and groups thiol amount (-62.68% and -34.85%), respectively in liver and kidneys. Indeed, exposure to RF increased the malondialdehyde (MDA, 29.69% and 51.35%) concentration respectively in liver and kidneys. Olive leaves extract administration (100 mg/kg, ip) in RF-exposed rats prevented glucose metabolism disruption and restored the activities of GPx, CAT and SOD and thiol group amount in liver and kidneys. Moreover, olive leave extract administration was able to bring down the elevated levels of MDA in liver but not in kidneys. Our investigations suggested that RF exposure induced a diabetes-like status through alteration of oxidative response. Olive leaves extract was able to correct glucose metabolism disorder by minimizing oxidative stress induced by RF in rat tissues. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Protection of the liver against CCl4-induced injury by intramuscular electrotransfer of a kallistatin-encoding plasmid.

    PubMed

    Diao, Yong; Zhao, Xiao-Feng; Lin, Jun-Sheng; Wang, Qi-Zhao; Xu, Rui-An

    2011-01-07

    To investigate the effect of transgenic expression of kallistatin (Kal) on carbon tetrachloride (CCl(4))-induced liver injury by intramuscular (im) electrotransfer of a Kal-encoding plasmid formulated with poly-L-glutamate (PLG). The pKal plasmid encoding Kal gene was formulated with PLG and electrotransferred into mice skeletal muscle before the administration of CCl4. The expression level of Kal was measured. The serum biomarker levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), malonyldialdehyde (MDA), and tumor necrosis factor (TNF)-α were monitored. The extent of CCl4-induced liver injury was analyzed histopathologically. The transgene of Kal was sufficiently expressed after an im injection of plasmid formulated with PLG followed by electroporation. In the Kal gene-transferred mice, protection against CCl4-induced liver injury was reflected by significantly decreased serum ALT, AST, MDA and TNF-α levels compared to those in control mice (P<0.01 to 0.05 in a dose-dependent manner). Histological observations also revealed that hepatocyte necrosis, hemorrhage, vacuolar change and hydropic degeneration were apparent in mice after CCl4 administration. In contrast, the damage was markedly attenuated in the Kal gene-transferred mice. The expression of hepatic fibrogenesis marker transforming growth factor-β1 was also reduced in the pKal transferred mice. Intramuscular electrotransfer of plasmid pKal which was formulated with PLG significantly alleviated the CCl4-induced oxidative stress and inflammatory response, and reduced the liver damage in a mouse model.

  18. Cardamom powder supplementation prevents obesity, improves glucose intolerance, inflammation and oxidative stress in liver of high carbohydrate high fat diet induced obese rats.

    PubMed

    Rahman, Md Mizanur; Alam, Mohammad Nazmul; Ulla, Anayt; Sumi, Farzana Akther; Subhan, Nusrat; Khan, Trisha; Sikder, Bishwajit; Hossain, Hemayet; Reza, Hasan Mahmud; Alam, Md Ashraful

    2017-08-14

    Cardamom is a well-known spice in Indian subcontinent, used in culinary and traditional medicine practices since ancient times. The current investigation was untaken to evaluate the potential benefit of cardamom powder supplementation in high carbohydrate high fat (HCHF) diet induced obese rats. Male Wistar rats (28 rats) were divided into four different groups such as Control, Control + cardamom, HCHF, HCHF + cardamom. High carbohydrate and high fat (HCHF) diet was prepared in our laboratory. Oral glucose tolerance test, organs wet weight measurements and oxidative stress parameters analysis as well as liver marker enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) activities were assayed on the tissues collected from the rats. Plasma lipids profiles were also measured in all groups of animals. Moreover, histological staining was also performed to evaluate inflammatory cells infiltration and fibrosis in liver. The current investigation showed that, HCHF diet feeding in rats developed glucose intolerance and increased peritoneal fat deposition compared to control rats. Cardamom powder supplementation improved the glucose intolerance significantly (p > 0.05) and prevented the abdominal fat deposition in HCHF diet fed rats. HCHF diet feeding in rats also developed dyslipidemia, increased fat deposition and inflammation in liver compared to control rats. Cardamom powder supplementation significantly prevented the rise of lipid parameters (p > 0.05) in HCHF diet fed rats. Histological assessments confirmed that HCHF diet increased the fat deposition and inflammatory cells infiltration in liver which was normalized by cardamom powder supplementation in HCHF diet fed rats. Furthermore, HCHF diet increased lipid peroxidation, decreased antioxidant enzymes activities and increased advanced protein oxidation product level significantly (p > 0.05) both in plasma and liver tissue which were modulated by

  19. Hepatocurative potential of sesquiterpene lactones of Taraxacum officinale on carbon tetrachloride induced liver toxicity in mice.

    PubMed

    Mahesh, A; Jeyachandran, R; Cindrella, L; Thangadurai, D; Veerapur, V P; Muralidhara Rao, D

    2010-06-01

    The hepatocurative potential of ethanolic extract (ETO) and sesquiterpene lactones enriched fraction (SL) of Taraxacum officinale roots was evaluated against carbon tetrachloride (CCl 4 ) induced hepatotoxicity in mice. The diagnostic markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin contents were significantly elevated, whereas significant reduction in the level of reduced glutathione (GSH) and enhanced hepatic lipid peroxidation, liver weight and liver protein were observed in CCl 4 induced hepatotoxicity in mice. Post-treatment with ETO and SL significantly protected the hepatotoxicity as evident from the lower levels of hepatic enzyme markers, such as serum transaminase (ALT, AST), ALP and total bilirubin. Further, significant reduction in the liver weight and liver protein in drug-treated hepatotoxic mice and also reduced oxidative stress by increasing reduced glutathione content and decreasing lipid peroxidation level has been noticed. The histopathological evaluation of the liver also revealed that ETO and SL reduced the incidence of liver lesions induced by CCl 4 . The results indicate that sesquiterpene lactones have a protective effect against acute hepatotoxicity induced by the administration of CCl 4 in mice. Furthermore, observed activity of SL may be due to the synergistic action of two sesquiterpene lactones identified from enriched ethyl acetate fraction by HPLC method.

  20. Resolvin D1 attenuates CCl4-induced acute liver injury involving up-regulation of HO-1 in mice.

    PubMed

    Chen, Xiahong; Gong, Xia; Jiang, Rong; Wang, Bin; Kuang, Ge; Li, Ke; Wan, Jingyuan

    2016-01-01

    Acute hepatic failure involves in excessive oxidative stress and inflammatory responses, leading to a high mortality due to lacking effective therapy. Resolvin D1 (RvD1), an endogenous lipid mediator derived from polyunsaturated fatty acids, has been shown anti-inflammatory and anti-oxidative actions, however, whether RvD1 has protective effects on hepatic failure remains elusive. In this study, the roles and molecular mechanisms of RvD1 were explored in carbon tetrachloride (CCl4)-induced acute liver injury. Our results showed that RvD1 protected mice against CCl4-induced hepatic damage, as evaluated by reduced aminotransferase activities and malondialdehyde content, elevated glutathione and superoxide dismutase activities, and alleviated hepatic pathological damage. Moreover, RvD1 significantly attenuated serum tumor necrosis factor-α and interleukin-6 levels as well as hepatic myeloperoxidase activity, whereas enhanced serum IL-10 level in CCl4-administered mice. Further, RvD1 markedly up-regulated the expression and activity of heme oxygenase-1 (HO-1). However, inhibition of HO-1 activity reversed the protective effects of RvD1 on CCl4-induced liver injury. These results suggest that RvD1 could effectively prevent CCl4-induced liver injury by inhibition of oxidative stress and inflammation, and the underlying mechanism may be related to up-regulation of HO-1.

  1. 5-HMF Attenuates Liver Fibrosis in CCl4-Plus-Alcohol-Induced Mice by Suppression of Oxidative Stress.

    PubMed

    Han, Xin-Yue; Hu, Jun-Nan; Wang, Zi; Wei, Sheng-Nan; Zheng, Si-Wen; Wang, Ying-Ping; Li, Wei

    2017-01-01

    The aim of this study was to investigate the effects of 5-hydroxymethyl-2-furfural (5-HMF) on liver fibrosis induced by carbon tetrachloride (CCl 4 ) and alcohol. Male ICR mice were treated with CCl 4 dissolved in olive oil (10% v/v, 2.5 μg/L) intraperitoneally (i.p.), and given at a dose of 2.5×10 -5 mg/kg B.W. twice a week for 7 wk. Concurrently, mice received drinking water with or without alcohol. The mice in treatment groups and positive control group were gavaged with 5-HMF (7.5, 15, and 30 mg/kg B.W.) or Huganpian (350 mg/kg B.W.) daily starting in the fourth week and lasting for 4 wk. The blood samples were analyzed for biochemical markers of hepatic injury and tissue samples were subjected for estimation of liver antioxidants and histopathological studies. The concentrations of HA (hyaluronic acid), LN (laminin), CIV (collagen type IV), and MDA (malondialdehyde), as well as the serum levels of ALT (alanine aminotransferase) and AST (aspartate aminotransferase) were markedly reduced by 5-HMF. On the other hand, enzymatic antioxidants SOD (superoxide dismutase), CAT (catalase) and GSH-Px (glutathione peroxidase) were markedly elevated in liver tissue treated with 5-HMF. Histopathological examination revealed that 5-HMF treatment noticeably prevented hepatocyte apoptosis, fatty degeneration and inflammatory cell infiltration on liver fibrosis induced by CCl 4 and alcohol. Hoechst 33258 staining also revealed hepatocyte apoptosis. 5-HMF could exert protective effects against liver injury and reduce liver fibrosis induced by CCl 4 and alcohol in mice.

  2. Ligand-activated PPARα-dependent DNA demethylation regulates the fatty acid β-oxidation genes in the postnatal liver.

    PubMed

    Ehara, Tatsuya; Kamei, Yasutomi; Yuan, Xunmei; Takahashi, Mayumi; Kanai, Sayaka; Tamura, Erina; Tsujimoto, Kazutaka; Tamiya, Takashi; Nakagawa, Yoshimi; Shimano, Hitoshi; Takai-Igarashi, Takako; Hatada, Izuho; Suganami, Takayoshi; Hashimoto, Koshi; Ogawa, Yoshihiro

    2015-03-01

    The metabolic function of the liver changes sequentially during early life in mammals to adapt to the marked changes in nutritional environment. Accordingly, hepatic fatty acid β-oxidation is activated after birth to produce energy from breast milk lipids. However, how it is induced during the neonatal period is poorly understood. Here we show DNA demethylation and increased mRNA expression of the fatty acid β-oxidation genes in the postnatal mouse liver. The DNA demethylation does not occur in the fetal mouse liver under the physiologic condition, suggesting that it is specific to the neonatal period. Analysis of mice deficient in the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) and maternal administration of a PPARα ligand during the gestation and lactation periods reveal that the DNA demethylation is PPARα dependent. We also find that DNA methylation of the fatty acid β-oxidation genes are reduced in the adult human liver relative to the fetal liver. This study represents the first demonstration that the ligand-activated PPARα-dependent DNA demethylation regulates the hepatic fatty acid β-oxidation genes during the neonatal period, thereby highlighting the role of a lipid-sensing nuclear receptor in the gene- and life-stage-specific DNA demethylation of a particular metabolic pathway. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  3. The methyl donor S-adenosylmethionine prevents liver hypoxia and dysregulation of mitochondrial bioenergetic function in a rat model of alcohol-induced fatty liver disease.

    PubMed

    King, Adrienne L; Mantena, Sudheer K; Andringa, Kelly K; Millender-Swain, Telisha; Dunham-Snary, Kimberly J; Oliva, Claudia R; Griguer, Corinne E; Bailey, Shannon M

    2016-10-01

    Mitochondrial dysfunction and bioenergetic stress play an important role in the etiology of alcoholic liver disease. Previous studies from our laboratory show that the primary methyl donor S-Adenosylmethionine (SAM) minimizes alcohol-induced disruptions in several mitochondrial functions in the liver. Herein, we expand on these earlier observations to determine whether the beneficial actions of SAM against alcohol toxicity extend to changes in the responsiveness of mitochondrial respiration to inhibition by nitric oxide (NO), induction of the mitochondrial permeability transition (MPT) pore, and the hypoxic state of the liver. For this, male Sprague-Dawley rats were pair-fed control and alcohol-containing liquid diets with and without SAM for 5 weeks and liver hypoxia, mitochondrial respiration, MPT pore induction, and NO-dependent control of respiration were examined. Chronic alcohol feeding significantly enhanced liver hypoxia, whereas SAM supplementation attenuated hypoxia in livers of alcohol-fed rats. SAM supplementation prevented alcohol-mediated decreases in mitochondrial state 3 respiration and cytochrome c oxidase activity. Mitochondria isolated from livers of alcohol-fed rats were more sensitive to calcium-mediated MPT pore induction (i.e., mitochondrial swelling) than mitochondria from pair-fed controls, whereas SAM treatment normalized sensitivity for calcium-induced swelling in mitochondria from alcohol-fed rats. Liver mitochondria from alcohol-fed rats showed increased sensitivity to NO-dependent inhibition of respiration compared with pair-fed controls. In contrast, mitochondria isolated from the livers of SAM treated alcohol-fed rats showed no change in the sensitivity to NO-mediated inhibition of respiration. Collectively, these findings indicate that the hepato-protective effects of SAM against alcohol toxicity are mediated, in part, through a mitochondrial mechanism involving preservation of key mitochondrial bioenergetic parameters and the

  4. Ameliorative Effects of Allium sativum Extract on iNOS Gene Expression and NO Production in Liver of Streptozotocin + Nicotinamide-Induced Diabetic Rats.

    PubMed

    Ziamajidi, Nasrin; Behrouj, Hamid; Abbasalipourkabir, Roghayeh; Lotfi, Fatemeh

    2018-04-01

    Diabetes mellitus (DM) is one of the most prevalent diseases in the world, which is strongly associated with liver dysfunction. Hyperglycemia, through an oxidative stress pathway, damages various tissues. Herbal medicine is a good candidate to ameliorate hyperglycemia and oxidative stress. In this study, the effects of aqueous Allium sativum (garlic) extract (AGE) on gene expression of inducible nitric oxide synthases (iNOS) and production of nitric oxide (NO) were evaluated in the liver tissue of diabetic rats. Four groups of rats contained normal control rats, garlic control rats (AGE), Streptozotocin (STZ) + nicotinamide-induced diabetic rats (DM), and diabetic rats treated with garlic (DM + AGE). Glucose levels and liver enzymes activities were determined by colorimetric assay in the serum. Gene expression of iNOS by real-time PCR, NO levels by Griess method, oxidative stress parameters by spectrophotometric method and histopathological examination by hematoxylin and eosin staining method were evaluated in the liver tissues. Glucose levels, activities of liver enzymes, oxidative stress markers, iNOS gene expression, and NO production increased significantly in diabetic rats in comparison with control rats, whereas after oral administration of garlic, these parameters decreased significantly, close to the normal levels. Hence, the beneficial effects of garlic on the liver injury of diabetes could be included in the hypoglycaemic and antioxidant properties of garlic via a decrease in gene expression of iNOS and subsequent NO production.

  5. Seasonal variations in fine particle composition from Beijing prompt oxidative stress response in mouse lung and liver.

    PubMed

    Pardo, Michal; Xu, Fanfan; Qiu, Xinghua; Zhu, Tong; Rudich, Yinon

    2018-06-01

    Exposure to air pollution can induce oxidative stress, inflammation and adverse health effects. To understand how seasonal and chemical variations drive health impacts, we investigated indications for oxidative stress and inflammation in mice exposed to water and organic extracts from urban fine particles/PM 2.5 (particles with aerodynamic diameter ≤ 2.5 μm) collected in Beijing, China. Higher levels of pollution components were detected in heating season (HS, winter and part of spring) PM 2.5 than in the non-heating season (NHS, summer and part of spring and autumn) PM 2.5 . HS samples were high in metals for the water extraction and high in polycyclic aromatic hydrocarbons (PAHs) for the organic extraction compared to their controls. An increased inflammatory response was detected in the lung and liver following exposure to the organic extracts compared to the water extracts, and mostly in the HS PM 2.5 . While reduced antioxidant response was observed in the lung, it was activated in the liver, again, more in the HS extracts. Nrf2 transcription factor, a master regulator of stress response that controls the basal oxidative capacity and induces the expression of antioxidant response, and its related genes were induced. In the liver, elevated levels of lipid peroxidation adducts were measured, correlated with histologic analysis that revealed morphologic features of cell damage and proliferation, indicating oxidative and toxic damage. In addition, expression of genes related to detoxification of PAHs was observed. Altogether, the study suggests that the acute effects of PM 2.5 can vary seasonally with stronger health effects in the HS than in the NHS in Beijing, China and that some secondary organs may be susceptible for the exposure damage. Specifically, the liver is a potential organ influenced by exposure to organic components such as PAHs from coal or biomass burning and heating. Copyright © 2018 Elsevier B.V. All rights reserved.

  6. Hepatoprotective effect of ethanolic extract of Curcuma longa on thioacetamide induced liver cirrhosis in rats

    PubMed Central

    2013-01-01

    Background Hepatology research has focused on developing traditional therapies as pharmacological medicines to treat liver cirrhosis. Thus, this study evaluated mechanisms of the hepatoprotective activity of Curcuma longa rhizome ethanolic extract (CLRE) on thioacetamide-induced liver cirrhosis in rats. Methods The hepatoprotective effect of CLRE was measured in a rat model of thioacetamide-induced liver cirrhosis over 8 weeks. Hepatic cytochrome P450 2E1 and serum levels of TGF-β1 and TNF-α were evaluated. Oxidative stress was measured by malondialdehyde, urinary 8-hydroxyguanosine and nitrotyrosine levels. The protective activity of CLRE free-radical scavenging mechanisms were evaluated through antioxidant enzymes. Protein expression of pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins in animal blood sera was studied and confirmed by immunohistochemistry of Bax, Bcl2 proteins and proliferating cell nuclear antigen. Results Histopathology, immunohistochemistry and liver biochemistry were significantly lower in the Curcuma longa-treated groups compared with controls. CLRE induced apoptosis, inhibited hepatocytes proliferation but had no effect on hepatic CYP2E1 levels. Conclusion The progression of liver cirrhosis could be inhibited by the antioxidant and anti-inflammatory activities of CLRE and the normal status of the liver could be preserved. PMID:23496995

  7. Age-related effect of aerobic exercise training on antioxidant and oxidative markers in the liver challenged by doxorubicin in rats.

    PubMed

    Ahmadian, Mehdi; Dabidi Roshan, Valiollah; Leicht, Anthony S

    2018-05-16

    The aims of the current study were to investigate the oxidant and antioxidant status of liver tissue challenged by doxorubicin and to examine the possible protective effects of aerobic exercise on doxorubicin-induced oxidative stress. Seventy-two rats were divided into three age groups (Young, Adult, and Elderly) with three treatment subgroups consisting of eight rats per age group: doxorubicin, aerobic exercise + doxorubicin, and aerobic exercise + saline. The experimental groups performed regular treadmill running for 3 weeks. Doxorubicin was administered by i.p. injection at a dosage of 20 mg kg -1 while the aerobic exercise + saline group received saline of a comparable volume. Heat shock protein 70, malondialdehyde, glutathione peroxidase, and protein carbonyl were determined from the liver homogenates following the intervention period. Treatment with doxorubicin induced hepatotoxicity in all groups with lower values of oxidative stress in young compared with the older groups. The inclusion of aerobic exercise training significantly increased heat shock protein 70 and antioxidant enzyme levels (glutathione peroxidase) whereas it decreased oxidative stress biomarkers (malondialdehyde and protein carbonyl) for all age groups. These results suggest that aerobic exercise training may be a potential, non-drug strategy to modulate doxorubicin-induced hepatotoxicity through its positive impact on antioxidant levels and oxidative stress biomarkers.

  8. Herbal and Dietary Supplement Induced Liver Injury

    PubMed Central

    de Boer, Ynto S.; Sherker, Averell H.

    2016-01-01

    Summary The increase in the use of herbal and dietary supplements (HDS) over the last decades has been accompanied with an increase in the reports of HDS associated hepatotoxicity. The spectrum of HDS induced liver injury is diverse and the outcome may vary from transient liver test elevations to fulminant hepatic failure resulting in death or requiring liver transplantation. There are no validated standardized tools to establish the diagnosis, but some HDS products do have a typical clinical signature that may help to identify HDS induced liver injury. PMID:27842768

  9. Dibenzoylmethane Protects Against CCl4-Induced Acute Liver Injury by Activating Nrf2 via JNK, AMPK, and Calcium Signaling.

    PubMed

    Cao, Mingnan; Wang, Huixia; Guo, Limei; Yang, Simin; Liu, Chun; Khor, Tin Oo; Yu, Siwang; Kong, Ah-Ng

    2017-11-01

    Oxidative stress is an important pathogenic factor in various hepatic diseases. Nuclear factor-erythroid 2-related factor-2 (Nrf2), which coordinates the expression of an array of antioxidant and detoxifying genes, has been proposed as a potential target for prevention and treatment of liver disease. Dibenzoylmethane (DBM) is a minor ingredient in licorice that activates Nrf2 and prevents various cancers and oxidative damage. In the present study, the mechanisms by which DBM activates Nrf2 signaling were delineated, and its protective effect against carbon tetrachloride (CCl 4 )-induced liver injury was examined. DBM potently induced the expression of HO-1 in cells and in the livers of mice, but this induction was diminished in Nrf2-deficient mice and cells. Overexpression of Nrf2 enhanced DBM-induced HO-1 expression, while overexpression of a dominant-negative fragment of Nrf2 inhibited this induction. DBM treatment resulted in dissociation from Keap1 and nuclear translocation of Nrf2. Moreover, DBM activated Akt/protein kinase B, mitogen-activated protein kinases, and AMP-activated protein kinase and increased intracellular calcium levels. Inhibition of JNK, AMPK, or intracellular calcium signaling significantly suppressed the induction of HO-1 expression by DBM. Finally, DBM treatment significantly inhibited CCl 4 -induced acute liver injury in wild-type but not in Nrf2-deficient mice. Taken together, our results revealed the mechanisms by which DBM activates Nrf2 and induces HO-1 expression, and provide molecular basis for the design and development of DBM and its derivatives for prevention or treatment of liver diseases by targeting Nrf2.

  10. Lipidomic profiling reveals protective function of fatty acid oxidation in cocaine-induced hepatotoxicity[S

    PubMed Central

    Shi, Xiaolei; Yao, Dan; Gosnell, Blake A.; Chen, Chi

    2012-01-01

    During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. However, the exact influences of cocaine on the homeostasis of lipid metabolism remain largely unknown. In this study, the progression of subacute hepatotoxicity, including centrilobular necrosis in the liver and elevation of transaminase activity in serum, was observed in a three-day cocaine treatment, accompanying the disruption of triacylglycerol (TAG) turnover. Serum TAG level increased on day 1 of cocaine treatment but remained unchanged afterwards. In contrast, hepatic TAG level was elevated continuously during three days of cocaine treatment and was better correlated with the development of hepatotoxicity. Lipidomic analyses of serum and liver samples revealed time-dependent separation of the control and cocaine-treated mice in multivariate models, which was due to the accumulation of long-chain acylcarnitines together with the disturbances of many bioactive phospholipid species in the cocaine-treated mice. An in vitro function assay confirmed the progressive inhibition of mitochondrial fatty acid oxidation after the cocaine treatment. Cotreatment of fenofibrate significantly increased the expression of peroxisome proliferator-activated receptor α (PPARα)-targeted genes and the mitochondrial fatty acid oxidation activity in the cocaine-treated mice, resulting in the inhibition of cocaine-induced acylcarnitine accumulation and other hepatotoxic effects. Overall, the results from this lipidomics-guided study revealed that the inhibition of fatty acid oxidation plays an important role in cocaine-induced liver injury. PMID:22904346

  11. Treatment with a Catalytic Superoxide Dismutase (SOD) Mimetic Improves Liver Steatosis, Insulin Sensitivity, and Inflammation in Obesity-Induced Type 2 Diabetes

    PubMed Central

    Delmastro-Greenwood, Meghan M.; Marré, Meghan L.; O’Connor, Erin C.; Novak, Elizabeth A.; Vincent, Garret; Mollen, Kevin P.; Lee, Sojin; Dong, H. Henry; Piganelli, Jon D.

    2017-01-01

    Oxidative stress and persistent inflammation are exaggerated through chronic over-nutrition and a sedentary lifestyle, resulting in insulin resistance. In type 2 diabetes (T2D), impaired insulin signaling leads to hyperglycemia and long-term complications, including metabolic liver dysfunction, resulting in non-alcoholic fatty liver disease (NAFLD). The manganese metalloporphyrin superoxide dismustase (SOD) mimetic, manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnP), is an oxidoreductase known to scavenge reactive oxygen species (ROS) and decrease pro-inflammatory cytokine production, by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. We hypothesized that targeting oxidative stress-induced inflammation with MnP would assuage liver complications and enhance insulin sensitivity and glucose tolerance in a high-fat diet (HFD)-induced mouse model of T2D. During 12 weeks of feeding, we saw significant improvements in weight, hepatic steatosis, and biomarkers of liver dysfunction with redox modulation by MnP treatment in HFD-fed mice. Additionally, MnP treatment improved insulin sensitivity and glucose tolerance, while reducing serum insulin and leptin levels. We attribute these effects to redox modulation and inhibition of hepatic NF-κB activation, resulting in diminished ROS and pro-inflammatory cytokine production. This study highlights the importance of controlling oxidative stress and secondary inflammation in obesity-mediated insulin resistance and T2D. Our data confirm the role of NF-κB-mediated inflammation in the development of T2D, and demonstrate the efficacy of MnP in preventing the progression to disease by specifically improving liver pathology and hepatic insulin resistance in obesity. PMID:29104232

  12. Oxidative stress-dependent contribution of HMGB1 to the interplay between apoptosis and autophagy in diabetic rat liver.

    PubMed

    Petrović, Anja; Bogojević, Desanka; Korać, Aleksandra; Golić, Igor; Jovanović-Stojanov, Sofija; Martinović, Vesna; Ivanović-Matić, Svetlana; Stevanović, Jelena; Poznanović, Goran; Grigorov, Ilijana

    2017-11-01

    The progression of oxidative stress, resulting cell damage, and cell death underlies the etiology of liver damage/dysfunction as a complication of diabetes. High-mobility group box 1 (HMGB1) protein, a chromatin-binding nuclear protein and damage-associated molecular pattern molecule, is integral to oxidative stress and signaling pathways regulating cell death and cell survival. We previously found that in streptozotocin (STZ)-induced diabetic rats, reduction of oxidative stress after melatonin administration lowered necrotic cell death and increased expression of HMGB1 and hepatocellular damage. In the present study, we examined whether alleviation of diabetes-attendant oxidative stress and ensuing change in HMGB1 expression influence the dynamic equilibrium between apoptosis/autophagy and liver damage. We observed that elevated HMGB1 protein levels in diabetic rat liver accompanied increased interactions of HMGB1 with TLR4 and RAGE, and activation of the intrinsic apoptotic pathway and Beclin 1-dependent autophagy. The absence of p62 degradation in diabetic rat liver pointed to defective autophagy which was responsible for lower autophagosome/autophagolysosome formation and an increased apoptosis/autophagy ratio. Compared to diabetic rats, in melatonin-treated diabetic rats, the structure of liver cells was preserved, HMGB1/TLR4 interaction and downstream apoptotic signaling were significantly reduced, HMGB1/Beclin 1 colocalization and interactions were augmented and Beclin 1-mediated autophagy, mithophagy in particular, were increased. We concluded that in mild oxidative stress, HMGB1 is cytoprotective, whereas in intense oxidative stress, HMGB1 actions promote cell death and liver damage. Since reduced HMGB1 binds to RAGE but not to TLR4, redox modification of HMGB1 as a mechanism regulating the cross-talk between apoptosis and autophagy in diabetes is discussed.

  13. Carvedilol Improves Inflammatory Response, Oxidative Stress and Fibrosis in the Alcohol-Induced Liver Injury in Rats by Regulating Kuppfer Cells and Hepatic Stellate Cells

    PubMed Central

    Leitão, Renata Ferreira de Carvalho; Brito, Gerly Anne de Castro; Miguel, Emilio de Castro; Guedes, Paulo Marcos Matta; de Araújo, Aurigena Antunes

    2016-01-01

    -α, procollagen type I (PCI), procollagen type III (PCIII), and NF-κB were decreased in the alcohol-CARV 5 mg/kg group relative to the alcohol-only group. Conclusions CARV can reduce the stress oxidative, inflammatory response and fibrosis in ethanol-induced liver injury in a rat model by downregulating signalling of Kuppfer cells and hepatic stellate cells (HSCs) through suppression of inflammatory cytokines. PMID:26891124

  14. Tauroursodeoxycholic acid attenuates endoplasmic reticulum stress and protects the liver from chronic intermittent hypoxia induced injury.

    PubMed

    Hou, Yanpeng; Yang, Huai'an; Cui, Zeshi; Tai, Xuhui; Chu, Yanling; Guo, Xing

    2017-09-01

    Obstructive sleep apnea that characterized by chronic intermittent hypoxia (CIH) has been reported to associate with chronic liver injury. Tauroursodeoxycholic acid (TUDCA) exerts liver-protective effects in various liver diseases. The purpose of this study was to test the hypothesis that TUDCA could protect liver against CIH injury. C57BL/6 mice were subjected to intermittent hypoxia for eight weeks and applied with TUDCA by intraperitoneal injection. The effect of TUDCA on liver histological changes, liver function, oxidative stress, inflammatory response, hepatocyte apoptosis and endoplasmic reticulum (ER) stress were investigated. The results showed that administration of TUDCA attenuated liver pathological changes, reduced serum alanine aminotransferase and aspartate aminotransferase level, suppressed reactive oxygen species activity, decreased tumor necrosis factor-α and interleukin-1β level and inhibited hepatocyte apoptosis induced by CIH. TUDCA also inhibited CIH-induced ER stress in liver as evidenced by decreased expression of ER chaperone 78 kDa glucose-related protein, unfolded protein response transducers and ER proapoptotic proteins. Altogether, the present study described a liver-protective effect of TUDCA in CIH mice model, and this effect seems at least partly through the inhibition of ER stress.

  15. 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

  16. Andrographis paniculata Leaf Extract Prevents Thioacetamide-Induced Liver Cirrhosis in Rats

    PubMed Central

    Bardi, Daleya Abdulaziz; Halabi, Mohammed Farouq; Hassandarvish, Pouya; Rouhollahi, Elham; Paydar, Mohammadjavad; Moghadamtousi, Soheil Zorofchian; Al-Wajeeh, Nahla Saeed; Ablat, Abdulwali; Abdullah, Nor Azizan; Abdulla, Mahmood Ameen

    2014-01-01

    This study investigated the hepatoprotective effects of ethanolic Andrographis paniculata leaf extract (ELAP) on thioacetamide-induced hepatotoxicity in rats. An acute toxicity study proved that ELAP is not toxic in rats. To examine the effects of ELAP in vivo, male Sprague Dawley rats were given intraperitoneal injections of vehicle 10% Tween-20, 5 mL/kg (normal control) or 200 mg/kg TAA thioacetamide (to induce liver cirrhosis) three times per week. Three additional groups were treated with thioacetamide plus daily oral silymarin (50 mg/kg) or ELAP (250 or 500 mg/kg). Liver injury was assessed using biochemical tests, macroscopic and microscopic tissue analysis, histopathology, and immunohistochemistry. In addition, HepG2 and WRL-68 cells were treated in vitro with ELAP fractions to test cytotoxicity. Rats treated with ELAP exhibited significantly lower liver/body weight ratios and smoother, more normal liver surfaces compared with the cirrhosis group. Histopathology using Hematoxylin and Eosin along with Masson’s Trichrome stain showed minimal disruption of hepatic cellular structure, minor fibrotic septa, a low degree of lymphocyte infiltration, and minimal collagen deposition after ELAP treatment. Immunohistochemistry indicated that ELAP induced down regulation of proliferating cell nuclear antigen. Also, hepatic antioxidant enzymes and oxidative stress parameters in ELAP-treated rats were comparable to silymarin-treated rats. ELAP administration reduced levels of altered serum liver biomarkers. ELAP fractions were non-cytotoxic to WRL-68 cells, but possessed anti-proliferative activity on HepG2 cells, which was confirmed by a significant elevation of lactate dehydrogenase, reactive oxygen species, cell membrane permeability, cytochrome c, and caspase-8,-9, and, -3/7 activity in HepG2 cells. A reduction of mitochondrial membrane potential was also detected in ELAP-treated HepG2 cells. The hepatoprotective effect of 500 mg/kg of ELAP is proposed to result

  17. Andrographis paniculata leaf extract prevents thioacetamide-induced liver cirrhosis in rats.

    PubMed

    Abdulaziz Bardi, Daleya; Halabi, Mohammed Farouq; Hassandarvish, Pouya; Rouhollahi, Elham; Paydar, Mohammadjavad; Moghadamtousi, Soheil Zorofchian; Al-Wajeeh, Nahla Saeed; Ablat, Abdulwali; Abdullah, Nor Azizan; Abdulla, Mahmood Ameen

    2014-01-01

    This study investigated the hepatoprotective effects of ethanolic Andrographis paniculata leaf extract (ELAP) on thioacetamide-induced hepatotoxicity in rats. An acute toxicity study proved that ELAP is not toxic in rats. To examine the effects of ELAP in vivo, male Sprague Dawley rats were given intraperitoneal injections of vehicle 10% Tween-20, 5 mL/kg (normal control) or 200 mg/kg TAA thioacetamide (to induce liver cirrhosis) three times per week. Three additional groups were treated with thioacetamide plus daily oral silymarin (50 mg/kg) or ELAP (250 or 500 mg/kg). Liver injury was assessed using biochemical tests, macroscopic and microscopic tissue analysis, histopathology, and immunohistochemistry. In addition, HepG2 and WRL-68 cells were treated in vitro with ELAP fractions to test cytotoxicity. Rats treated with ELAP exhibited significantly lower liver/body weight ratios and smoother, more normal liver surfaces compared with the cirrhosis group. Histopathology using Hematoxylin and Eosin along with Masson's Trichrome stain showed minimal disruption of hepatic cellular structure, minor fibrotic septa, a low degree of lymphocyte infiltration, and minimal collagen deposition after ELAP treatment. Immunohistochemistry indicated that ELAP induced down regulation of proliferating cell nuclear antigen. Also, hepatic antioxidant enzymes and oxidative stress parameters in ELAP-treated rats were comparable to silymarin-treated rats. ELAP administration reduced levels of altered serum liver biomarkers. ELAP fractions were non-cytotoxic to WRL-68 cells, but possessed anti-proliferative activity on HepG2 cells, which was confirmed by a significant elevation of lactate dehydrogenase, reactive oxygen species, cell membrane permeability, cytochrome c, and caspase-8,-9, and, -3/7 activity in HepG2 cells. A reduction of mitochondrial membrane potential was also detected in ELAP-treated HepG2 cells. The hepatoprotective effect of 500 mg/kg of ELAP is proposed to result from

  18. c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Saito, Chieko; Lemasters, John J.; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425

    Acetaminophen (APAP) overdose, which causes liver injury in animals and humans, activates c-jun N-terminal kinase (JNK). Although it was shown that the JNK inhibitor SP600125 effectively reduced APAP hepatotoxicity, the mechanisms of protection remain unclear. C57Bl/6 mice were treated with 10 mg/kg SP600125 or vehicle (8% dimethylsulfoxide) 1 h before 600 mg/kg APAP administration. APAP time-dependently induced JNK activation (detected by JNK phosphorylation). SP600125, but not the vehicle, reduced JNK activation, attenuated mitochondrial Bax translocation and prevented the mitochondrial release of apoptosis-inducing factor at 4-12 h. Nuclear DNA fragmentation, nitrotyrosine staining, tissue GSSG levels and liver injury (plasma ALT releasemore » and necrosis) were partially attenuated by the vehicle (- 65%) and completely eliminated by SP600125 (- 98%) at 6 and 12 h. Furthermore, SP600125 attenuated the increase of inducible nitric oxide synthase (iNOS) mRNA and protein. However, APAP did not enhance plasma nitrite + nitrate levels (NO formation); SP600125 had no effect on this parameter. The iNOS inhibitor L-NIL did not reduce NO formation or injury after APAP but prevented NO formation caused by endotoxin. Since SP600125 completely eliminated the increase in hepatic GSSG levels, an indicator of mitochondrial oxidant stress, it is concluded that the inhibition of peroxynitrite was mainly caused by reduced superoxide formation. Our data suggest that the JNK inhibitor SP600125 protects against APAP-induced liver injury in part by attenuation of mitochondrial Bax translocation but mainly by preventing mitochondrial oxidant stress and peroxynitrite formation and thereby preventing the mitochondrial permeability transition pore opening, a key event in APAP-induced cell necrosis.« less

  19. 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.

  20. Therapeutic role of Cuminum cyminum on ethanol and thermally oxidized sunflower oil induced toxicity.

    PubMed

    Aruna, K; Rukkumani, R; Varma, P Suresh; Menon, Venugopal P

    2005-05-01

    Ethanol is one of the most widely used and abused drugs, increasing lipid levels in humans and experimental animals. Heating of oil rich in polyunsaturated fatty acids (PUFA) produces various lipid peroxidative end products that can aggravate the pathological changes produced by ethanol. In the present communication, the effect of Cuminum cyminum was investigated on alcohol and thermally oxidized oil induced hyperlipidaemia. The results showed increased activity of aspartate transaminase (AST), alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT) and increased levels of cholesterol, triglycerides and phospholipids in the plasma of rats given alcohol, thermally oxidized oil and alcohol+thermally oxidized oil when compared with the normal control group. The levels of tissue (liver and kidney) cholesterol and triglycerides were increased significantly in rats groups given alcohol, thermally oxidized oil and alcohol+thermally oxidized oil when compared with the normal control rats. The levels were decreased when cumin was given along with alcohol and thermally oxidized oil. The level of phospholipids decreased significantly in the liver and kidney of groups given alcohol, thermally oxidized oil and alcohol+thermally oridized oil when compared with the normal control rats. The level increased when cumin was administered along with alcohol and thermally oxidized oil. The activity of phospholipase A and C increased significantly in the liver of groups given alcohol, thermally oxidized oil and alcohol+thermally oxidized oil when compared with the normal control rats, whereas the activity was decreased with the cumin treatment. The results obtained indicate that cumin can decrease the lipid levels in alcohol and thermally oxidized oil induced hepatotoxicity. Copyright (c) 2005 John Wiley & Sons, Ltd.

  1. Phoenix dactylifera protects against oxidative stress and hepatic injury induced by paracetamol intoxication in rats.

    PubMed

    Salem, Gamal A; Shaban, Ahmed; Diab, Hussain A; Elsaghayer, Wesam A; Mjedib, Manal D; Hnesh, Aomassad M; Sahu, Ravi P

    2018-05-16

    The current studies were sought to determine effects of antioxidant potential of aqueous and methanolic extracts of Phoenix dactylifera leaves (PLAE and PLME) against the widely-used analgesic paracetamol (PCM) induced hepatotoxicity. Groups of rats were treated with or without PCM (1500 mg/kg), PLAE and PLME (300 mg/kg) and n-acetylcysteine (NAC, 50 mg/kg) followed by assessments of liver function tests, oxidative stress, antioxidant defenses, and hepatotoxicity. We observed that PCM significantly elevated serum liver markers, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and bilirubin compared to control (untreated) group. These PCM-induced effects were associated with oxidative stress as demonstrated by increased levels of malondialdehyde (MDA) and reduced levels of hepatic antioxidant enzymes, glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Pretreatment of PLME decreased ALT and AST by 78.2% and tissue MDA by 54.1%, and increased hepatic GPx (3.5 folds), CAT (7 folds) and SOD (2.5 folds) compared to PCM group. These PLME-mediated effects were comparable to NAC pretreatment. Histological analysis demonstrates that PLME conserved hepatic tissues against lesions such as inflammation, centrilobular necrosis, and hemorrhages induced by PCM. In contrast, PLAE-mediated effects were less effective in reducing levels of liver function enzymes, oxidative stress, and liver histopathological profiles, and restoring antioxidant defenses against PCM-induced intoxication. These findings indicate that PLME exerts protective effects against PCM-induced hepatotoxicity via scavenging free radicals and restoring hepatic antioxidant enzymes. Thus, PLME and its bioactive components could further be evaluated for their pharmacological properties against drug-induced deleterious effects. Copyright © 2018. Published by Elsevier Masson SAS.

  2. Fluoride-induced iron overload contributes to hepatic oxidative damage in mouse and the protective role of Grape seed proanthocyanidin extract.

    PubMed

    Niu, Qiang; He, Ping; Xu, Shangzhi; Ma, Ruling; Ding, Yusong; Mu, Lati; Li, Shugang

    2018-01-01

    Emerging evidence has demonstrated that iron overload plays an important role in oxidative stress in the liver. This study aimed to explore whether fluoride-induced hepatic oxidative stress is associated with iron overload and whether grape seed proanthocyanidin extract (GSPE) alleviates oxidative stress by reducing iron overload. Forty Kunming male mice were randomly divided into 4 groups and treated for 5 weeks with distilled water (control), sodium fluoride (NaF) (100 mg/L), GSPE (400 mg/kg bw), or NaF (100 mg/L) + GSPE (400 mg/kg bw). Mice exposed to NaF showed typical poisoning changes of morphology, increased aspartate aminotransferase and alanine aminotransferase activities in the liver. NaF treatment also increased MDA accumulation, decreased GSH-Px, SOD and T-AOC levels in liver, indicative of oxidative stress. Intriguingly, all these detrimental effects were alleviated by GSPE. Further study revealed that NaF induced disorders of iron metabolism, as manifested by elevated iron level with increased hepcidin but decreased ferroportin expression, which contributed to hepatic oxidative stress. Importantly, the iron dysregulation induced by NaF could be normalized by GSPE. Collectively, these data provide a novel insight into mechanisms underlying fluorosis and highlight the potential of GSPE as a naturally occurring prophylactic treatment for fluoride-induced hepatotoxicity associated with iron overload.

  3. Chlorogenic acid prevents acetaminophen-induced liver injury: the involvement of CYP450 metabolic enzymes and some antioxidant signals*

    PubMed Central

    Pang, Chun; Sheng, Yu-chen; Jiang, Ping; Wei, Hai; Ji, Li-li

    2015-01-01

    Chlorogenic acid (CGA), a polyphenolic compound, is abundant in fruits, dietary vegetables, and some medicinal herbs. This study investigated the prevention of CGA against acetaminophen (AP)-induced hepatotoxicity and its engaged mechanisms. CGA reversed the decreased cell viability induced by AP in L-02 cells in vitro. In addition, CGA reduced the AP-induced increased serum levels of alanine/aspartate aminotransferase (ALT/AST) in vivo. The effect of CGA on cytochrome P450 (CYP) enzymatic (CYP2E1, CYP1A2, and CYP3A4) activities showed that CGA caused very little inhibition on CYP2E1 and CYP1A2 enzymatic activities, but not CYP3A4. The measurement of liver malondialdehyde (MDA), reactive oxygen species (ROS), and glutathione (GSH) levels showed that CGA prevented AP-induced liver oxidative stress injury. Further, CGA increased the AP-induced decreased mRNA expression of peroxiredoxin (Prx) 1, 2, 3, 5, 6, epoxide hydrolase (Ephx) 2, and polymerase (RNA) II (DNA directed) polypeptide K (Polr2k), and nuclear factor erythroid-2-related factor 2 (Nrf2). In summary, CGA ameliorates the AP-induced liver injury probably by slightly inhibiting CYP2E1 and CYP1A2 enzymatic properties. In addition, cellular important antioxidant signals such as Prx1, 2, 3, 5, 6, Ephx2, Polr2k, and Nrf2 also contributed to the protection of CGA against AP-induced oxidative stress injury. PMID:26160718

  4. Extract of Bauhinia vahlii Shows Antihyperglycemic Activity, Reverses Oxidative Stress, and Protects against Liver Damage in Streptozotocin-induced Diabetic Rats

    PubMed Central

    Elbanna, Ahmed H.; Nooh, Mohammed M.; Mahrous, Engy A.; Khaleel, Amal E.; Elalfy, Taha S.

    2017-01-01

    strong α-glucosidase inhibition while the nonpolar fraction (n-hexane extract) failed to show any activity in both assays. DEE was further investigated in streptozotocin-induced diabetic rat model where oral administration of DEE at 2 doses (150 and 300 mg/kg) for 4 weeks resulted in significant reduction in fasting blood glucose and glycated hemoglobin and reversal of oxidative stress signs as indicated by measurement of hepatic reduced glutathione, nitric oxide, and malondialdehyde levels. In addition, histopathological examination and measurement of serum aspartate transaminase and alanine transaminase levels showed that DEE protected the liver from signs of pathogenesis observed in diabetic untreated rats. Phytochemical analysis of DEE showed high flavonoid content with quercitrin as the major constituent (62.9 ± 0.18 mg/mg). Abbreviations used: ALT: Alanine transaminase, AST: Aspartate transaminase, DEE: Defatted ethanol extract, DPPH: 2,2-diphenyl-1-picrylhydrazyl, FBG: Fasting blood glucose, GAE: Gallic acid equivalent, GSH: Reduced glutathione, Hb1Ac: Glycated hemoglobin, HE: Hexane extract MDA: Malondialdehyde, QE: Quercetin equivalent, STZ: Streptozotocin, TAC: Total antioxidant capacity. PMID:29142421

  5. GDF‑15 prevents LPS and D‑galactosamine‑induced inflammation and acute liver injury in mice.

    PubMed

    Li, Min; Song, Kui; Huang, Xiaowen; Fu, Simao; Zeng, Qiyi

    2018-06-27

    Growth differentiation factor‑15 (GDF‑15) is a transforming growth factor (TGF)‑β superfamily member with a poorly characterized biological activity, speculated to be implicated in several diseases. The present study aimed to determine whether GDF‑15 participates in sepsis‑induced acute liver injury in mice. Lipopolysaccharide (LPS) and D‑galactosamine (D‑GalN) were administered to mice to induce acute liver injury. Survival of mice, histological changes in liver tissue, and levels of inflammatory biomarkers in serum and liver tissue were evaluated following treatment with GDF‑15. The underlying mechanism was investigated by western blotting, ELISA, flow cytometry, and reverse transcription‑quantitative polymerase chain reaction using Kupffer cells. The results demonstrated that GDF‑15 prevented LPS/D‑GalN‑induced death, increase in inflammatory cell infiltration and serum alanine aminotransferase and aspartate aminotransferase activities. In addition, GDF‑15 treatment reduced the production of hepatic malondialdehyde and myeloperoxidase, and attenuated the increase of interleukin (IL)‑6, tumor necrosis factor (TNF)‑α, and IL‑1β expression in serum and liver tissue, accompanied by inducible nitric oxide synthase (iNOS) inactivation in the liver. Similar changes in the expression of inflammatory cytokines, IL‑6, TNF‑α and IL‑1β, and iNOS activation were observed in the Kupffer cells. Further mechanistic experiments revealed that GDF‑15 effectively protected against LPS‑induced nuclear factor (NF)‑κB pathway activation by regulating TGFβ‑activated kinase 1 (TAK1) phosphorylation in Kupffer cells. In conclusion, GDF‑15 reduced the activation of pro‑inflammatory factors, and prevented LPS‑induced liver injury, most likely by disrupting TAK1 phosphorylation, and consequently inhibiting the activation of the NF‑κB pathway in the liver.

  6. Oxidative Stress Mechanisms Do Not Discriminate between Genotoxic and Nongenotoxic Liver Carcinogens.

    PubMed

    Deferme, Lize; Wolters, Jarno; Claessen, Sandra; Briedé, Jacco; Kleinjans, Jos

    2015-08-17

    It is widely accepted that in chemical carcinogenesis different modes-of-action exist, e.g., genotoxic (GTX) versus nongenotoxic (NGTX) carcinogenesis. In this context, it has been suggested that oxidative stress response pathways are typical for NGTX carcinogenesis. To evaluate this, we examined oxidative stress-related changes in gene expression, cell cycle distribution, and (oxidative) DNA damage in human hepatoma cells (HepG2) exposed to GTX-, NGTX-, and noncarcinogens, at multiple time points (4-8-24-48-72 h). Two GTX (azathriopine (AZA) and furan) and two NGTX (tetradecanoyl-phorbol-acetate, (TPA) and tetrachloroethylene (TCE)) carcinogens as well as two noncarcinogens (diazinon (DZN, d-mannitol (Dman)) were selected, while per class one compound was deemed to induce oxidative stress and the other not. Oxidative stressors AZA, TPA, and DZN induced a 10-fold higher number of gene expression changes over time compared to those of furan, TCE, or Dman treatment. Genes commonly expressed among AZA, TPA, and DZN were specifically involved in oxidative stress, DNA damage, and immune responses. However, differences in gene expression between GTX and NGTX carcinogens did not correlate to oxidative stress or DNA damage but could instead be assigned to compound-specific characteristics. This conclusion was underlined by results from functional readouts on ROS formation and (oxidative) DNA damage. Therefore, oxidative stress may represent the underlying cause for increased risk of liver toxicity and even carcinogenesis; however, it does not discriminate between GTX and NGTX carcinogens.

  7. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity

    PubMed Central

    Shalapour, Shabnam; Lin, Xue-Jia; Bastian, Ingmar N.; Brain, John; Burt, Alastair D.; Aksenov, Alexander A.; Vrbanac, Alison F.; Li, Weihua; Perkins, Andres; Matsutani, Takaji; Zhong, Zhenyu; Dhar, Debanjan; Navas-Molina, Jose A.; Xu, Jun; Loomba, Rohit; Downes, Michael; Yu, Ruth T.; Evans, Ronald M.; Dorrestein, Pieter C.; Knight, Rob; Benner, Christopher; Anstee, Quentin M.; Karin, Michael

    2018-01-01

    The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA+) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8+ T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8+ T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA+ cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8+ T-lymphocyte activation as a tumour-promoting mechanism. PMID:29144460

  8. The pathogenesis of ethanol versus methionine and choline deficient diet-induced liver injury.

    PubMed

    Gyamfi, Maxwell Afari; Damjanov, Ivan; French, Samuel; Wan, Yu-Jui Yvonne

    2008-02-15

    The differences and similarities of the pathogenesis of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) were examined. Mice (six/group) received one of four Lieber-Decarli liquid diets for 6 weeks: (1) paired-fed control diet; (2) control diet with ethanol (ethanol); (3) paired-fed methionine/choline deficient (MCD) diet; and (4) MCD plus ethanol (combination). Hepatotoxicity, histology, and gene expression changes were examined. Both MCD and ethanol induced macrovesicular steatosis. However, the combination diet produced massive steatosis with minor necrosis and inflammation. MCD and combination diets, but not ethanol, induced serum ALT levels by 1.6- and 10-fold, respectively. MCD diet, but not ethanol, also induced serum alkaline phosphatase levels suggesting bile duct injury. Ethanol increased liver fatty acid binding protein (L-FABP) mRNA and protein levels. In contrast, the combination diet decreased L-FABP mRNA and protein levels and increased hepatic free fatty acid and lipid peroxide levels. Ethanol, but not MCD, reduced hepatic S-adenosylmethionine (SAM) and GSH levels. Hepatic TNFalpha protein levels were increased in all treatment groups, however, IL-6, a hepatoprotective cytokine which promotes liver regeneration was increased in ethanol-fed mice (2-fold), but decreased in the combination diet-treated mice. In addition, the combination diet reduced phosphorylated STAT3 and Bcl-2 levels. While MCD diet might cause bile duct injury and cholestasis, ethanol preferentially interferes with the SAM-GSH oxidative stress pathway. The exacerbated liver injury induced by the combination diet might be explained by reduced L-FABP, increased free fatty acids, oxidative stress, and decreased IL-6 protein levels. The combination diet is an efficient model of steatohepatitis.

  9. Zebrafish as model organisms for studying drug-induced liver injury

    PubMed Central

    Vliegenthart, A D Bastiaan; Tucker, Carl S; Del Pozo, Jorge; Dear, James W

    2014-01-01

    Drug-induced liver injury (DILI) is a major challenge in clinical medicine and drug development. New models are needed for predicting which potential therapeutic compounds will cause DILI in humans, and new markers and mediators of DILI still need to be identified. This review highlights the strengths and weaknesses of using zebrafish as a high-throughput in vivo model for studying DILI. Although the zebrafish liver architecture is different from that of the mammalian liver, the main physiological processes remain similar. Zebrafish metabolize drugs using similar pathways to those in humans; they possess a wide range of cytochrome P450 enzymes that enable metabolic reactions including hydroxylation, conjugation, oxidation, demethylation and de-ethylation. Following exposure to a range of hepatotoxic drugs, the zebrafish liver develops histological patterns of injury comparable to those of mammalian liver, and biomarkers for liver injury can be quantified in the zebrafish circulation. The zebrafish immune system is similar to that of mammals, but the zebrafish inflammatory response to DILI is not yet defined. In order to quantify DILI in zebrafish, a wide variety of methods can be used, including visual assessment, quantification of serum enzymes and experimental serum biomarkers and scoring of histopathology. With further development, the zebrafish may be a model that complements rodents and may have value for the discovery of new disease pathways and translational biomarkers. PMID:24773296

  10. In vivo Studies on the Protective Effect of Propolis on Doxorubicin-Induced Toxicity in Liver of Male Rats.

    PubMed

    Singla, Shivani; Kumar, Neelima R; Kaur, Jaspreet

    2014-05-01

    Since anticancer drugs are to be administered for long durations of time and are associated with systemic toxicities, the present studies were conducted to evaluate the protective potential of honey bee propolis against a widely used anticancer drug, doxorubicin (DXR) induced toxicity and oxidative damage in liver tissues of rats. Sixteen male Sprague Dawley rats, weighing between 200-220 g, were used and were divided into four equal groups. Propolis was given orally to rats [250 mg/kg body weight (bw) for 14 consecutive days] and DXR [25 mg/kg bw; intraperitoneally (i.p) was administered on 12(th), 13(th) and 14(th) day of the experiment. All the animals were sacrificed on day 15(th) day by decapitation. Blood and tissue samples were collected for measurement of toxicity and oxidative damage parameters (enzymatic assays and biochemical estimations). Administration of DXR for 3 days at a cumulative dose of 25 mg/kg bw, induced toxicity and oxidative stress in rats as significantly decreased activity of catalase (CAT), superoxide dismutase (SOD), glutathione-S-transferase (GST), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were observed in rat liver supernatants when compared to control group. Increased activity of serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) was obtained in DXR administered rats. Also there are significantly increased levels of lipid peroxides (measured as malondialdehyde formation) and significantly decreased level of glutathione (GSH) in doxorubicin treated rat liver supernatants as compared to healthy controls. On the other hand, administration of animals with propolis prior to DXR treatment led to significant modulation of the oxidative damage related parameters in liver and hepatotoxicity parameters in blood, when compared to doxorubicin treated group. However results were still not comparable to control group or only propolis group indicating partial protection by propolis at

  11. Hepatoprotective effect of manganese chloride against CCl4-induced liver injury in rats.

    PubMed

    Eidi, Akram; Mortazavi, Pejman; Behzadi, Khodabakhsh; Rohani, Ali Haeri; Safi, Shahabeddin

    2013-11-01

    The aim of the present study is to evaluate the protective effect of manganese chloride against carbon tetrachloride (CCl4)-induced liver injury in rats. Manganese chloride (0.001, 0.01, 0.05 and 0.1 g/kg bw) was administered intragastrically for 28 consecutive days to male CCl4-treated rats. The hepatoprotective activity was assessed using various biochemical parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT) and superoxide dismutase (SOD). Histopathological changes in the liver of different groups were also studied. Administration of CCl4 increased the serum ALT, AST, ALP and GGT but decreased SOD levels in rats. Treatment with manganese chloride significantly attenuated these changes to nearly normal levels. The animals treated with manganese chloride have shown decreased necrotic zones and hepatocellular degeneration when compared to the liver exposed to CCl4 intoxication alone. Thus, the histopathological studies also supported the protective effect of manganese chloride. Therefore, the results of this study suggest that manganese chloride exerts hepatoprotection via promoting antioxidative properties against CCl4-induced oxidative liver damage.

  12. Vinpocetine protects liver against ischemia-reperfusion injury.

    PubMed

    Zaki, Hala Fahmy; Abdelsalam, Rania Mohsen

    2013-12-01

    Hepatic ischemia-reperfusion (IR) injury is a clinical problem that leads to cellular damage and organ dysfunction mediated mainly via production of reactive oxygen species and inflammatory cytokines. Vinpocetine has long been used in cerebrovascular disorders. This study aimed to explore the protective effect of vinpocetine in IR injury to the liver. Ischemia was induced in rats by clamping the common hepatic artery and portal vein for 30 min followed by 30 min of reperfusion. Serum transaminases and liver lactate dehydrogenase (LDH) activities, liver inflammatory cytokines, oxidative stress biomarkers, and liver histopathology were assessed. IR resulted in marked histopathology changes in liver tissues coupled with elevations in serum transaminases and liver LDH activities. IR also increased the production of liver lipid peroxides, nitric oxide, and inflammatory cytokines interleukin-1β and interleukin-6, in parallel with a reduction in reduced glutathione and interleukin-10 in the liver. Pretreatment with vinpocetine protected against liver IR-induced injury, in a dose-dependent manner, as evidenced by the attenuation of oxidative stress as well as inflammatory and liver injury biomarkers. The effects of vinpocetine were comparable with that of curcumin, a natural antioxidant, and could be attributed to its antioxidant and anti-inflammatory properties.

  13. Inhibition of arsenic induced-rat liver injury by grape seed exact through suppression of NADPH oxidase and TGF-{beta}/Smad activation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pan Xinjuan; Dai Yujie; Li Xing

    2011-08-01

    Chronic arsenic exposure induces oxidative damage to liver leading to liver fibrosis. We aimed to define the effect of grape seed extract (GSE), an antioxidant dietary supplement, on arsenic-induced liver injury. First, Male Sprague-Dawley rats were exposed to a low level of arsenic in drinking water (30 ppm) with or without GSE (100 mg/kg, every other day by oral gavage) for 12 months and the effect of GSE on arsenic-induced hepatotoxicity was examined. The results from this study revealed that GSE co-treatment significantly attenuated arsenic-induced low antioxidant defense, oxidative damage, proinflammatory cytokines and fibrogenic genes. Moreover, GSE reduced arsenic-stimulated Smad2/3more » phosphorylation and protein levels of NADPH oxidase subunits (Nox2, Nox4 and p47phox). Next, we explored the molecular mechanisms underlying GSE inhibition of arsenic toxicity using cultured rat hepatic stellate cells (HSCs). From the in vitro study, we found that GSE dose-dependently reduced arsenic-stimulated ROS production and NADPH oxidase activities. Both NADPH oxidases flavoprotein inhibitor DPI and Nox4 siRNA blocked arsenic-induced ROS production, whereas Nox4 overexpression suppressed the inhibitory effects of GSE on arsenic-induced ROS production and NADPH oxidase activities, as well as expression of TGF-{beta}1, type I procollagen (Coll-I) and {alpha}-smooth muscle actin ({alpha}-SMA) mRNA. We also observed that GSE dose-dependently inhibited TGF-{beta}1-induced transactivation of the TGF-{beta}-induced smad response element p3TP-Lux, and that forced expression of Smad3 attenuated the inhibitory effects of GSE on TGF-{beta}1-induced mRNA expression of Coll-I and {alpha}-SMA. Collectively, GSE could be a potential dietary therapeutic agent for arsenic-induced liver injury through suppression of NADPH oxidase and TGF-{beta}/Smad activation. - Research Highlights: > GSE attenuated arsenic-induced low antioxidant defense, oxidative damage, proinflammatory cytokines

  14. The protective effect of total phenolics from Oenanthe Javanica on acute liver failure induced by D-galactosamine.

    PubMed

    Ai, Guo; Huang, Zheng-Ming; Liu, Qing-Chuan; Han, Yan-Quan; Chen, Xi

    2016-06-20

    Water dropwort [Oenanthe javanica (O. javanica)] is an aquatic perennial herb cultivated in East Asian countries. It has been popularly used in traditional Chinese medicine which is beneficial for the treatment of many diseases, including jaundice and various types of chronic and acute hepatitis. In the present study, we investigated the hepatoprotective effect of total phenolics from O. javanica (TPOJ) against D-galactosamine (D-GalN) induced liver injury in mice. The hepatoprotective activity of TPOJ (125, 250 and 500mg/kg) was investigated on D-GalN (800mg/kg)-induced liver damages in mice. Blood and liver were collected for biochemical and microscopic analysis. RT-PCR was used to determine the changes in hepatic nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression. Protein levels of iNOS, COX-2, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were determined by western blotting. In the animal studies, TPOJ could improve the survival of acute liver failure model significantly and prevente the D-GalN-induced elevation of the serum enzymatic markers and nonenzymatic markers levels significantly. Meanwhile, TPOJ-treatment decreased the malondialdehyde (MDA) level and elevated the content of glutathione (GSH) in the liver as compared to those in the D-GalN group. Hepatic activities and protein expressions of antioxidative enzymes, including SOD, GPx, and CAT were enhanced dose dependently with TPOJ. At the same time, application of TPOJ effectively suppressed the D-GalN-induced proinflammatory mRNA and protein expression of iNOS and COX-2. Subsequently, the serum levels of proinflammatory mediators, nitric oxide (NO) and prostaglandin E2 (PGE2) were reduced. Additionally, histological analyses also showed that TPOJ reduced the extent of liver lesions induced by D-GalN. Our investigation demonstrated the hepatoprotective activity of TPOJ and revealed that TPOJ attributed its significance in the traditional use for treating

  15. Sulforaphane prevents microcystin-LR-induced oxidative damage and apoptosis in BALB/c mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sun Xiaoyun; Mi Lixin; Liu Jin

    2011-08-15

    Microcystins (MCs), the products of blooming algae Microcystis, are waterborne environmental toxins that have been implicated in the development of liver cancer, necrosis, and even fatal intrahepatic bleeding. Alternative protective approaches in addition to complete removal of MCs in drinking water are urgently needed. In our previous work, we found that sulforaphane (SFN) protects against microcystin-LR (MC-LR)-induced cytotoxicity by activating the NF-E2-related factor 2 (Nrf2)-mediated defensive response in human hepatoma (HepG2) and NIH 3T3 cells. The purpose of this study was to investigate and confirm efficacy the SFN-induced multi-mechanistic defense system against MC-induced hepatotoxicity in an animal model. We reportmore » that SFN protected against MC-LR-induced liver damage and animal death at a nontoxic and physiologically relevant dose in BALB/c mice. The protection by SFN included activities of anti-cytochrome P450 induction, anti-oxidation, anti-inflammation, and anti-apoptosis. Our results suggest that SFN may protect mice against MC-induced hepatotoxicity. This raises the possibility of a similar protective effect in human populations, particularly in developing countries where freshwaters are polluted by blooming algae. - Graphical abstract: Display Omitted Research Highlights: > SFN protected against MC-LR-induced liver damage and animal death in BALB/c mice. > The dose of SFN is at a nontoxic and physiologically relevant dose. > The protection included activities of anti-oxidation, anti-inflammation, and anti-apoptosis. > SFN may protect mice against MC-induced hepatotoxicity.« less

  16. Evidence that the capacity of nongenotoxic carcinogens to induce oxidative stress is subject to marked variability.

    PubMed

    Henderson, Colin J; Cameron, Amy R; Chatham, Lynsey; Stanley, Lesley A; Wolf, Charles Roland

    2015-05-01

    Many drugs and environmental chemicals which are not directly mutagenic have the capacity to increase the incidence of tumors in the liver and other tissues. For this reason, such compounds are known as nongenotoxic carcinogens. The mechanisms underlying their effects remain unclear; however, their capacity to induce oxidative stress is considered to be a critical step in the carcinogenic process, although the evidence that this is actually the case remains equivocal and sparse. We have exploited a novel heme oxygenase-1 reporter mouse to evaluate the capacity of nongenotoxic carcinogens with different mechanisms of action to induce oxidative stress in the liver in vivo. When these compounds were administered at doses reported to cause liver tumors, marked differences in activation of the reporter were observed. 1,4-Dichlorobenzene and nafenopin were strong inducers of oxidative stress, whereas phenobarbital, piperonyl butoxide, cyproterone acetate, and WY14,643 were, at best, only very weak inducers. In the case of phenobarbital and thioacetamide, the number of LacZ-positive hepatocytes increased with time, and for the latter also with dose. The data obtained demonstrate that although some nongenotoxic carcinogens can induce oxidative stress, it is not a dominant feature of the response to these compounds. Therefore in contrast to the current models, these data suggest that oxidative stress is not a key determinant in the mechanism of nongenotoxic carcinogenesis but may contribute to the effects in a compound-specific manner. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.

  17. Overexpression of the long noncoding RNA TUG1 protects against cold-induced injury of mouse livers by inhibiting apoptosis and inflammation.

    PubMed

    Su, Song; Liu, Jiang; He, Kai; Zhang, Mengyu; Feng, Chunhong; Peng, Fangyi; Li, Bo; Xia, Xianming

    2016-04-01

    Hepatic injury provoked by cold storage is a major problem affecting liver transplantation, as exposure to cold induces apoptosis in hepatic tissues. Long noncoding RNAs (lncRNAs) are increasingly understood to regulate apoptosis, but the contribution of lncRNAs to cold-induced liver injury remains unknown. Using RNA-seq, we determined the differential lncRNA expression profile in mouse livers after cold storage and found that expression of the lncRNA TUG1 was significantly down-regulated. Overexpression of TUG1 attenuated cold-induced apoptosis in mouse hepatocytes and liver sinusoidal endothelial cells LSECs, in part by blocking mitochondrial apoptosis and endoplasmic reticulum (ER) stress pathways. Moreover, TUG1 attenuated apoptosis, inflammation, and oxidative stress in vivo in livers subjected to cold storage. Overexpression of TUG1 also improved hepatocyte function and prolonged hepatic graft survival rates in mice. These results suggest that the lncRNA TUG1 exerts a protective effect against cold-induced liver damage by inhibiting apoptosis in mice, and suggests a potential role for TUG1 as a target for the prevention of cold-induced liver damage in liver transplantation. RNA-seq data are available from GEO using accession number GSE76609. © 2016 Federation of European Biochemical Societies.

  18. 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. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Chronic intermittent hypoxia induces liver fibrosis in mice with diet-induced obesity via TLR4/MyD88/MAPK/NF-kB signaling pathways.

    PubMed

    Kang, Hyeon Hui; Kim, In Kyoung; Lee, Hye In; Joo, Hyonsoo; Lim, Jeong Uk; Lee, Jongmin; Lee, Sang Haak; Moon, Hwa Sik

    2017-08-19

    Obstructive sleep apnea (OSA) is associated with nonalcoholic fatty liver disease (NAFLD), and causes chronic intermittent hypoxia (CIH) during sleep. Inflammation is associated with the development of metabolic complications induced by CIH. Research suggests that innate immune mechanisms are involved in the pro-inflammatory pathways of liver fibrosis. The purpose of this study was to investigate whether innate immune responses induce liver fibrosis, and to evaluate mechanisms underlying hepatic inflammation related to CIH in a murine diet-induced obesity (DIO) model. Inflammatory and oxidative stress markers, TLR4, MyD88, Toll/interleukin-1-receptor-domain-containing adaptor-inducing interferon-β (TRIF), I-κB, NF-κB, p38 MAPK, c-JNK, and ERK activation, were measured in the serum and liver. As a result, α1(I)-collagen mRNA was significantly higher in DIO mice exposed to CIH than in the control groups. CIH mice exhibited liver fibrosis and significantly higher protein expression of TLR4, MyD88, phosphorylated (phospho-) I-κB, and phospho-ERK1/2 activation in the liver, and higher expression of NF-κB than that in the controls. TRIF, p38 MAPK, and JNK activation did not differ significantly between groups. We conclude that CIH in DIO mice leads to liver fibrosis via TLR4/MyD88/MAPK/NF-kB signaling pathways. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Hepatic FGF21 mediates sex differences in high-fat high-fructose diet-induced fatty liver.

    PubMed

    Chukijrungroat, Natsasi; Khamphaya, Tanaporn; Weerachayaphorn, Jittima; Songserm, Thaweesak; Saengsirisuwan, Vitoon

    2017-08-01

    The role of gender in the progression of fatty liver due to chronic high-fat high-fructose diet (HFFD) has not been studied. The present investigation assessed whether HFFD induced hepatic perturbations differently between the sexes and examined the potential mechanisms. Male, female, and ovariectomized (OVX) Sprague-Dawley rats were fed either a control diet or HFFD for 12 wk. Indexes of liver damage and hepatic steatosis were analyzed biochemically and histologically together with monitoring changes in hepatic gene and protein expression. HFFD induced a higher degree of hepatic steatosis in females, with significant increases in proteins involved in hepatic lipogenesis, whereas HFFD significantly induced liver injury, inflammation, and oxidative stress only in males. Interestingly, a significant increase in hepatic fibroblast growth factor 21 (FGF21) protein expression was observed in HFFD-fed males but not in HFFD-fed females. Ovarian hormone deprivation by itself led to a significant reduction in FGF21 with hepatic steatosis, and HFFD further aggravated hepatic fat accumulation in OVX rats. Importantly, estrogen replacement restored hepatic FGF21 levels and reduced hepatic steatosis in HFFD-fed OVX rats. Collectively, our results indicate that male rats are more susceptible to HFFD-induced hepatic inflammation and that the mechanism underlying this sex dimorphism is mediated through hepatic FGF21 expression. Our findings reveal sex differences in the development of HFFD-induced fatty liver and indicate the protective role of estrogen against HFFD-induced hepatic steatosis. Copyright © 2017 the American Physiological Society.

  1. Methimazole-induced hypothyroidism causes cellular damage in the spleen, heart, liver, lung and kidney.

    PubMed

    Cano-Europa, Edgar; Blas-Valdivia, Vanessa; Franco-Colin, Margarita; Gallardo-Casas, Carlos Angel; Ortiz-Butrón, Rocio

    2011-01-01

    It is known that a hypothyroidism-induced hypometabolic state protects against oxidative damage caused by toxins. However, some workers demonstrated that antithyroid drug-induced hypothyroidism can cause cellular damage. Our objective was to determine if methimazole (an antithyroid drug) or hypothyroidism causes cellular damage in the liver, kidney, lung, spleen and heart. Twenty-five male Wistar rats were divided into 5 groups: euthyroid, false thyroidectomy, thyroidectomy-induced hypothyroidism, methimazole-induced hypothyroidism (60 mg/kg), and treatment with methimazole (60 mg/kg) and a T₄ injection (20 μg/kg/d sc). At the end of the treatments (4 weeks for the pharmacological groups and 8 weeks for the surgical groups), the animals were anesthetized with sodium pentobarbital and they were transcardially perfused with 10% formaldehyde. The spleen, heart, liver, lung and kidney were removed and were processed for embedding in paraffin wax. Coronal sections were stained with hematoxylin-eosin. At the end of treatment, animals with both the methimazole- and thyroidectomy-induced hypothyroidism had a significant reduction of serum concentration of thyroid hormones. Only methimazole-induced hypothyroidism causes cellular damage in the kidney, lung, liver, heart, kidney and spleen. In addition, animals treated with methimazole and T₄ showed cellular damage in the lung, spleen and renal medulla with lesser damage in the liver, renal cortex and heart. The thyroidectomy only altered the lung structure. The alterations were prevented by T₄ completely in the heart and partially in the kidney cortex. These results indicate that tissue damage found in hypothyroidism is caused by methimazole. Copyright © 2009 Elsevier GmbH. All rights reserved.

  2. The Protective Effect of Glycyrrhetinic Acid on Carbon Tetrachloride-Induced Chronic Liver Fibrosis in Mice via Upregulation of Nrf2

    PubMed Central

    Chen, Shaoru; Zou, Liyi; Li, Li; Wu, Tie

    2013-01-01

    This study was designed to investigate the potentially protective effects of glycyrrhetinic acid (GA) and the role of transcription factor nuclear factor-erythroid 2(NF-E2)-related factor 2 (Nrf2) signaling in the regulation of Carbon Tetrachloride (CCl4)-induced chronic liver fibrosis in mice. The potentially protective effects of GA on CCl4-induced chronic liver fibrosis in mice were depicted histologically and biochemically. Firstly, histopathological changes including regenerative nodules, inflammatory cell infiltration and fibrosis were induced by CCl4.Then, CCl4 administration caused a marked increase in the levels of serum aminotransferases (GOT, GPT), serum monoamine oxidase (MAO) and lipid peroxidation (MDA) as well as MAO in the mice liver homogenates. Also, decreased nuclear Nrf2 expression, mRNA levels of its target genes such as superoxide dismutase 3 (SOD3), catalase (CAT), glutathione peroxidase 2 (GPX2), and activity of cellular antioxidant enzymes were found after CCl4 exposure. All of these phenotypes were markedly reversed by the treatment of the mice with GA. In addition, GA exhibited the antioxidant effects in vitro by on FeCl2-ascorbate induced lipid peroxidation in mouse liver homogenates, and on DPPH scavenging activity. Taken together, these results suggested that GA can protect the liver from oxidative stress in mice, presumably through activating the nuclear translocation of Nrf2, enhancing the expression of its target genes and increasing the activity of the antioxidant enzymes. Therefore, GA may be an effective hepatoprotective agent and viable candidate for treating liver fibrosis and other oxidative stress-related diseases. PMID:23341968

  3. Antioxidant potential of the methanol-methylene chloride extract of Terminalia glaucescens leaves on mice liver in streptozotocin-induced stress.

    PubMed

    Njomen, Guy Bertrand Sabas Nya; Kamgang, René; Oyono, Jean Louis Essame; Njikam, Njifutie

    2008-11-01

    The antioxidant effect of the methanol-methylene chloride extract of Terminalia glaucescens (Combretaceae) leaves was investigated in streptozotocin (STZ)-induced oxidative stress. Oxidative stress was induced in mice by a daily dose of STZ (45 mg/kg body weight i.p.) for five days. From day one, before STZ injection, normal and diabetic-test mice received an oral dose of the extract (100 or 300 mg/kg b.w.) daily. Plasma metabolites, lipid peroxidation, and antioxidant enzymes in the liver were assessed and gain in body weight recorded. In normal mice the plant extract reduced food and water intake, blood glucose and LDL-C level and body weight gain, did not affect the lipid peroxidation in the liver, while the antioxidant enzyme activities seemed increased. Blood glucose was decreased (P < 0.05) in normal mice treated with 300 mg/kg extract. Diabetic mice pretreated with 100 mg/kg extract as diabetic control mice (DC) showed significant (P < 0.001) body weight loss, polyphagia and polydipsia, high plasma glucose level, decrease in the liver catalase, peroxidase, and superoxide dismutase activities, and increase in lipid peroxidation. The HDL-C level was lowered (P < 0.05) whereas LDL-C increased. In 300 mg/kg extract-pretreated diabetic mice the extract prevented body weight loss, increase of blood glucose level, lipid peroxidation in liver, food and water intake, and lowering of plasma HDL-C level and liver antioxidants; this extract prevented LDL-C level increase. These results indicate that T. glaucescens protects against STZ-induced oxidative stress and could thus explain its traditional use for diabetes and obesity treatment or management.

  4. Mechanistic Modelling of Drug-Induced Liver Injury: Investigating the Role of Innate Immune Responses.

    PubMed

    Shoda, Lisl Km; Battista, Christina; Siler, Scott Q; Pisetsky, David S; Watkins, Paul B; Howell, Brett A

    2017-01-01

    Drug-induced liver injury (DILI) remains an adverse event of significant concern for drug development and marketed drugs, and the field would benefit from better tools to identify liver liabilities early in development and/or to mitigate potential DILI risk in otherwise promising drugs. DILIsym software takes a quantitative systems toxicology approach to represent DILI in pre-clinical species and in humans for the mechanistic investigation of liver toxicity. In addition to multiple intrinsic mechanisms of hepatocyte toxicity (ie, oxidative stress, bile acid accumulation, mitochondrial dysfunction), DILIsym includes the interaction between hepatocytes and cells of the innate immune response in the amplification of liver injury and in liver regeneration. The representation of innate immune responses, detailed here, consolidates much of the available data on the innate immune response in DILI within a single framework and affords the opportunity to systematically investigate the contribution of the innate response to DILI.

  5. Fructo-oligosaccharide systemically diminished D-galactose-induced oxidative molecule damages in BALB/cJ mice.

    PubMed

    Hsia, Chien-Hsun; Wang, Cheng-Hsin; Kuo, Yi-Wen; Ho, Ying-Jui; Chen, Hsiao-Ling

    2012-06-01

    Subcutaneous (s.c.) D-galactose (DG) treatment has been shown to facilitate the development of biomarkers for Alzheimer's disease in C57BL/6J mice. The aim of the present study was to determine whether this treatment in young BALB/cJ mice, another mouse strain, enhanced oxidative stress to similar extents shown in older mice, and to further determine the effects of fructo-oligosaccharide (FO), a prebiotic fibre and vitamin E (antioxidant control) on the DG-induced oxidative damage of lipids, proteins and mitochondrial DNA, and erythrocyte antioxidant enzyme activities. Mice (12 weeks of age, n 40) were divided into four groups: vehicle (s.c. saline)+control (modified rodent chow); DG (s.c. 1·2 g/kg body weight)+control; DG+FO (5 %, w/w); DG+vitamin E (α-tocopherol, 0·2 %). Then, the animals were killed after 52 d of treatment. Another natural ageing (NA) group without any injection was killed at 47 weeks of age, which served as an aged control. The results indicated that the DG treatment enhanced malonaldehyde dimethyl acetal (MDA) levels in the plasma, liver and cerebral cortex, and protein carbonyl levels in the liver and hippocampus to similar levels shown in the NA group. FO, similar to α-tocopherol, systemically normalised DG-induced elevations in the levels of MDA in the plasma, liver and cerebral cortex, protein carbonyls in the liver and hippocampus, hepatic mitochondrial 8-oxo-deoxyguanosine and erythrocyte superoxide dismutase activity. In conclusion, the s.c. DG treatment in younger BALB/cJ mice resembled the oxidative status in older mice. FO supplementation systemically prevented DG-induced oxidative stress, probably through its fermentation products and prebiotic effect.

  6. Chronic intermittent hypoxia and acetaminophen induce synergistic liver injury in mice.

    PubMed

    Savransky, Vladimir; Reinke, Christian; Jun, Jonathan; Bevans-Fonti, Shannon; Nanayakkara, Ashika; Li, Jianguo; Myers, Allen C; Torbenson, Michael S; Polotsky, Vsevolod Y

    2009-02-01

    Obstructive sleep apnoea (OSA) leads to chronic intermittent hypoxia (CIH) during sleep. Obstructive sleep apnoea has been associated with liver injury. Acetaminophen (APAP; known as paracetamol outside the USA) is one of the most commonly used drugs which has known hepatotoxicity. The goal of the present study was to examine whether CIH increases liver injury, hepatic oxidative stress and inflammation induced by chronic APAP treatment. Adult C57BL/6J mice were exposed to CIH or intermittent air (IA) for 4 weeks. Mice in both groups were treated with intraperitoneal injections of either APAP (200 mg kg(-1)) or normal saline daily. A combination of CIH and APAP caused liver injury, with marked increases in serum alanine aminotransferase, aspartate aminotransferase (AST), gamma-glutamyl transferase and total bilirubin levels, whereas CIH alone induced only elevation in serum AST levels. Acetaminophen alone did not affect serum levels of liver enzymes. Histopathology revealed hepatic necrosis and increased apoptosis in mice exposed to CIH and APAP, whereas the liver remained intact in all other groups. Mice exposed to CIH and APAP exhibited decreased hepatic glutathione in conjunction with a fivefold increase in nitrotyrosine levels, suggesting formation of toxic peroxynitrite in hepatocytes. Acetaminophen or CIH alone had no effect on either glutathione or nitrotyrosine. A combination of CIH and APAP caused marked increases in pro-inflammatory chemokines, monocyte chemoattractant protein-1 and macrophage inflammatory protein-2, which were not observed in mice exposed to CIH or APAP alone. We conclude that CIH and chronic APAP treatment lead to synergistic liver injury, which may have clinical implications for patients with OSA.

  7. Radiation-Induced Liver Damage: Correlation of Histopathology with Hepatobiliary Magnetic Resonance Imaging, a Feasibility Study

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Seidensticker, Max, E-mail: max.seidensticker@med.ovgu.de; Burak, Miroslaw; Kalinski, Thomas

    PurposeRadiotherapy of liver malignancies shows promising results (radioembolization, stereotactic irradiation, interstitial brachytherapy). Regardless of the route of application, a certain amount of nontumorous liver parenchyma will be collaterally damaged by radiation. The functional reserve may be significantly reduced with an impact on further treatment planning. Monitoring of radiation-induced liver damage by imaging is neither established nor validated. We performed an analysis to correlate the histopathological presence of radiation-induced liver damage with functional magnetic resonance imaging (MRI) utilizing hepatobiliary contrast media (Gd-BOPTA).MethodsPatients undergoing local high-dose-rate brachytherapy for whom a follow-up hepatobiliary MRI within 120 days after radiotherapy as well as an evaluablemore » liver biopsy from radiation-exposed liver tissue within 7 days before MRI were retrospectively identified. Planning computed tomography (CT)/dosimetry was merged to the CT-documentation of the liver biopsy and to the MRI. Presence/absence of radiation-induced liver damage (histopathology) and Gd-BOPTA uptake (MRI) as well as the dose applied during brachytherapy at the site of tissue sampling was determined.ResultsFourteen biopsies from eight patients were evaluated. In all cases with histopathological evidence of radiation-induced liver damage (n = 11), no uptake of Gd-BOPTA was seen. In the remaining three, cases no radiation-induced liver damage but Gd-BOPTA uptake was seen. Presence of radiation-induced liver damage and absence of Gd-BOPTA uptake was correlated with a former high-dose exposition.ConclusionsAbsence of hepatobiliary MRI contrast media uptake in radiation-exposed liver parenchyma may indicate radiation-induced liver damage. Confirmatory studies are warranted.« less

  8. Drug-induced liver injury due to antibiotics.

    PubMed

    Björnsson, Einar S

    Drug-induced liver injury (DILI) is an important differential diagnosis in patients with abnormal liver tests and normal hepatobiliary imaging. Of all known liver diseases, the diagnosis of DILI is probably one of the most difficult one to be established. In all major studies on DILI, antibiotics are the most common type of drugs that have been reported. The clinical phenotype of different types of antibiotics associated with liver injury is highly variable. Some widely used antibiotics such as amoxicillin-clavulanate have been shown to have a delayed onset on liver injury and recently cefazolin has been found to lead to liver injury 1-3 weeks after exposure of a single infusion. The other extreme is the nature of nitrofurantoin-induced liver injury, which can occur after a few years of treatment and lead to acute liver failure (ALF) or autoimmune-like reaction. Most patients with liver injury associated with use of antibiotics have a favorable prognosis. However, patients with jaundice have approximately 10% risk of death from liver failure and/or require liver transplantation. In rare instances, the hepatoxicity can lead to chronic injury and vanishing bile duct syndrome. Given, sometimes very severe consequences of the adverse liver reactions, it cannot be over emphasized that the indication for the different antibiotics should be evidence-based and symptoms and signs of liver injury from the drugs should lead to prompt cessation of therapy.

  9. Protective effects of Centella asiatica leaf extract on dimethylnitrosamine-induced liver injury in rats

    PubMed Central

    Choi, Myung-Joo; Zheng, Hong-Mei; Kim, Jae Min; Lee, Kye Wan; Park, Yu Hwa; Lee, Don Haeng

    2016-01-01

    Oxidative stress in liver injury is a major pathogenetic factor in the progression of liver damage. Centella asiatica (L.) Urban, known in the United States as Gotu kola, is widely used as a traditional herbal medicine in Chinese or Indian Pennywort. The efficacy of Centella asiatica is comprehensive and is used as an anti-inflammatory agent, for memory improvement, for its antitumor activity and for treatment of gastric ulcers. The present study investigated the protective effects of Centella asiatica on dimethylnitrosamine (DMN)-induced liver injury in rats. The rats in the treatment groups were treated with Centella asiatica at either 100 or 200 mg/kg in distilled water (D.W) or with silymarin (200 mg/kg in D.W) by oral administration for 5 days daily following intraperitoneal injections of 30 mg/kg DMN. Centella asiatica significantly decreased the relative liver weights in the DMN-induced liver injury group, compared with the control. The assessment of liver histology showed that Centella asiatica significantly alleviated mass periportal ± bridging necrosis, intralobular degeneration and focal necrosis, with fibrosis of liver tissues. Additionally, Centella asiatica significantly decreased the level of malondialdehyde, significantly increased the levels of antioxidant enzymes, including superoxide dismutase, glutathione peroxidase and catalase, and may have provided protection against the deleterious effects of reactive oxygen species. In addition, Centella asiatica significantly decreased inflammatory mediators, including interleukin (IL)-1β, IL-2, IL-6, IL-10, IL-12, tumor necrosis factor-α, interferon-γ and granulocyte/macrophage colony-stimulating factor. These results suggested that Centella asiatica had hepatoprotective effects through increasing the levels of antioxidant enzymes and reducing the levels of inflammatory mediators in rats with DMN-induced liver injury. Therefore, Centella asiatica may be useful in preventing liver damage. PMID:27748812

  10. Nrf2-mediated antioxidant response by ethanolic extract of Sida cordifolia provides protection against alcohol-induced oxidative stress in liver by upregulation of glutathione metabolism.

    PubMed

    Rejitha, S; Prathibha, P; Indira, M

    2015-03-01

    Objective The study aimed to evaluate the antioxidant property of ethanolic extract of Sida cordifolia (SAE) on alcohol-induced oxidative stress and to elucidate its mechanism of action. Methods Male albino rats of the Sprague-Dawley strain were grouped into four: (1) control, (2) alcohol (4 g/kg body weight), (3) SAE (50 mg/100 g body weight), and (4) alcohol (4 g/kg body weight) + SAE (50 mg/100 g body weight). Alcohol and SAE were given orally each day by gastric intubation. The duration of treatment was 90 days. Results The activities of toxicity markers in liver and serum increased significantly in alcohol-treated rats and to a lesser extent in the group administered SAE + alcohol. The activity of alcohol dehydrogenase and the reactive oxygen species level were increased significantly in alcohol-treated rats but attenuated in the SAE co-administered group. Oxidative stress was increased in alcohol-treated rats as evidenced by the lowered activities of antioxidant enzymes, decreased level of reduced glutathione (GSH), increased lipid peroxidation products, and decreased expression of γ-glutamyl cysteine synthase in liver. The co-administration of SAE with alcohol almost reversed these changes. The activity of glutathione-S-transferase and translocation of Nrf2 from cytosol to nucleus in the liver was increased in both the alcohol and alcohol + SAE groups, but the maximum changes were observed in the latter group. Discussion The SAE most likely elicits its antioxidant potential by reducing oxidative stress, enhancing the translocation of Nrf2 to nucleus and thereby regulating glutathione metabolism, leading to enhanced GSH content.

  11. Traditional Chinese Medicine and Herb-induced Liver Injury: Comparison with Drug-induced Liver Injury.

    PubMed

    Jing, Jing; Teschke, Rolf

    2018-03-28

    Cases of suspected herb-induced liver injury (HILI) caused by herbal Traditional Chinese Medicines (TCMs) and of drug-induced liver injury (DILI) are commonly published in the scientific literature worldwide. As opposed to the multiplicity of botanical chemicals in herbal TCM products, which are often mixtures of several herbs, conventional Western drugs contain only a single synthetic chemical. It is therefore of interest to study how HILI by TCM and DILI compare with each other, and to what extent results from each liver injury type can be transferred to the other. China is among the few countries with a large population using synthetic Western drugs as well as herbal TCM. Therefore, China is well suited to studies of liver injury comparing drugs with TCM herbs. Despite some concordance, recent analyses of liver injury cases with verified causality, using the Roussel Uclaf Causality Assessment Method, revealed major differences in HILI caused by TCMs as compared to DILI with respect to the following features: HILI cases are less frequently observed as compared to DILI, have a smaller proportion of females and less unintentional rechallenge events, and present a higher rate of hepatocellular injury features. Since many results were obtained among Chinese residents who had access to and had used Western drugs and TCM herbs, such ethnic homogeneity supports the contention that the observed differences of HILI and DILI in the assessed population are well founded.

  12. Traditional Chinese Medicine and Herb-induced Liver Injury: Comparison with Drug-induced Liver Injury

    PubMed Central

    Jing, Jing; Teschke, Rolf

    2017-01-01

    Abstract Cases of suspected herb-induced liver injury (HILI) caused by herbal Traditional Chinese Medicines (TCMs) and of drug-induced liver injury (DILI) are commonly published in the scientific literature worldwide. As opposed to the multiplicity of botanical chemicals in herbal TCM products, which are often mixtures of several herbs, conventional Western drugs contain only a single synthetic chemical. It is therefore of interest to study how HILI by TCM and DILI compare with each other, and to what extent results from each liver injury type can be transferred to the other. China is among the few countries with a large population using synthetic Western drugs as well as herbal TCM. Therefore, China is well suited to studies of liver injury comparing drugs with TCM herbs. Despite some concordance, recent analyses of liver injury cases with verified causality, using the Roussel Uclaf Causality Assessment Method, revealed major differences in HILI caused by TCMs as compared to DILI with respect to the following features: HILI cases are less frequently observed as compared to DILI, have a smaller proportion of females and less unintentional rechallenge events, and present a higher rate of hepatocellular injury features. Since many results were obtained among Chinese residents who had access to and had used Western drugs and TCM herbs, such ethnic homogeneity supports the contention that the observed differences of HILI and DILI in the assessed population are well founded. PMID:29577033

  13. 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

    2017-05-01

    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. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Coexistence of hyperlipidemia and acute cerebral ischemia/reperfusion induces severe liver damage in a rat model

    PubMed Central

    Gong, Wei-Hong; Zheng, Wen-Xia; Wang, Jun; Chen, Shi-Hui; Pang, Bo; Hu, Xia-Min; Cao, Xiao-Lu

    2012-01-01

    AIM: To investigate the correlation of hyperlipemia (HL) and acute cerebral ischemia/reperfusion (I/R) injury on liver damage and its mechanism. METHODS: Rats were divided into 4 groups: control, HL, I/R and HL+I/R. After the induction of HL via a high-fat diet for 18 wk, middle cerebral artery occlusion was followed by 24 h of reperfusion to capture I/R. Serum alanine transaminase (ALT) and aspartate aminotransferase (AST) were analyzed as part of liver function tests and liver damage was further assessed by histological examination. Hepatocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. The expression of genes related to apoptosis (caspase-3, bcl-2) was assayed by immunohistochemistry and Western blotting. Serum tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and liver mitochondrial superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA) and Ca2+ levels were measured to determine inflammatory and oxidative/antioxidative status respectively. Microsomal hydroxylase activity of the cytochrome P450 2E1 (CYP2E1)-containing enzyme was measured with aniline as the substrate, and CYP2E1 expression in the liver tissue and microsome was determined by immunohistochemistry and Western blotting respectively. RESULTS: HL alone induced by high-fat diet for 18 wk resulted in liver damage, indicated by histopathological analysis, and a considerable increase in serum ALT (25.13 ± 16.90 vs 9.56 ± 1.99, P < 0.01) and AST levels (18.01 ± 10.00 vs 11.33 ± 4.17, P < 0.05) compared with control. Moreover, HL alone induced hepatocyte apoptosis, which was determined by increased TUNEL-positive cells (4.47 ± 0.45 vs 1.5 ± 0.22, P < 0.01), higher caspase-3 and lower bcl-2 expression. Interestingly, compared with those in control, HL or I/R groups, massive increases of serum ALT (93.62 ± 24.00 vs 9.56 ± 1.99, 25.13 ± 16.90 or 12.93 ± 6.14, P < 0.01) and AST (82.32 ± 26.92 vs 11.33 ± 4

  15. Lipoic acid prevents suppression of connective tissue proliferation in the rat liver induced by n-3 PUFAs. A pilot study.

    PubMed

    Arend, A; Zilmer, M; Vihalemm, T; Selstam, G; Sepp, E

    2000-01-01

    As previously shown, dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) suppress connective tissue proliferation in the rat liver wound concurrent with an elevated level of lipid peroxidation. The present study was undertaken to investigate the influence of alpha-lipoic acid (LA), a natural anti-oxidant, on these effects of n-3 PUFAs. Rats were fed with a commercial pellet diet (control group) or with diets enriched with 10% of sunflower oil (n-6 group) or 10% of fish oil (n-3 group) for 8 weeks followed by addition of LA to the same diets for 10 days. Then a liver thermic wound was induced and the administration of LA was continued for 6 days. The proliferation of the connective tissue, the level of lipid peroxidation and their peroxidizability and the content of prostaglandins E2 and F2alpha were measured in the liver wounds. LA prevented the suppression of connective tissue proliferation in the healing wound induced by n-3 PUFAs, avoided the increase in peroxidation of lipids, reduced peroxidizability of lipids and modulated the decrease in PGE2 and PGF2alpha. The results indicate that dietary LA may prevent the suppression of liver wound healing induced by n-3 PUFAs.

  16. Liver microRNA profile of induced allograft tolerance

    PubMed Central

    Vitalone, Matthew James; Wai, Liang; Fujiki, Masato; Lau, Audrey H.; Littau, Erik; Esquivel, Carlos; Martinez, Olivia M.; Krams, Sheri M.

    2016-01-01

    Introduction Although the liver is less immunogenic than other solid organs, most liver transplant recipients receive lifelong immunosuppression. In both experimental models and clinical transplantation, total Lymphoid Irradiation (TLI) has been shown to induce allograft tolerance. Our goal was to identify the microRNAs (miRNAs) expressed in tolerant liver allograft recipients in an experimental model of TLI-induced tolerance. Methods To identify the miRNAs associated with TLI-induced tolerance we examined syngeneic recipients (Lewis→Lewis) and allogeneic recipients (DA→Lewis) of orthotropic liver transplants that received post-transplant TLI, allogeneic recipients that were not treated post-transplantation and experienced acute rejection, and native DA livers. QPCR miRNA array cards were used to profile liver grafts. Results We identified 12 miRNAs that were specifically and significantly increased during acute rejection. In early tolerance, 33 miRNAs were altered compared to syngeneic livers, with 80% of the miRNAs increased. In established tolerance 42 miRNAs were altered. In addition, miR-142-5p and miR-181a demonstrated increased expression in tolerant livers (both early and established tolerance) as compared to syngeneic livers. A principal component analysis of all miRNAs assayed, demonstrated a profile in established tolerance that was closely related to that seen in syngeneic livers. Conclusions The miRNA profile of established tolerant allografts is very similar to syngeneic grafts suggesting tolerance may be a return to an immunological state of quiescence. PMID:26950716

  17. The association effect of insulin and clonazepam on oxidative stress in liver of an experimental animal model of diabetes and depression.

    PubMed

    Wayhs, Carlos Alberto Yasin; Tortato, Caroline; Mescka, Caroline Paula; Pasquali, Matheus Augusto; Schnorr, Carlos Eduardo; Nin, Maurício Schüler; Barros, Helena Maria Tannhauser; Moreira, José Claudio Fonseca; Vargas, Carmen Regla

    2013-05-01

    It is known that oxidative stress occurs in peripheral blood in an experimental animal model of diabetes and depression, and acute treatment with insulin and clonazepam (CNZ) has a protective effect on oxidative stress in this model. This study evaluated the effect of insulin plus CNZ on oxidative stress parameters in the liver of diabetic male rats induced with streptozotocin (STZ) and subjected to forced swimming test (FST). Diabetes was induced by a single intraperitoneal (i.p.) dose of STZ 60 mg/kg in male Wistar rats. Insulin (4 IU/kg) plus CNZ acute i.p. treatment (0.25 mg/kg) was administered 24, 5 and 1 h before the FST. Nondiabetic control rats received i.p. injections of saline (1 mL/kg). Protein oxidative damage was evaluated by carbonyl formation and the antioxidant redox parameters were analyzed by the measurements of enzymatic activities of the superoxide dismutase (SOD), catalase and glyoxalase I (GLO). Glycemia levels also were determined. Our present study has shown an increase in carbonyl content from diabetic rats subjected to FST (2.04 ± 0.55), while the activity of catalase (51.83 ± 19.02) and SOD (2.30 ± 1.23) were significantly decreased in liver from these animals, which were reverted by the treatment. Also, the activity of GLO (0.15 ± 0.02) in the liver of the animals was decreased. Our findings showed that insulin plus CNZ acute treatment ameliorate the antioxidant redox parameters and protect against protein oxidative damage in the liver of diabetic rats subjected to FST.

  18. Possible role of Arthrospira platensis in reversing oxidative stress-mediated liver damage in rats exposed to lead.

    PubMed

    Khalil, Samah R; Elhady, Walaa M; Elewa, Yaser H A; Abd El-Hameed, Noura E; Ali, Sozan A

    2018-01-01

    Environmental pollutants, particularly metallic elements, mobilized and released into the environment, eventually accumulate in the food chain and thus pose a serious threat to human and animal health. In the present study, the role of Arthrospira (Spirulina platensis; SP) as a protector against oxidative stress-mediated liver damage induced by an exposure to lead acetate (LA; as a metallic pollutant) was assessed. To achieve this aim, rats were orally administered with 300 mg/kg bw SP for 15 days, before and concurrently with an intraperitoneal injection of 50 mg/kg bw LA (6 injections throughout 15 days). As a result, co-administration of SP with LA reduced the amount of lead that accumulated in both blood and liver tissue of the exposed rats and minimized the increased levels of lipid peroxidation, protein oxidation, DNA oxidative damage, and liver enzyme endpoints. In addition, because of SP administration, the levels of depleted biomarkers of antioxidant status and total antioxidant capacity in LA-exposed rats improved. Moreover, SP protected the liver tissue against the changes caused by LA exposure and also decreased the reactivity of HSP70 in the cytoplasm of hepatocytes. Collectively, our data suggest that SP has a potential use as a food supplement in the regions highly polluted with heavy metals such as lead. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  19. Antibiotic tigecycline enhances cisplatin activity against human hepatocellular carcinoma through inducing mitochondrial dysfunction and oxidative damage

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tan, Jun; Song, Meijun; Zhou, Mi

    Targeting mitochondrial metabolism has been recently demonstrated to be a promising therapeutic strategy for the treatment of various cancer. In this work, we demonstrate that antibiotic tigecycline is selectively against hepatocellular carcinoma (HCC) through inducing mitochondrial dysfunction and oxidative damage. Tigecycline is more effective in inhibiting proliferation and inducing apoptosis of HCC than normal liver cells. Importantly, tigecycline significantly enhances the inhibitory effects of chemotherapeutic drug cisplatin in HCC in vitro and in vivo. Mechanistically, tigecycline specifically inhibits mitochondrial translation as shown by the decreased protein levels of Cox-1 and -2 but not Cox-4 or Grp78, and increased mRNA levels of Cox-1more » and -2 but not Cox-4 in HCC cells exposed to tigecycline. In addition, tigecycline significantly induces mitochondrial dysfunction in HCC cells via decreasing mitochondrial membrane potential, complex I and IV activities, mitochondrial respiration and ATP levels. Tigecycline also increases levels of mitochondrial superoxide, hydrogen peroxide and ROS levels. Consistent with oxidative stress, oxidative damage on DNA, protein and lipid are also observed in tigecycline-treated cells. Importantly, antioxidant N-acetyl-L-cysteine (NAC) reverses the effects of tigecycline, suggesting that oxidative stress is required for the action of tigecycline in HCC cells. We further show that HCC cells have higher level of mitochondrial biogenesis than normal liver cells which might explain the different sensitivity to tigecycline between HCC and normal liver cells. Our work is the first to demonstrate that tigecycline is a promising candidate for HCC treatment and highlight the therapeutic value of targeting mitochondrial metabolism in HCC. - Highlights: • Tigecycline selectively targets HCC in vitro and in vivo. • Tigecycline enhances HCC cell response to chemotherapeutic drug. • Tigecycline inhibits mitochondrial

  20. 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.

  1. Anti-Oxidative Defences Are Modulated Differentially in Three Freshwater Teleosts in Response to Ammonia-Induced Oxidative Stress

    PubMed Central

    Giblen, Terri; Zinta, Gaurav; De Rop, Michelle; Asard, Han; Blust, Ronny; De Boeck, Gudrun

    2014-01-01

    Oxidative stress and the antioxidant response induced by high environmental ammonia (HEA) were investigated in the liver and gills of three freshwater teleosts differing in their sensitivities to ammonia. The highly ammonia-sensitive salmonid Oncorhynchus mykiss (rainbow trout), the less ammonia sensitive cyprinid Cyprinus carpio (common carp) and the highly ammonia-resistant cyprinid Carassius auratus (goldfish) were exposed to 1 mM ammonia (as NH4HCO3) for 0 h (control), 3 h, 12 h, 24 h, 48 h, 84 h and 180 h. Results show that HEA exposure increased ammonia accumulation significantly in the liver of all the three fish species from 24 h–48 h onwards which was associated with an increment in oxidative stress, evidenced by elevation of xanthine oxidase activity and levels of hydrogen peroxide (H2O2) and malondialdehyde (MDA). Unlike in trout, H2O2 and MDA accumulation in carp and goldfish liver was restored to control levels (84 h–180 h); which was accompanied by a concomitant increase in superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase activity and reduced ascorbate content. Many of these defence parameters remained unaffected in trout liver, while components of the glutathione redox cycle (reduced glutathione, glutathione peroxidase and glutathione reductase) enhanced to a greater extent. The present findings suggest that trout rely mainly on glutathione dependent defensive mechanism while carp utilize SOD, CAT and ascorbate as anti-oxidative sentinels. Hepatic cells of goldfish appear to utilize each of these protective systems, and showed more effective anti-oxidative compensatory responses towards HEA than carp, while trout were least effective. The present work also indicates that HEA exposure resulted in a relatively mild oxidative stress in the gills of all three species. This probably explains the almost complete lack of anti-oxidative responses in branchial tissue. This research suggests that oxidative stress, as well as the antioxidant

  2. Protective role of silymarin and D-penicillamine against lead-induced liver toxicity and oxidative stress.

    PubMed

    Jalali, Seyedeh Missagh; Najafzadeh, Hossein; Bahmei, Sadegh

    2017-06-01

    This study was performed to assess hepatotoxicity and alterations in liver antioxidant defence in acute lead (Pb) exposure and the protective effects of silymarin in comparison to D-penicillamine in rats. Forty eight Albino rats were divided in eight groups and received the following treatments in a 10-day experiment - group 1: normal saline as control; group 2: 25-mg/kg Pb acetate, intraperitoneally (IP) for the last 5 days; group 3: 100-mg/kg D-penicillamine, IP for the last 5 days; group 4: 200-mg/kg silymarin, orally for 10 days; and groups 5, 6, 7 and 8: in addition to Pb, they received D-penicillamine, for the last 5 days, silymarin for 10 days, a combination of silymarin for 10 days and D-penicillamine for the last 5 days and silymarin for the last 5 days, respectively. Pb acetate exposure induced significant elevation in serum alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzyme activities in group 2 compared to control group. Significant reductions in serum total protein and albumin in all Pb-exposed groups and in serum glucose in groups 2, 6 and 8 were also observed. Liver tissue superoxide dismutase and glutathione peroxidase were significantly lower in groups 2 and 8 compared to control group. Silymarin pretreatment and D-penicillamine administration in groups 5, 7 and 8 could significantly lower ALP, ALT and AST and improve liver antioxidant enzymes. Thus, acute Pb exposure induced hepatotoxicity with suppression of liver antioxidant defence system and silymarin, as an antioxidant could alleviate this effect.

  3. Possible gasoline-induced chronic liver injury due to occupational malpractice in a motor mechanic: a case report.

    PubMed

    Gunathilaka, Mahesh Lakmal; Niriella, Madunil Anuk; Luke, Nathasha Vihangi; Piyarathna, Chathura Lakmal; Siriwardena, Rohan Chaminda; De Silva, Arjuna Priyadarshin; de Silva, Hithanadura Janaka

    2017-07-03

    Hydrocarbon-induced occupational liver injury is a well-known clinical entity among petroleum industry workers. There are many types of hydrocarbon exposure, with inhalation being the most common. Hydrocarbon-induced occupational liver injury is a rarely suspected and commonly missed etiological agent for liver injury. We report a case of a non-petroleum industry worker with chronic liver disease secondary to hydrocarbon-induced occupational liver injury caused by chronic low-grade hydrocarbon ingestion due to occupational malpractice. A 23-year-old Sri Lankan man who was a motor mechanic presented to our hospital with decompensated cirrhosis. He had been chronically exposed to gasoline via inadvertent ingestion due to occupational malpractice. He used to remove gasoline from carburetors by sucking and failed to practice mouth washing thereafter. On evaluation, he had histologically proven established cirrhosis. A comprehensive history and workup ruled out other nonoccupational etiologies for cirrhosis. The patient's long-term occupational gasoline exposure and clinical course led us to a diagnosis of hydrocarbon-induced occupational liver injury leading to decompensated cirrhosis. Hydrocarbon-induced occupational liver injury should be considered as a cause when evaluating a patient with liver injury with possible exposure in relevant occupations.

  4. Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yamazaki, Makoto; Miyake, Manami; Sato, Hiroko

    2013-04-01

    Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points. Statistical analysis and pathway mapping of the nearly 1900 metabolitesmore » profiled in the plasma, urine, and liver revealed diverse time and dose dependent metabolic cascades leading to DILI by the hepatotoxins. The most consistent change induced by the hepatotoxins, detectable even at the early time point/low dose, was the significant elevations of a panel of bile acids in the plasma and urine, suggesting that DILI impaired hepatic bile acid uptake from the circulation. Furthermore, bile acid amidation in the hepatocytes was altered depending on the severity of the hepatotoxin-induced oxidative stress. The alteration of the bile acids was most evident by the necrosis and cholestasis hepatotoxins, with more subtle effects by the steatosis and idiosyncratic hepatotoxins. Taking together, our data suggest that the perturbation of bile acid homeostasis is an early event of DILI. Upon further validation, selected bile acids in the circulation could be potentially used as sensitive and early DILI preclinical biomarkers. - Highlights: ► We used metabolomics to gain insights on drug induced liver injury (DILI) in rats. ► We profiled rats treated with thirteen hepatotoxins at two doses and two time points. ► The toxins

  5. Neutrophil-cytokine interactions in a rat model of sulindac-induced idiosyncratic liver injury.

    PubMed

    Zou, Wei; Roth, Robert A; Younis, Husam S; Malle, Ernst; Ganey, Patricia E

    2011-12-18

    Previous studies indicated that lipopolysaccharide (LPS) interacts with the nonsteroidal anti-inflammatory drug sulindac (SLD) to produce liver injury in rats. In the present study, the mechanism of SLD/LPS-induced liver injury was further investigated. Accumulation of polymorphonuclear neutrophils (PMNs) in the liver was greater in SLD/LPS-cotreated rats compared to those treated with SLD or LPS alone. In addition, PMN activation occurred specifically in livers of rats cotreated with SLD/LPS. The hypothesis that PMNs and proteases released from them play critical roles in the hepatotoxicity was tested. SLD/LPS-induced liver injury was attenuated by prior depletion of PMNs or by treatment with the PMN protease inhibitor, eglin C. Previous studies suggested that tumor necrosis factor-α (TNF) and the hemostatic system play critical roles in the pathogenesis of liver injury induced by SLD/LPS. TNF and plasminogen activator inhibitor-1 (PAI-1) can contribute to hepatotoxicity by affecting PMN activation and fibrin deposition. Therefore, the role of TNF and PAI-1 in PMN activation and fibrin deposition in the SLD/LPS-induced liver injury model was tested. Neutralization of TNF or inhibition of PAI-1 attenuated PMN activation. TNF had no effect on PAI-1 production or fibrin deposition. In contrast, PAI-1 contributed to fibrin deposition in livers of rats treated with SLD/LPS. In summary, PMNs, TNF and PAI-1 contribute to the liver injury induced by SLD/LPS cotreatment. TNF and PAI-1 independently contributed to PMN activation, which is critical to the pathogenesis of liver injury. Moreover, PAI-1 contributed to liver injury by promoting fibrin deposition. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  6. Hepatoprotective effects of kaempferol 3-O-rutinoside and kaempferol 3-O-glucoside from Carthamus tinctorius L. on CCl4-induced oxidative liver injury in mice.

    PubMed

    Wang, Yu; Tang, Changyun; Zhang, Hao

    2015-06-01

    Safflower (Carthamus tinctorius L.) is a traditional medicinal and edible herb with a long history of use in China. In this study, a model of hepatotoxicity induced by carbon tetrachloride (CCl 4 ) in mice was used to investigate the hepatoprotective effects of kaempferol 3-O-rutinoside (K-3-R) and kaempferol 3-O-glucoside (K-3-G), two kaempferol glycosides isolated from C. tinctorius L. K-3-R and K-3-G, at doses of 200 mg/kg and 400 mg/kg, were given orally to male mice once/d for 7 days before they received CCl 4 intraperitoneally. Our results showed that K-3-R and K-3-G treatment increased the level of total protein (TP) and prevented the CCl 4 -induced increases in serum aspartate aminotransferase (AST), serum alkaline phosphatase (ALP), and hepatic malondialdehyde (MDA) levels. Additionally, mice treated with K-3-R and K-3-G had significantly restored glutathione (GSH) levels and showed normal catalase (CAT) and superoxide dismutase (SOD) activities, compared to CCl 4 -treated mice. K-3-R and K-3-G also mitigated the CCl 4 -induced liver histological alteration, as indicated by histopathological evaluation. These findings demonstrate that K-3-R and K-3-G have protective effects against acute CCl 4 -induced oxidative liver damage. Copyright © 2014. Published by Elsevier B.V.

  7. Apocynin prevented inflammation and oxidative stress in carbon tetra chloride induced hepatic dysfunction in rats.

    PubMed

    Rahman, Md Mizanur; Muse, Awale Yousuf; Khan, D M Isha Olive; Ahmed, Ismaile Hussein; Subhan, Nusrat; Reza, Hasan Mahmud; Alam, Md Ashraful; Nahar, Lutfun; Sarker, Satyajit Dey

    2017-08-01

    Liver fibrosis is a leading pathway to cirrhosis and a global clinical issue. Oxidative stress mediated tissue damage is one of the prime causes of hepatic dysfunction and fibrosis. Apocynin is one of many strong antioxidants. To evaluate the effect of apocynin in the CCl 4 administered hepatic dysfunction in rats. Female Long Evans rats were administered with CCl 4 orally (1mL/kg) twice a week for 2 weeks and were treated with apocynin (100mg/kg). Both plasma and liver tissues were analyzed for alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase activities. Oxidative stress parameters were also measured by determining malondialdehyde (MDA), nitric oxide (NO), myeloperoxidase (MPO), advanced protein oxidation product (APOP). In addition, antioxidant enzyme activities such as superoxide dismutase (SOD) and catalase activities in plasma and liver tissues were analyzed. Moreover, inflammation and tissue fibrosis were confirmed by histological staining of liver tissue sections. Apocynin significantly reduced serum AST, ALT, and ALP activities in carbon tetrachloride treated rats. It also exhibited a considerable reduction of the oxidative stress markers (MDA, MPO, NO, and APOP level) which was elevated due to CCl 4 administration in rats. Apocynin treatment also restored the catalase and superoxide dismutase activity in CCl 4 treated rats. Histological analysis of liver sections revealed that apocynin prevented inflammatory cells infiltration and fibrosis in CCl 4 administered rats. These results suggest that apocynin protects liver damage induced by CCl 4 by inhibiting lipid peroxidation and stimulating the cellular antioxidant system. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  8. Potential Role of the Gut/Liver/Lung Axis in Alcohol-Induced Tissue Pathology

    PubMed Central

    Massey, Veronica L.; Beier, Juliane I.; Ritzenthaler, Jeffrey D.; Roman, Jesse; Arteel, Gavin E.

    2015-01-01

    Both Alcoholic Liver Disease (ALD) and alcohol-related susceptibility to acute lung injury are estimated to account for the highest morbidity and mortality related to chronic alcohol abuse and, thus, represent a focus of intense investigation. In general, alcohol-induced derangements to both organs are considered to be independent and are often evaluated separately. However, the liver and lung share many general responses to damage, and specific responses to alcohol exposure. For example, both organs possess resident macrophages that play key roles in mediating the immune/inflammatory response. Additionally, alcohol-induced damage to both organs appears to involve oxidative stress that favors tissue injury. Another mechanism that appears to be shared between the organs is that inflammatory injury to both organs is enhanced by alcohol exposure. Lastly, altered extracellular matrix (ECM) deposition appears to be a key step in disease progression in both organs. Indeed, recent studies suggest that early subtle changes in the ECM may predispose the target organ to an inflammatory insult. The purpose of this chapter is to review the parallel mechanisms of liver and lung injury in response to alcohol consumption. This chapter will also explore the potential that these mechanisms are interdependent, as part of a gut-liver-lung axis. PMID:26437442

  9. Agmatine protects rat liver from nicotine-induced hepatic damage via antioxidative, antiapoptotic, and antifibrotic pathways.

    PubMed

    El-Sherbeeny, Nagla A; Nader, Manar A; Attia, Ghalia M; Ateyya, Hayam

    2016-12-01

    Tobacco smoking with its various forms is a global problem with proved hazardous effects to human health. The present work was planned to study the defending role of agmatine (AGM) on hepatic oxidative stress and damage induced by nicotine in rats. Thirty-two rats divided into four groups were employed: control group, nicotine-only group, AGM group, and AGM-nicotine group. Measurements of serum hepatic biochemical markers, lipid profile, and vascular cell adhesion molecule-1 were done. In addition, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) activity, and nitrate/nitrite (NOx) levels were estimated in the liver homogenates. Immunohistochemistry for Bax and transforming growth factor beta (TGF-β1) and histopathology of the liver were also included. Data of the study demonstrated that nicotine administration exhibited marked liver deterioration, an increase in liver enzymes, changes in lipid profile, and an elevation in MDA with a decline in levels of SOD, GSH, and NOx (nitrate/nitrite). Also, levels of proapoptotic Bax and profibrotic TGF-β1 showed marked elevation in the liver. AGM treatment to rats in nicotine-only group ameliorated all the previous changes. These findings indicate that AGM could successfully overcome the nicotine-evoked hepatic oxidative stress and tissue injury, apoptosis, and fibrosis.

  10. 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.

  11. Hepatoprotective and antioxidant activity of aqueous extract of Hybanthus enneaspermus against CCl4-induced liver injury in rats.

    PubMed

    Vuda, Madhusudanarao; D'Souza, Roshan; Upadhya, Suhas; Kumar, Vijay; Rao, Namita; Kumar, Vasanth; Boillat, Colette; Mungli, Prakash

    2012-11-01

    The hepatoprotective, curative and anti-oxidant properties of aqueous extract of Hybanthus enneaspermus (Violaceae) used against CCl4-induced liver damage in rats were investigated in the present study. Liver damage was induced by CCl4 (1 ml/kg i.p.), and silymarin was used as a standard drug to compare hepatoprotective, curative and antioxidant effects of the extract. Rats were treated with aqueous extract of H. enneaspermus at a dose of either 200 or 400 mg/kg after division into pre-treatment (once daily for 14 days before CCl4 intoxication) and post-treatment (2, 6, 24 and 48 h after CCl4 intoxication) groups. Pre-treatment and post-treatment with aqueous extract of H. enneaspermus showed significant hepatoprotection by reducing the aspartate transaminase, alanine transaminase, and alkaline phosphatase enzymatic activities and total bilirubin levels which had been raised by CCl4 administration. Pre- and post-treatment with aqueous extract significantly decreased hepatic lipid peroxidation as well as producing a corresponding increase in tissue total thiols. Post-treatment with aqueous extract improved ceruloplasmin levels. The histopathological examination of rat liver sections treated with aqueous extract confirms the serum biochemical observations. The present study results demonstrate the protective, curative and anti-oxidant effects of H. enneaspermus aqueous extract used against CCl4-induced hepatotoxicity in rats, and suggest a potential therapeutic use of H. enneaspermus as an alternative for patients with acute liver diseases. Copyright © 2011 Elsevier GmbH. All rights reserved.

  12. TWEAK induces liver progenitor cell proliferation

    PubMed Central

    Jakubowski, Aniela; Ambrose, Christine; Parr, Michael; Lincecum, John M.; Wang, Monica Z.; Zheng, Timothy S.; Browning, Beth; Michaelson, Jennifer S.; Baestcher, Manfred; Wang, Bruce; Bissell, D. Montgomery; Burkly, Linda C.

    2005-01-01

    Progenitor (“oval”) cell expansion accompanies many forms of liver injury, including alcohol toxicity and submassive parenchymal necrosis as well as experimental injury models featuring blocked hepatocyte replication. Oval cells can potentially become either hepatocytes or biliary epithelial cells and may be critical to liver regeneration, particularly when hepatocyte replication is impaired. The regulation of oval cell proliferation is incompletely understood. Herein we present evidence that a TNF family member called TWEAK (TNF-like weak inducer of apoptosis) stimulates oval cell proliferation in mouse liver through its receptor Fn14. TWEAK has no effect on mature hepatocytes and thus appears to be selective for oval cells. Transgenic mice overexpressing TWEAK in hepatocytes exhibit periportal oval cell hyperplasia. A similar phenotype was obtained in adult wild-type mice, but not Fn14-null mice, by administering TWEAK-expressing adenovirus. Oval cell expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was significantly reduced in Fn14-null mice as well as in adult wild-type mice with a blocking anti-TWEAK mAb. Importantly, TWEAK stimulated the proliferation of an oval cell culture model. Finally, we show increased Fn14 expression in chronic hepatitis C and other human liver diseases relative to its expression in normal liver, which suggests a role for the TWEAK/Fn14 pathway in human liver injury. We conclude that TWEAK has a selective mitogenic effect for liver oval cells that distinguishes it from other previously described growth factors. PMID:16110324

  13. Hepatoprotective and antioxidant activity of Phaseolus trilobus, Ait on bile duct ligation induced liver fibrosis in rats.

    PubMed

    Fursule, R A; Patil, S D

    2010-06-16

    Phaseolus trilobus Ait (Fabaceae) is extensively used by tribal people of Nandurbar district (Maharashtra, India) in the treatment of Jaundice and other liver disorders. of the present study was to assess the medicinal claim of Phaseolus trilobus as hepatoprotective and antioxidant. The hepatoprotective activity of methanol and aqueous extract of Phaseolus trilobus was evaluated by bile duct ligation induced liver fibrosis and antioxidant activity was evaluated using in vitro and in vivo antioxidant models viz anti-lipid peroxidation assay, super oxide radical scavenging assay and glutathione estimation in liver. Liver function tests were carried out to detect hepatoprotective activity, which was further supported by histopathological examination. Methanol and aqueous extracts of Phaseolus trilobus reduced elevated level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), bilirubin and hydroxyproline significantly (p<0.01) in bile duct ligated Wistar rats, proving hepatoprotective activity comparable with Silymarin. Both the extracts were found to reduce the elevated levels of serum thiobarbituric acid reactive substance (TBARS) and elevate superoxide scavenging radical activity proving antioxidant activity comparable with ascorbic acid. The reduced level of glutathione was found to be elevated in liver proving antioxidant activity comparable with Silymarin. Phaseolus trilobus posses hepatoprotective property and is effective in oxidative stress induced cholestatic hepatic injury. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  14. Hsp72 protects against liver injury via attenuation of hepatocellular death, oxidative stress, and JNK signaling.

    PubMed

    Levada, Kateryna; Guldiken, Nurdan; Zhang, Xiaoji; Vella, Giovanna; Mo, Fa-Rong; James, Laura P; Haybaeck, Johannes; Kessler, Sonja M; Kiemer, Alexandra K; Ott, Thomas; Hartmann, Daniel; Hüser, Norbert; Ziol, Marianne; Trautwein, Christian; Strnad, Pavel

    2018-05-01

    Heat shock protein (Hsp) 72 is a molecular chaperone that has broad cytoprotective functions and is upregulated in response to stress. To determine its hepatic functions, we studied its expression in human liver disorders and its biological significance in newly generated transgenic animals. Double transgenic mice overexpressing Hsp72 (gene Hspa1a) under the control of a tissue-specific tetracycline-inducible system (Hsp72-LAP mice) were produced. Acute liver injury was induced by a single injection of acetaminophen (APAP). Feeding with either a methionine choline-deficient (MCD; 8 weeks) or a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-supplemented diet (DDC; 12 weeks) was used to induce lipotoxic injury and Mallory-Denk body (MDB) formation, respectively. Primary hepatocytes were treated with palmitic acid. Patients with non-alcoholic steatohepatitis and chronic hepatitis C infection displayed elevated HSP72 levels. These levels increased with the extent of hepatic inflammation and HSP72 expression was induced after treatment with either interleukin (IL)-1β or IL-6. Hsp72-LAP mice exhibited robust, hepatocyte-specific Hsp72 overexpression. Primary hepatocytes from these animals were more resistant to isolation-induced stress and Hsp72-LAP mice displayed lower levels of hepatic injury in vivo. Mice overexpressing Hsp72 had fewer APAP protein adducts and were protected from oxidative stress and APAP-/MCD-induced cell death. Hsp72-LAP mice and/or hepatocytes displayed significantly attenuated Jnk activation. Overexpression of Hsp72 did not affect steatosis or the extent of MDB formation. Our results demonstrate that HSP72 induction occurs in human liver disease, thus, HSP72 represents an attractive therapeutic target owing to its broad hepatoprotective functions. HSP72 constitutes a stress-inducible, protective protein. Our data demonstrate that it is upregulated in patients with chronic hepatitis C and non-alcoholic steatohepatitis. Moreover, Hsp72

  15. Amelioration of tamoxifen-induced liver injury in rats by grape seed extract, black seed extract and curcumin.

    PubMed

    El-Beshbishy, Hesham A; Mohamadin, Ahmed M; Nagy, Ayman A; Abdel-Naim, Ashraf B

    2010-03-01

    Liver injury was induced in female rats using tamoxifen (TAM). Grape seeds (Vitis vinifera) extract (GSE), black seed (Nigella sativa) extract (NSE), curcumin (CUR) or silymarin (SYL) were orally administered to TAM-intoxicated rats. Liver histopathology of TAM-intoxicated:rats showed pathological changes. TAM-intoxication elicited declines in liver antioxidant enzymes levels (glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase), reduced glutathione (GSH) and GSH/GSSG ratio plus the hepatic elevations in lipid peroxides, oxidized glutathione (GSSG), tumor necrosis factor-alpha (TNF-alpha) and serum liver enzymes; alanine transaminase, aspartate transaminase, alkaline phosphatase, lactate dehydrogenase and gamma glutamyl transferase levels. Oral intake of NSE, GSE, CUR or SYL to TAM-intoxicated rats, attenuated histopathological changes and corrected all parameters mentioned above. Improvements were prominent in case of NSE (similarly SYL) > CUR > GSE. Data indicated that NSE, GSE or CUR act as free radicals scavengers and protect TAM-induced liver injury in rats.

  16. 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

  17. Anabolic steroid-induced cardiomyopathy underlying acute liver failure in a young bodybuilder.

    PubMed

    Bispo, Miguel; Valente, Ana; Maldonado, Rosário; Palma, Rui; Glória, Helena; Nóbrega, João; Alexandrino, Paula

    2009-06-21

    Heart failure may lead to subclinical circulatory disturbances and remain an unrecognized cause of ischemic liver injury. We present the case of a previously healthy 40-year-old bodybuilder, referred to our Intensive-Care Unit of Hepatology for treatment of severe acute liver failure, with the suspicion of toxic hepatitis associated with anabolic steroid abuse. Despite the absence of symptoms and signs of congestive heart failure at admission, an anabolic steroid-induced dilated cardiomyopathy with a large thrombus in both ventricles was found to be the underlying cause of the liver injury. Treatment for the initially unrecognized heart failure rapidly restored liver function to normal. To our knowledge, this is the first reported case of severe acute liver failure due to an unrecognized anabolic steroid-induced cardiomyopathy. Awareness of this unique presentation will allow for prompt treatment of this potentially fatal cause of liver failure.

  18. Role of vitamin B6 status on antioxidant defenses, glutathione, and related enzyme activities in mice with homocysteine-induced oxidative stress.

    PubMed

    Hsu, Cheng-Chin; Cheng, Chien-Hsiang; Hsu, Chin-Lin; Lee, Wan-Ju; Huang, Shih-Chien; Huang, Yi-Chia

    2015-01-01

    Vitamin B6 may directly or indirectly play a role in oxidative stress and the antioxidant defense system. The purpose of this study was to examine the associations of vitamin B6 status with cysteine, glutathione, and its related enzyme activities in mice with homocysteine-induced oxidative stress. Four-week-old male BALB/c mice were weighed and divided into one of four dietary treatment groups fed either a normal diet (as a control group and a homocysteine group), a vitamin B6-deficient diet (as a B6-deficient group), or a B6-supplemented diet (a pyridoxine-HCl-free diet supplemented with 14 mg/kg of pyridoxine-HCl, as a B6 supplement group) for 28 days. Homocysteine thiolactone was then added to drinking water in three groups for 21 days to induce oxidative stress. At the end of the study, mice were sacrificed by decapitation and blood and liver samples were obtained. Mice with vitamin B6-deficient diet had the highest homocysteine concentration in plasma and liver among groups. Significantly increased hepatic malondialdehyde levels were observed in the vitamin B6-deficient group. Among homocysteine-treated groups, mice with vitamin B6-deficient diet had the highest plasma glutathione concentration and relatively lower hepatic glutathione concentration. The glutathione peroxidase activities remained relatively stable in plasma and liver whether vitamin B6 was adequate, deficient, or supplemented. Mice with deficient vitamin B6 intakes had an aggravate effect under homocysteine-induced oxidative stress. The vitamin B6-deficient status seems to mediate the oxidative stress in connection with the redistribution of glutathione from liver to plasma, but not further affect glutathione-related enzyme activities in mice with homocysteine-induced oxidative stress.

  19. Symbiotic formulation in experimentally induced liver fibrosis in rats: intestinal microbiota as a key point to treat liver damage?

    PubMed

    D'Argenio, Giuseppe; Cariello, Rita; Tuccillo, Concetta; Mazzone, Giovanna; Federico, Alessandro; Funaro, Annalisa; De Magistris, Laura; Grossi, Enzo; Callegari, Maria L; Chirico, Marilena; Caporaso, Nicola; Romano, Marco; Morelli, Lorenzo; Loguercio, Carmela

    2013-05-01

    Evidence indicates that intestinal microbiota may participate in both the induction and the progression of liver damage. The aim of our research was the detection and evaluation of the effects of chronic treatment with a symbiotic formulation on CCl4 -induced rat liver fibrosis. CCl4 significantly increased gastric permeability in respect to basal values, and the treatment with symbiotic significantly decreased it. CCl4 per se induced a decrease in intestinal permeability. This effect was also seen in fibrotic rats treated with symbiotic and was still evident when normal rats were treated with symbiotic alone (P < 0.001 in all cases). Circulating levels of pro-inflammatory cytokine TNF-α were significantly increased in rats with liver fibrosis as compared with normal rats, while symbiotic treatment normalized the plasma levels of TNF-α and significantly enhanced anti-inflammatory cytokine IL 10. TNF-α, TGF-β, TLR4, TLR2, iNOS and α-SMA mRNA expression in the liver were up-regulated in rats with CCl4 -induced liver fibrosis and down-regulated by symbiotic treatment. Moreover, IL-10 and eNOS mRNA levels were increased in the CCL4 (+) symbiotic group. Symbiotic treatment of fibrotic rats normalized serum ALT, AST and improved histology and liver collagen deposition. DGGE analysis of faecal samples revealed that CCl4 administration and symbiotic treatment either alone or in combination produced modifications in faecal profiles vs controls. Our results provide evidence that in CCl4 -induced liver fibrosis, significant changes in gastro-intestinal permeability and in faecal flora occur. Treatment with a specific symbiotic formulation significantly affects these changes, leading to improvement in both liver inflammation and fibrosis. © 2013 John Wiley & Sons A/S.

  20. Dietary Zinc Deficiency Exaggerates Ethanol-Induced Liver Injury in Mice: Involvement of Intrahepatic and Extrahepatic Factors

    PubMed Central

    Sun, Xinguo; Song, Zhenyuan; McClain, Craig J.; Zhou, Zhanxiang

    2013-01-01

    Clinical studies have demonstrated that alcoholics have a lower dietary zinc intake compared to health controls. The present study was undertaken to determine the interaction between dietary zinc deficiency and ethanol consumption in the pathogenesis of alcoholic liver disease. C57BL/6N mice were subjected to 8-week feeding of 4 experimental liquid diets: (1) zinc adequate diet, (2) zinc adequate diet plus ethanol, (3) zinc deficient diet, and (4) zinc deficient diet plus ethanol. Ethanol exposure with adequate dietary zinc resulted in liver damage as indicated by elevated plasma alanine aminotransferase level and increased hepatic lipid accumulation and inflammatory cell infiltration. Dietary zinc deficiency alone increased hepatic lipid contents, but did not induce hepatic inflammation. Dietary zinc deficiency showed synergistic effects on ethanol-induced liver damage. Dietary zinc deficiency exaggerated ethanol effects on hepatic genes related to lipid metabolism and inflammatory response. Dietary zinc deficiency worsened ethanol-induced imbalance between hepatic pro-oxidant and antioxidant enzymes and hepatic expression of cell death receptors. Dietary zinc deficiency exaggerated ethanol-induced reduction of plasma leptin, although it did not affect ethanol-induced reduction of white adipose tissue mass. Dietary zinc deficiency also deteriorated ethanol-induced gut permeability increase and plasma endotoxin elevation. These results demonstrate, for the first time, that dietary zinc deficiency is a risk factor in alcoholic liver disease, and multiple intrahepatic and extrahepatic factors may mediate the detrimental effects of zinc deficiency. PMID:24155903

  1. Proteomic Analyses of Cysteine Redox in High-Fat-Fed and Fasted Mouse Livers: Implications for Liver Metabolic Homeostasis.

    PubMed

    Li, Yixing; Luo, Zupeng; Wu, Xilong; Zhu, Jun; Yu, Kai; Jin, Yi; Zhang, Zhiwang; Zhao, Shuhong; Zhou, Lei

    2018-01-05

    Intensive oxidative stress occurs during high-fat-diet-induced hepatic fat deposition, suggesting a critical role for redox signaling in liver metabolism. Intriguingly, evidence shows that fasting could also result in redox-profile changes largely through reduced oxidant or increased antioxidant levels. However, a comprehensive landscape of redox-modified hepatic substrates is lacking, thereby hindering our understanding of liver metabolic homeostasis. We employed a proteomic approach combining iodoacetyl tandem mass tag and nanoliquid chromatography tandem mass spectrometry to quantitatively probe the effects of high-fat feeding and fasting on in vivo redox-based cysteine modifications. Compared with control groups, ∼60% of cysteine residues exhibited downregulated oxidation ratios by fasting, whereas ∼94% of these ratios were upregulated by high-fat feeding. Importantly, in fasted livers, proteins exhibiting diminished cysteine oxidation were annotated in pathways associated with fatty acid metabolism, carbohydrate metabolism, insulin, peroxisome proliferator-activated receptors, and oxidative respiratory chain signaling, suggesting that fasting-induced redox changes targeted major metabolic pathways and consequently resulted in hepatic lipid accumulation.

  2. Preventive effects of dexmedetomidine on the liver in a rat model of acid-induced acute lung injury.

    PubMed

    Sen, Velat; Güzel, Abdulmenap; Şen, Hadice Selimoğlu; Ece, Aydın; Uluca, Unal; Söker, Sevda; Doğan, Erdal; Kaplan, İbrahim; Deveci, Engin

    2014-01-01

    The aim of this study was to examine whether dexmedetomidine improves acute liver injury in a rat model. Twenty-eight male Wistar albino rats weighing 300-350 g were allocated randomly to four groups. In group 1, normal saline (NS) was injected into the lungs and rats were allowed to breathe spontaneously. In group 2, rats received standard ventilation (SV) in addition to NS. In group 3, hydrochloric acid was injected into the lungs and rats received SV. In group 4, rats received SV and 100 µg/kg intraperitoneal dexmedetomidine before intratracheal HCl instillation. Blood samples and liver tissue specimens were examined by biochemical, histopathological, and immunohistochemical methods. Acute lung injury (ALI) was found to be associated with increased malondialdehyde (MDA), total oxidant activity (TOA), oxidative stress index (OSI), and decreased total antioxidant capacity (TAC). Significantly decreased MDA, TOA, and OSI levels and significantly increased TAC levels were found with dexmedetomidine injection in group 4 (P < 0.05). The highest histologic injury scores were detected in group 3. Enhanced hepatic vascular endothelial growth factor (VEGF) expression and reduced CD68 expression were found in dexmedetomidine group compared with the group 3. In conclusion, the presented data provide the first evidence that dexmedetomidine has a protective effect on experimental liver injury induced by ALI.

  3. Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver.

    PubMed

    Woodman, Andrew G; Mah, Richard; Keddie, Danae; Noble, Ronan M N; Panahi, Sareh; Gragasin, Ferrante S; Lemieux, Hélène; Bourque, Stephane L

    2018-06-01

    Prenatal iron deficiency alters fetal developmental trajectories, which results in persistent changes in organ function. Here, we studied the effects of prenatal iron deficiency on fetal kidney and liver mitochondrial function. Pregnant Sprague-Dawley rats were fed partially or fully iron-restricted diets to induce a state of moderate or severe iron deficiency alongside iron-replete control rats. We assessed mitochondrial function via high-resolution respirometry and reactive oxygen species generation via fluorescence microscopy on gestational d 21. Hemoglobin levels were reduced in dams in the moderate (-31%) and severe groups (-54%) compared with controls, which was accompanied by 55% reductions in fetal hemoglobin levels in both moderate and severe groups versus controls. Male iron-deficient kidneys exhibited globally reduced mitochondrial content and respiration, as well as increased cytosolic superoxide and decreased NO. Female iron-deficient kidneys exhibited complex II down-regulation and increased mitochondrial oxidative stress. Male iron-deficient livers exhibited reduced complex IV respiration and increased cytosolic superoxide, whereas female liver tissues exhibited no alteration in oxidant levels or mitochondrial function. These findings indicate that prenatal iron deficiency causes changes in mitochondrial content and function as well as oxidant status in a sex- and organ-dependent manner, which may be an important mechanism that underlies the programming of cardiovascular disease.-Woodman, A. G., Mah, R., Keddie, D., Noble, R. M. N., Panahi, S., Gragasin, F. S., Lemieux, H., Bourque, S. L. Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver.

  4. Acetaminophen-induced acute liver injury in HCV transgenic mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle

    2013-01-15

    The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wildmore » type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.« less

  5. Protective effects of Centella asiatica leaf extract on dimethylnitrosamine‑induced liver injury in rats.

    PubMed

    Choi, Myung-Joo; Zheng, Hong-Mei; Kim, Jae Min; Lee, Kye Wan; Park, Yu Hwa; Lee, Don Haeng

    2016-11-01

    Oxidative stress in liver injury is a major pathogenetic factor in the progression of liver damage. Centella asiatica (L.) Urban, known in the United States as Gotu kola, is widely used as a traditional herbal medicine in Chinese or Indian Pennywort. The efficacy of Centella asiatica is comprehensive and is used as an anti‑inflammatory agent, for memory improvement, for its antitumor activity and for treatment of gastric ulcers. The present study investigated the protective effects of Centella asiatica on dimethylnitrosamine (DMN)‑induced liver injury in rats. The rats in the treatment groups were treated with Centella asiatica at either 100 or 200 mg/kg in distilled water (D.W) or with silymarin (200 mg/kg in D.W) by oral administration for 5 days daily following intraperitoneal injections of 30 mg/kg DMN. Centella asiatica significantly decreased the relative liver weights in the DMN‑induced liver injury group, compared with the control. The assessment of liver histology showed that Centella asiatica significantly alleviated mass periportal ± bridging necrosis, intralobular degeneration and focal necrosis, with fibrosis of liver tissues. Additionally, Centella asiatica significantly decreased the level of malondialdehyde, significantly increased the levels of antioxidant enzymes, including superoxide dismutase, glutathione peroxidase and catalase, and may have provided protection against the deleterious effects of reactive oxygen species. In addition, Centella asiatica significantly decreased inflammatory mediators, including interleukin (IL)‑1β, IL‑2, IL‑6, IL‑10, IL‑12, tumor necrosis factor‑α, interferon‑γ and granulocyte/macrophage colony‑stimulating factor. These results suggested that Centella asiatica had hepatoprotective effects through increasing the levels of antioxidant enzymes and reducing the levels of inflammatory mediators in rats with DMN‑induced liver injury. Therefore, Centella asiatica may be useful

  6. PROTECTIVE EFFECT OF MORINGA PEREGRINA LEAVES EXTRACT ON ACETAMINOPHEN -INDUCED LIVER TOXICITY IN ALBINO RATS.

    PubMed

    Azim, Samy Abdelfatah Abdel; Abdelrahem, Mohamed Taha; Said, Mostafa Mohamed; Khattab, Alshaimaa

    2017-01-01

    Acetaminophen is a common antipyretic drug but at overdose can cause severe hepatotoxicity that may further develop into liver failure and hepatic centrilobular necrosis in experimental animals and humans. This study was undertaken to assess the ameliorative role of Moringa peregrina leaves extract against acetaminophen toxicity in rats. Induction of hepatotoxicity was done by chronic oral administration of acetaminophen (750 mg/kg bwt) for 4 weeks. To study the possible hepatoprotective effect, Moringa peregrina leaves extract (200 mg/kg bwt) or Silymarin (50 mg/kg bwt) was administered orally, for 4 weeks, along with acetaminophen. acetaminophen significantly increased serum liver enzymes and caused oxidative stress, evidenced by significantly increased tissue malondialdehyde, glutathione peroxidase, hepatic DNA fragmentation, and significant decrease of glutathione and antioxidant enzymes in liver, blood and brain. On the other hand, administration of Moringa peregrina leaves extract reversed acetaminophen-related toxic effects through: powerful malondialdehyde suppression, glutathione peroxidase normalization and stimulation of the cellular antioxidants synthesis represented by significant increase of glutathione, catalase and superoxide dismutase in liver, blood and brain, besides, DNA fragmentation was significantly decreased in the liver tissue. acetaminophen induced oxidative damage can be improved by Moringa peregrina leaves extract-treatment, due to its antioxidant potential.

  7. PROTECTIVE EFFECT OF MORINGA PEREGRINA LEAVES EXTRACT ON ACETAMINOPHEN -INDUCED LIVER TOXICITY IN ALBINO RATS

    PubMed Central

    Azim, Samy Abdelfatah Abdel; Abdelrahem, Mohamed Taha; Said, Mostafa Mohamed; khattab, Alshaimaa

    2017-01-01

    Background: Acetaminophen is a common antipyretic drug but at overdose can cause severe hepatotoxicity that may further develop into liver failure and hepatic centrilobular necrosis in experimental animals and humans. This study was undertaken to assess the ameliorative role of Moringa peregrina leaves extract against acetaminophen toxicity in rats. Materials and methods: Induction of hepatotoxicity was done by chronic oral administration of acetaminophen (750 mg/kg bwt) for 4 weeks. To study the possible hepatoprotective effect, Moringa peregrina leaves extract (200 mg/kg bwt) or Silymarin (50 mg/kg bwt) was administered orally, for 4 weeks, along with acetaminophen. Results: acetaminophen significantly increased serum liver enzymes and caused oxidative stress, evidenced by significantly increased tissue malondialdehyde, glutathione peroxidase, hepatic DNA fragmentation, and significant decrease of glutathione and antioxidant enzymes in liver, blood and brain. On the other hand, administration of Moringa peregrina leaves extract reversed acetaminophen-related toxic effects through: powerful malondialdehyde suppression, glutathione peroxidase normalization and stimulation of the cellular antioxidants synthesis represented by significant increase of glutathione, catalase and superoxide dismutase in liver, blood and brain, besides, DNA fragmentation was significantly decreased in the liver tissue. Conclusion: acetaminophen induced oxidative damage can be improved by Moringa peregrina leaves extract-treatment, due to its antioxidant potential. PMID:28573237

  8. Aloe vera attenuated liver injury in mice with acetaminophen-induced hepatitis.

    PubMed

    Werawatganon, Duangporn; Linlawan, Sittikorn; Thanapirom, Kessarin; Somanawat, Kanjana; Klaikeaw, Naruemon; Rerknimitr, Rungsun; Siriviriyakul, Prasong

    2014-07-08

    An overdose of the acetaminophen causes liver injury. This study aims to examine the anti-oxidative, anti-inflammatory effects of Aloe vera in mice with acetaminophen induced hepatitis. Male mice were randomly divided into three groups (n = 8 each). Control group were given orally distilled water (DW). APAP group were given orally N-acetyl-P-aminophenol (APAP) 400 mg/kg suspended in DW. Aloe vera-treated group were given orally APAP and Aloe vera (150 mg/kg) suspended in DW. Twenty-four hours later, the liver was removed to determine hepatic malondialdehyde (MDA), hepatic glutathione (GSH), the number of interleukin (IL)-12 and IL-18 positive stained cells (%) by immunohistochemistry method, and histopathological examination. Then, the serum was collected to determine transaminase (ALT). In APAP group, ALT, hepatic MDA and the number of IL-12 and IL-18 positive stained cells were significantly increased when compared to control group (1210.50 ± 533.86 vs 85.28 ± 28.27 U/L, 3.60 ± 1.50 vs 1.38 ± 0.15 nmol/mg protein, 12.18 ± 1.10 vs 1.84 ± 1.29%, and 13.26 ± 0.90 vs 2.54 ± 1.29%, P = 0.000, respectively), whereas hepatic GSH was significantly decreased when compared to control group (5.98 ± 0.30 vs 11.65 ± 0.43 nmol/mg protein, P = 0.000). The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive stained cells, and hepatic GSH in Aloe vera-treated group were improved as compared with APAP group (606.38 ± 495.45 vs 1210.50 ± 533.86 U/L, P = 0.024; 1.49 ± 0.64 vs 3.60 ± 1.50 nmol/mg protein, P = 0.001; 5.56 ± 1.25 vs 12.18 ± 1.10%, P = 0.000; 6.23 ± 0.94 vs 13.26 ± 0.90%, P = 0.000; and 10.02 ± 0.20 vs 5.98 ± 0.30 nmol/mg protein, P = 0.000, respectively). Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in Aloe vera-treated group, the liver architecture was improved histopathology. APAP overdose can cause liver injury. Our result indicate that Aloe vera attenuate APAP-induced

  9. Uric Acid Induces Hepatic Steatosis by Generation of Mitochondrial Oxidative Stress

    PubMed Central

    Lanaspa, Miguel A.; Sanchez-Lozada, Laura G.; Choi, Yea-Jin; Cicerchi, Christina; Kanbay, Mehmet; Roncal-Jimenez, Carlos A.; Ishimoto, Takuji; Li, Nanxing; Marek, George; Duranay, Murat; Schreiner, George; Rodriguez-Iturbe, Bernardo; Nakagawa, Takahiko; Kang, Duk-Hee; Sautin, Yuri Y.; Johnson, Richard J.

    2012-01-01

    Metabolic syndrome represents a collection of abnormalities that includes fatty liver, and it currently affects one-third of the United States population and has become a major health concern worldwide. Fructose intake, primarily from added sugars in soft drinks, can induce fatty liver in animals and is epidemiologically associated with nonalcoholic fatty liver disease in humans. Fructose is considered lipogenic due to its ability to generate triglycerides as a direct consequence of the metabolism of the fructose molecule. Here, we show that fructose also stimulates triglyceride synthesis via a purine-degrading pathway that is triggered from the rapid phosphorylation of fructose by fructokinase. Generated AMP enters into the purine degradation pathway through the activation of AMP deaminase resulting in uric acid production and the generation of mitochondrial oxidants. Mitochondrial oxidative stress results in the inhibition of aconitase in the Krebs cycle, resulting in the accumulation of citrate and the stimulation of ATP citrate lyase and fatty-acid synthase leading to de novo lipogeneis. These studies provide new insights into the pathogenesis of hepatic fat accumulation under normal and diseased states. PMID:23035112

  10. 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.

  11. Hepatoprotective Role of Wheatgrass on Alcohol and ΔPUFA-Induced Oxidative Stress in Rats.

    PubMed

    Durairaj, Varalakshmi; Shakya, Garima; Rajagopalan, Rukkumani

    2015-06-01

    Alcohol abuse is recognized as the most common cause for the development of various abnormalities including liver disease. Excessive free radicals are generated during the metabolism of ethanol. The ingestion of alcohol along with polyunsaturated fatty acid (PUFA) aggravates the production of free radicals and enhances the oxidative stress. Medicinal plants contain active phytocomponents, which are the principal healthcare resources. We aimed to analyze the effect of wheatgrass extract on alcohol and thermally oxidized PUFA (ΔPUFA) induced oxidative stress in male albino Wistar rats. The levels of marker enzymes gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), lipid peroxidative markers; thiobarbutric acid reactive substances (TBARS) and lipid hydroperoxides (LH), the levels of enzymatic (catalase [CAT], superoxide dismutase [SOD], glutathione peroxidase [GPx]) and nonenzymatic (reduced glutathione [GSH], vitamin E, vitamin C) antioxidants were analyzed in liver to evaluate the effects of wheatgrass. The levels of TBARS and LH were significantly (p ≤ .05) increased in alcohol + ΔPUFA group, which were found to be reduced on treatment with wheatgrass. The levels of both enzymatic and nonenzymatic antioxidants were significantly (p ≤ .05) decreased in alcohol + ΔPUFA group, which were found to be restored on treatment with wheatgrass. From the results obtained, we conclude that wheatgrass protects the liver against alcohol and ΔPUFA induced oxidative stress.

  12. Metronidazole-induced encephalopathy in a patient with liver cirrhosis.

    PubMed

    Cheong, Hyeong Cheol; Jeong, Taek Geun; Cho, Young Bum; Yang, Bong Joon; Kim, Tae Hyeon; Kim, Haak Cheoul; Cho, Eun-Young

    2011-06-01

    Encephalopathy is a disorder characterized by altered brain function, which can be attributed to various causes. Encephalopathy associated with metronidazole administration occurs rarely and depends on the cumulative metronidazole dose, and most patients with this condition recover rapidly after discontinuation of therapy. Because metronidazole is metabolized in the liver and can be transported by the cerebrospinal fluid and cross the blood-brain barrier, it may induce encephalopathy even at a low cumulative dose in patients with hepatic dysfunction. We experienced a patient who showed ataxic gait and dysarthric speech after receiving metronidazole for the treatment of hepatic encephalopathy that was not controlled by the administration of lactulose. The patient was diagnosed as metronidazole-induced encephalopathy, and stopping drug administration resulted in a complete recovery from encephalopathy. This case shows that caution should be exercised when administering metronidazole because even a low dose can induce encephalopathy in patients with liver cirrhosis.

  13. Antioxidant properties of proanthocyanidins attenuate carbon tetrachloride (CCl4)-induced steatosis and liver injury in rats via CYP2E1 regulation.

    PubMed

    Dai, Ning; Zou, Yuan; Zhu, Lei; Wang, Hui-Fang; Dai, Mu-Gen

    2014-06-01

    Liver steatosis is characterized by lipid dysregulation and fat accumulation in the liver and can lead to oxidative stress in liver. Since proanthocyanidins are present in plant-based foods and have powerful antioxidant properties, we investigated whether proanthocyanidins can prevent oxidative stress and subsequent liver injury. Carbon tetrachloride (CCl4) treatment can cause steatosis in rats that models both alcoholic and non-alcoholic fatty liver disease in humans. We pre-treated rats by oral administration of proanthocyanidins extracted from grape seeds 7 days prior to intragastrically administering CCl4. Proanthocyanidin treatment continued for an additional 2 weeks, after which time liver and serum were harvested, and mediators of liver injury, oxidative stress, and histological features were evaluated. CCl4-treated rats exhibited significant increases in the following parameters as compared to non-treated rats: fat droplets in the liver, liver injury (ALT, AST), and DNA damage (8-OHdG). Additionally, CCl4 treatment decreased antioxidant enzymes SOD, GSH, GPX, and CAT in the liver due to their rapid depletion after battling against oxidative stress. Compared to CCl4-treated rats, treatment with proanthocyanidins effectively suppressed lipid accumulation, liver injury, DNA damage, as well as restored antioxidant enzyme levels. Further investigation revealed that proanthocyanidins treatment also inhibited expression of CYP2E1 in liver, which prevented the initial step of generating free radicals from CCl4. The data presented here show that treatment with orally administered proanthocyanidins prevented liver injury in the CCl4-induced steatosis model, likely through exerting antioxidant actions to suppress oxidative stress and inhibiting the free radical-generating CYP2E1 enzyme.

  14. Exaggerated Liver Injury Induced by Renal Ischemia Reperfusion in Diabetes: Effect of Exenatide

    PubMed Central

    Vaghasiya, Jitendra D.; Sheth, Navin R.; Bhalodia, Yagnik S.; Jivani, Nurudin P.

    2010-01-01

    Background/Aim: This study was designed to investigate the possible effect of exenatide (Glucagon like Peptide-1 receptor agonist) on liver injury (distant organ) induced by renal ischemia reperfusion (IR) in diabetic rats. Materials and Methods: In vivo renal IR was performed in both type 2 diabetic and normal rats. Each protocol comprised ischemia for 30 minutes followed by reperfusion for 24 hours and a treatment period of 14 days before induction of ischemia. Results: Lipid peroxidation, xanthine oxidase activity, myeloperoxidase activity and nitric oxide level in liver tissue were significantly increased (P < 0.01, P < 0.001, P < 0.001, P < 0.05, respectively), after IR in diabetic rats compared to normal rats. Antioxidant enzymes like glutathione, superoxide dismutase, catalase and glutathione peroxidase were significantly reduced (P < 0.05, P < 0.05, P < 0.01, P < 0.05, respectively), after IR in diabetic rats compared to normal rats. Exenatide treatment significantly normalized (P < 0.01), these biochemical parameters in treated rats compared to diabetic IR rats. Serum creatinine phosphokinase activity and liver function enzymes were also significantly normalized (P < 0.001, P < 0.001, respectively), after administration of exenatide. Conclusion: Exenatide exerted protective effect on exaggerated remote organ (liver) injury induced by renal IR in diabetes. PMID:20616412

  15. Involvement of constitutive androstane receptor in liver hypertrophy and liver tumor development induced by triazole fungicides.

    PubMed

    Tamura, Kei; Inoue, Kaoru; Takahashi, Miwa; Matsuo, Saori; Irie, Kaoru; Kodama, Yukio; Gamo, Toshie; Ozawa, Shogo; Yoshida, Midori

    2015-04-01

    We clarified the involvement of constitutive androstane receptor (CAR) in triazole-induced liver hypertrophy and tumorigenesis using CAR-knockout (CARKO) mice. Seven-week-old male CARKO and wild-type (WT) mice were treated with 200 ppm cyproconazole (Cypro), 1500 ppm tebuconazole (Teb), or 200 ppm fluconazole (Flu) in the diet for 27 weeks after initiation by diethylnitrosamine (DEN). At weeks 4 (without DEN) and 13 (with DEN), WT mice in all treatment groups and CARKO mice in Teb group revealed liver hypertrophy with mainly Cyp2b10 and following Cyp3a11 inductions in the liver. Teb also induced Cyp4a10 in both genotypes. Cypro induced slight and duration-dependent liver hypertrophy in CARKO mice. At week 27, Cypro and Teb significantly increased eosinophilic altered foci and/or adenomas in WT mice. These proliferating lesions were clearly reduced in CARKO mice administered both compounds. The eosinophilic adenomas caused by Flu decreased in CARKO mice. The present study indicates that CAR is the main mediator of liver hypertrophy induced by Cypro and Flu, but not Teb. In contrast, CAR played a crucial role in liver tumor development induced by all three triazoles. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Short-term exposure to nonylphenol induces pancreatic oxidative stress and alters liver glucose metabolism in adult female rats.

    PubMed

    Jubendradass, R; D'Cruz, Shereen Cynthia; Mathur, P P

    2011-01-01

    Nonylphenol is known to have estrogenic properties and has been reported to cause health hazards to animals and humans. The effects of nonylphenol on pancreas are not clearly elucidated. In this study, we sought to evaluate the effects of nonylphenol on the oxidative status of pancreas and consequential effects of nonylphenol on some of the end points of carbohydrate metabolism in the female rats. Rats were administered nonylphenol orally at the doses of 1.5, 15, and 150 mg/kg of body weight per day for 7 days. After 24 h of last dosing, the animals were sacrificed by cervical dislocation. The activities of pancreatic superoxide dismutase and catalase were significantly decreased with a concomitant increase in the levels of H2O2 and lipid peroxidation. Nonylphenol increased plasma insulin levels with a concomitant decrease in the levels of plasma glucose as compared to the control groups of rats. A dose-dependent increase in the activities of liver hexokinase and phosphofructokinase was recorded along with decreased activity of glycogen phosphorylase in liver. Western blot analysis revealed a significant decrease in the levels of GLUT-2. These results show that nonylphenol causes oxidative stress in pancreas and impairs liver glucose homeostasis. Copyright © 2010 Wiley Periodicals, Inc.

  17. Interstrain differences in the severity of liver injury induced by a choline- and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism

    PubMed Central

    Tryndyak, Volodymyr; de Conti, Aline; Kobets, Tetyana; Kutanzi, Kristy; Koturbash, Igor; Han, Tao; Fuscoe, James C.; Latendresse, John R.; Melnyk, Stepan; Shymonyak, Svitlana; Collins, Leonard; Ross, Sharon A.; Rusyn, Ivan; Beland, Frederick A.; Pogribny, Igor P.

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a major health problem and a leading cause of chronic liver disease in the United States and developed countries. In humans, genetic factors greatly influence individual susceptibility to NAFLD. The goals of this study were to compare the magnitude of interindividual differences in the severity of liver injury induced by methyl-donor deficiency among individual inbred strains of mice and to investigate the underlying mechanisms associated with the variability. Feeding mice a choline- and folate-deficient diet for 12 wk caused liver injury similar to NAFLD. The magnitude of liver injury varied among the strains, with the order of sensitivity being A/J ≈ C57BL/6J ≈ C3H/HeJ < 129S1/SvImJ ≈ CAST/EiJ < PWK/PhJ < WSB/EiJ. The interstrain variability in severity of NAFLD liver damage was associated with dysregulation of genes involved in lipid metabolism, primarily with a down-regulation of the peroxisome proliferator receptor α (PPARα)-regulated lipid catabolic pathway genes. Markers of oxidative stress and oxidative stress-induced DNA damage were also elevated in the livers but were not correlated with severity of liver damage. These findings suggest that the PPARα-regulated metabolism network is one of the key mechanisms determining interstrain susceptibility and severity of NAFLD in mice.—Tryndyak, V., de Conti, A., Kobets, T., Kutanzi, K., Koturbash, I., Han, T., Fuscoe, J. C., Latendresse, J. R., Melnyk, S., Shymonyak, S., Collins, L., Ross, S. A., Rusyn, I., Beland, F. A., Pogribny, I. P. Interstrain differences in the severity of liver injury induced by a choline- and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism. PMID:22872676

  18. Role and mechanisms of autophagy in acetaminophen-induced liver injury.

    PubMed

    Chao, Xiaojuan; Wang, Hua; Jaeschke, Hartmut; Ding, Wen-Xing

    2018-04-23

    Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in the USA and many other countries. Although the metabolism and pathogenesis of APAP has been extensively investigated for decades, the mechanisms by which APAP induces liver injury are incompletely known, which hampers the development of effective therapeutic approaches to tackle this important clinical problem. Autophagy is a highly conserved intracellular degradation pathway, which aims at recycling cellular components and damaged organelles in response to adverse environmental conditions and stresses as a survival mechanism. There is accumulating evidence indicating that autophagy is activated in response to APAP overdose in specific liver zone areas, and pharmacological activation of autophagy protects against APAP-induced liver injury. Increasing evidence also suggests that hepatic autophagy is impaired in nonalcoholic fatty livers (NAFLD), and NAFLD patients are more susceptible to APAP-induced liver injury. Here, we summarized the current progress on the role and mechanisms of autophagy in protecting against APAP-induced liver injury. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. The effect of copper deficiency on fetal growth and liver anti-oxidant capacity in the Cohen diabetic rat model

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ergaz, Zivanit, E-mail: zivanit@hadassah.org.il; Shoshani-Dror, Dana; Guillemin, Claire

    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.more » 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

  20. Forskolin, a hedgehog signalling inhibitor, attenuates carbon tetrachloride-induced liver fibrosis in rats.

    PubMed

    El-Agroudy, Nermeen N; El-Naga, Reem N; El-Razeq, Rania Abd; El-Demerdash, Ebtehal

    2016-11-01

    Liver fibrosis is one of the leading causes of morbidity and mortality worldwide with very limited therapeutic options. Given the pivotal role of activated hepatic stellate cells in liver fibrosis, attention has been directed towards the signalling pathways underlying their activation and fibrogenic functions. Recently, the hedgehog (Hh) signalling pathway has been identified as a potentially important therapeutic target in liver fibrosis. The present study was designed to explore the antifibrotic effects of the potent Hh signalling inhibitor, forskolin, and the possible molecular mechanisms underlying these effects. Male Sprague-Dawley rats were treated with either CCl 4 and/or forskolin for 6 consecutive weeks. Serum hepatotoxicity markers were determined, and histopathological evaluation was performed. Hepatic fibrosis was assessed by measuring α-SMA expression and collagen deposition by Masson's trichrome staining and hydroxyproline content. The effects of forskolin on oxidative stress markers (GSH, GPx, lipid peroxides), inflammatory markers (NF-κB, TNF-α, COX-2, IL-1β), TGF-β1 and Hh signalling markers (Ptch-1, Smo, Gli-2) were also assessed. Hepatic fibrosis induced by CCl 4 was significantly reduced by forskolin, as indicated by decreased α-SMA expression and collagen deposition. Forskolin co-treatment significantly attenuated oxidative stress and inflammation, reduced TGF-β1 levels and down-regulated mRNA expression of Ptch-1, Smo and Gli-2 through cAMP-dependent PKA activation. In our model, forskolin exerted promising antifibrotic effects which could be partly attributed to its antioxidant and anti-inflammatory effects, as well as to its inhibition of Hh signalling, mediated by cAMP-dependent activation of PKA. © 2016 The British Pharmacological Society.

  1. Forskolin, a hedgehog signalling inhibitor, attenuates carbon tetrachloride‐induced liver fibrosis in rats

    PubMed Central

    El‐Agroudy, Nermeen N; El‐Naga, Reem N; El‐Razeq, Rania Abd

    2016-01-01

    Background and Purpose Liver fibrosis is one of the leading causes of morbidity and mortality worldwide with very limited therapeutic options. Given the pivotal role of activated hepatic stellate cells in liver fibrosis, attention has been directed towards the signalling pathways underlying their activation and fibrogenic functions. Recently, the hedgehog (Hh) signalling pathway has been identified as a potentially important therapeutic target in liver fibrosis. The present study was designed to explore the antifibrotic effects of the potent Hh signalling inhibitor, forskolin, and the possible molecular mechanisms underlying these effects. Experimental Approach Male Sprague‐Dawley rats were treated with either CCl4 and/or forskolin for 6 consecutive weeks. Serum hepatotoxicity markers were determined, and histopathological evaluation was performed. Hepatic fibrosis was assessed by measuring α‐SMA expression and collagen deposition by Masson's trichrome staining and hydroxyproline content. The effects of forskolin on oxidative stress markers (GSH, GPx, lipid peroxides), inflammatory markers (NF‐κB, TNF‐α, COX‐2, IL‐1β), TGF‐β1 and Hh signalling markers (Ptch‐1, Smo, Gli‐2) were also assessed. Key Results Hepatic fibrosis induced by CCl4 was significantly reduced by forskolin, as indicated by decreased α‐SMA expression and collagen deposition. Forskolin co‐treatment significantly attenuated oxidative stress and inflammation, reduced TGF‐β1 levels and down‐regulated mRNA expression of Ptch‐1, Smo and Gli‐2 through cAMP‐dependent PKA activation. Conclusion and Implications In our model, forskolin exerted promising antifibrotic effects which could be partly attributed to its antioxidant and anti‐inflammatory effects, as well as to its inhibition of Hh signalling, mediated by cAMP–dependent activation of PKA. PMID:27590029

  2. Pu-erh Tea Reduces Nitric Oxide Levels in Rats by Inhibiting Inducible Nitric Oxide Synthase Expression through Toll-Like Receptor 4

    PubMed Central

    Xu, Yang; Wang, Guan; Li, Chunjie; Zhang, Min; Zhao, Hang; Sheng, Jun; Shi, Wei

    2012-01-01

    Pu-erh tea undergoes a unique fermentation process and contains theabrownins, polysaccharides and caffeine; although it is unclear about which component is associated with the down regulation of nitric oxide levels or how this process is mediated. To address this question we examined the effects of pu-erh tea on nitric oxide synthase (NOS) genes. Cohorts of rats were separately given four-week treatments of water as control, pu-erh tea, or the tea components: theabrownins, caffeine or polysaccharides. Five experimental groups were injected with lipopolysaccharides (LPS) to induce nitric oxide (NO) production, while the corresponding five control groups were injected with saline as a negative control. The serum and liver NO concentrations were examined and the NOS expression of both mRNA and protein was measured in liver. The results showed that the rats which were fed pu-erh tea or polysaccharides had lower levels of NO which corresponded with the down-regulation of inducible nitric oxide synthase (iNOS) expression. We further demonstrate that this effect is mediated through reduction of Toll-like receptor 4 (TLR4) signaling. Thus we find that the polysaccharide components in pu-erh tea reduce NO levels in an animal model by inhibiting the iNOS expression via signaling through TLR4. PMID:22837686

  3. 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.

  4. Liver proteomics for therapeutic drug discovery: inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure

    PubMed Central

    Dear, James W.; Leelahavanichkul, Asada; Aponte, Angel; Hu, Xuzhen; Constant, Stephanie L.; Hewitt, Stephen M.; Yuen, Peter S.T.; Star, Robert A.

    2008-01-01

    Objective Sepsis-induced multi-organ failure continues to have a high mortality. The liver is an organ central to the disease pathogenesis. The objective of this study was to identify the liver proteins that change in abundance with sepsis and, therefore, identify new drug targets. Design Proteomic discovery study and drug target validation Setting Research institute laboratory Subjects Three month old C57BL/6 mice Interventions We used a mouse model of sepsis based on cecal ligation and puncture (CLP) but with fluid and antibiotic resuscitation. Liver proteins that changed in abundance were identified by difference in-gel electrophoresis (DIGE). We compared liver proteins from 6 hr post-CLP to sham-operated mice (‘early proteins’) and 24 hr post-CLP with 6 hr post-CLP (‘late proteins’). Proteins that changed in abundance were identified by tandem mass spectrometry. We then inhibited the receptor for one protein and determined the effect on sepsis-induced organ dysfunction. Results The liver proteins that changed in abundance after sepsis had a range of functions such as acute phase proteins, coagulation, ER stress, oxidative stress, apoptosis, mitochondrial proteins and nitric oxide metabolism. We found that cyclophilin increased in abundance after CLP. When the receptor for this protein, CD147, was inhibited sepsis-induced renal dysfunction was reduced. There was also a significant reduction in serum cytokine production when CD147 was inhibited. Conclusion By applying proteomics to a clinically relevant mouse model of sepsis we identified a number of novel proteins that changed in abundance. The inhibition of the receptor for one of these proteins, cyclophilin, attenuated sepsis-induced acute renal failure. The application of proteomics to sepsis research can facilitate the discovery of new therapeutic targets. PMID:17944020

  5. Rutin exhibits hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease by reducing hepatic lipid levels and mitigating lipid-induced oxidative injuries.

    PubMed

    Liu, Qingsheng; Pan, Ran; Ding, Lei; Zhang, Fuli; Hu, Linfeng; Ding, Bin; Zhu, Linwensi; Xia, Yongliang; Dou, Xiaobing

    2017-08-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic lipids and oxidative injury of hepatocytes. Rutin is a natural flavonoid with significant roles in combating cellular oxidative stress and regulating lipid metabolism. The current study aims to investigate the molecular mechanisms underlying rutin's hypolipidemic and hepatoprotective effects in nonalcoholic fatty liver disease. Rutin treatment was applied to male C57BL/6 mice maintained on a high-fat diet and HepG2 cells challenged with oleic acid. Hepatic lipid accumulation was evaluated by triglyceride assay and Oil Red O staining. Oxidative hepatic injury was assessed by malondialdehyde assay, superoxide dismutase assay and reactive oxygen species assay. The expression levels of various lipogenic and lipolytic genes were determined by quantitative real-time polymerase chain reactions. In addition, liver autophagy was investigated by enzyme-linked immunosorbent assay. In both fat-challenged murine liver tissues and HepG2 cells, rutin treatment was shown to significantly lower triglyceride content and the abundance of lipid droplets. Rutin was also found to reduce cellular malondialdehyde level and restore superoxide dismutase activity in hepatocytes. Among the various lipid-related genes, rutin treatment was able to restore the expression of peroxisome proliferator-activated receptor alpha (PPAR-α) and its downstream targets, carnitine palmitoyltransferase 1 and 2 (CPT-1 and CPT-2), while suppressing those of sterol regulatory element-binding protein 1c (SREBP-1c), diglyceride acyltransfase 1 and 2 (DGAT-1 and 2), as well as acyl-CoA carboxylase (ACC). In addition, rutin was shown to repress the autophagic function of liver tissues by down-regulating key autophagy biomarkers, including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β). The experimental data demonstrated that rutin could reduce triglyceride content and mitigate oxidative injuries in fat

  6. Liver metabolomics study reveals protective function of Phyllanthus urinaria against CCl4-induced liver injury.

    PubMed

    Guo, Qing; Zhang, Qian-Qian; Chen, Jia-Qing; Zhang, Wei; Qiu, Hong-Cong; Zhang, Zun-Jian; Liu, Bu-Ming; Xu, Feng-Guo

    2017-07-01

    Phyllanthus Urinaria L. (PUL) is a traditional Chinese medicine used to treat hepatic and renal disorders. However, the mechanism of its hepatoprotective action is not fully understood. In the present study, blood biochemical indexes and liver histopathological changes were used to estimate the extent of hepatic injury. GC/MS and LC/MS-based untargeted metabolomics were used in combination to characterize the potential biomarkers associated with the protective activity of PUL against CCl 4 -induced liver injury in rats. PUL treatment could reverse the increase in ALT, AST and ALP induced by CCl 4 and attenuate the pathological changes in rat liver. Significant changes in liver metabolic profiling were observed in PUL-treated group compared with liver injury model group. Seventeen biomarkers related to the hepatoprotective effects of PUL against CCl 4 -induced liver injury were screened out using nonparametric test and Pearson's correlation analysis (OPLS-DA). The results suggested that the potential hepatoprotective effects of PUL in attenuating CCl 4 -induced hepatotoxicity could be partially attributed to regulating L-carnitine, taurocholic acid, and amino acids metabolism, which may become promising targets for treatment of liver toxicity. In conclusion, this study provides new insights into the mechanism of the hepatoprotection of Phyllanthus Urinaria. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  7. Silymarin attenuated hepatic steatosis through regulation of lipid metabolism and oxidative stress in a mouse model of nonalcoholic fatty liver disease (NAFLD).

    PubMed

    Ni, Xunjun; Wang, Haiyan

    2016-01-01

    Silymarin, which derived from the milk thistle plant (silybum marianum), has been used for centuries as a natural remedy for diseases of the liver and biliary tract. Considering the therapeutic potential to liver disease, we tested efficacy of silymarin on hepatic steatosis with a high fat diet (HFD)-induced mouse model of non-alcoholic fatty liver disease (NAFLD), and investigated possible effects on lipid metabolic pathways. In our study, silymarin could attenuate the hepatic steatosis, which was proved by both Oil Red O staining and hepatic triglyceride (TG) level determination. Furthermore, compared with INT-747, a potent and selective FXR agonist, silymarin could preserve plasmatic high-density lipoprotein cholesterol (HDL-C) to a higher level and low-density lipoprotein cholesterol (LDL-C) to a lower level, which benefited more to the circulation system. Through real-time PCR analysis, we clarified a vital protective role of silymarin in mRNA regulation of genes involved in lipid metabolism and oxidative stress. It was also shown that silymarin had no effects on body weight, food intake, and liver transaminase. Taken together, silymarin could attenuate hepatic steatosis in a mouse model of NAFLD through regulation of lipid metabolism and oxidative stress, and benefit to the circulation system. All these findings shed new light on NAFLD treatment.

  8. Protective effects of α-mangostin against acetaminophen-induced acute liver injury in mice.

    PubMed

    Fu, Tianhua; Wang, Shijie; Liu, Jinping; Cai, Enbo; Li, Haijun; Li, Pingya; Zhao, Yan

    2018-05-15

    The purpose of this study was to evaluate the protective effects of α-mangostin against acetaminophen (APAP)-induced acute liver injury and discover its potential mechanisms in mice. Mice were continuously treated with α-mangostin (12.5 and 25 mg/kg) by intragastric administration once daily for 6 days, and injected intraperitoneally with APAP (300 mg/kg) after 1 h of α-mangostin administration on the last day. After APAP exposure for 24 h, the liver and serum were gathered to evaluate the hepatotoxicity. The results showed that α-mangostin effectively decreased the serum levels of alanine aminotransferase, aspartate transaminase, tumor necrosis factor (TNF-α), interleukin-1β and 6 (IL-1β, IL-6), and hepatic malondialdehyde level; and recovered hepatic glutathione (GSH), superoxide dismutase and catalase activities. Liver histopathological observation provided further evidence that α-mangostin pretreatment significantly inhibited APAP-induced hepatocellular necrosis, infiltration of inflammatory cell and hyperemia. According to the analysis of western-blot and RT-PCR detection, α-mangostin pretreatment validly inhibited the phosphorylation of ERK, JNK and p38 MAPK induced by APAP, which was consistent with the changes of TNF-α, IL-6 and IL-1β levels; the phosphorylation of IκBα and the translocation of NF-κBp65 were also attenuated by α-mangostin. These results provided a new mechanism for the protective effects of α-mangostin against APAP-induced acute liver injury. α-Mangostin significantly restrainted the oxidative stress induced by APAP. Moreover, the anti-inflammatory property of α-mangostin, which is mediated by the NF-κB and MAPK signaling pathways, also contributed to its hepatoprotective effect. Taken together, we believed that α-mangostin might be a potential material for drug development against drug-related hepatotoxicity. Copyright © 2018. Published by Elsevier B.V.

  9. Character and temporal evolution of apoptosis in acetaminophen-induced acute liver failure*.

    PubMed

    Possamai, Lucia A; McPhail, Mark J W; Quaglia, Alberto; Zingarelli, Valentina; Abeles, R Daniel; Tidswell, Robert; Puthucheary, Zudin; Rawal, Jakirty; Karvellas, Constantine J; Leslie, Elaine M; Hughes, Robin D; Ma, Yun; Jassem, Wayel; Shawcross, Debbie L; Bernal, William; Dharwan, Anil; Heaton, Nigel D; Thursz, Mark; Wendon, Julia A; Mitry, Ragai R; Antoniades, Charalambos G

    2013-11-01

    To evaluate the role of hepatocellular and extrahepatic apoptosis during the evolution of acetaminophen-induced acute liver failure. A prospective observational study in two tertiary liver transplant units. Eighty-eight patients with acetaminophen-induced acute liver failure were recruited. Control groups included patients with nonacetaminophen-induced acute liver failure (n = 13), nonhepatic multiple organ failure (n = 28), chronic liver disease (n = 19), and healthy controls (n = 11). Total and caspase-cleaved cytokeratin-18 (M65 and M30) measured at admission and sequentially on days 3, 7, and 10 following admission. Levels were also determined from hepatic vein, portal vein, and systemic arterial blood in seven patients undergoing transplantation. Protein arrays of liver homogenates from patients with acetaminophen-induced acute liver failure were assessed for apoptosis-associated proteins, and histological assessment of liver tissue was performed. Admission M30 levels were significantly elevated in acetaminophen-induced acute liver failure and non-acetaminophen induced acute liver failure patients compared with multiple organ failure, chronic liver disease, and healthy controls. Admission M30 levels correlated with outcome with area under receiver operating characteristic of 0.755 (0.639-0.885, p < 0.001). Peak levels in patients with acute liver failure were seen at admission then fell significantly but did not normalize over 10 days. A negative gradient of M30 from the portal to hepatic vein was demonstrated in patients with acetaminophen-induced acute liver failure (p = 0.042) at the time of liver transplant. Analysis of protein array data demonstrated lower apoptosis-associated protein and higher catalase concentrations in acetaminophen-induced acute liver failure compared with controls (p < 0.05). Explant histological analysis revealed evidence of cellular proliferation with an absence of histological evidence of apoptosis. Hepatocellular apoptosis occurs

  10. Glutamine inhibits CCl4 induced liver fibrosis in mice and TGF-β1 mediated epithelial-mesenchymal transition in mouse hepatocytes.

    PubMed

    Shrestha, Nirajan; Chand, Lokendra; Han, Myung Kwan; Lee, Seung Ok; Kim, Chan Young; Jeong, Yeon Jun

    2016-07-01

    Glutamine, traditionally a non-essential amino acid, now has been considered as essential in serious illness and injury. It is a major precursor for glutathione synthesis. However, the anti-fibrotic effect of glutamine and its molecular mechanism in experimental liver fibrosis have not been explored. In the present study we aimed to examine the potential role of glutamine in carbon tetrachloride (CCl4) induced liver fibrosis and TGF-β1 mediated epithelial mesenchymal transition (EMT) and apoptosis in mouse hepatocytes. Liver fibrosis was induced by intraperitoneal injection of CCl4 three times a week for 10 weeks. Glutamine treatment effectively attenuated liver injury and oxidative stress. Collagen content was significantly decreased in liver sections of glutamine treated mice compared to CCl4 model mice. Furthermore, glutamine decreased expression level of α-SMA and TGF-β in liver tissue. Our in vitro study showed that TGF-β1 treatment in hepatocytes resulted in loss of E-cadherin and increased expression of mesenchymal markers and EMT related transcription factor. In addition, TGF-β1 increased the expression of apoptotic markers. However, glutamine interestingly suppressed TGF-β1 mediated EMT and apoptosis. In conclusion, our results suggest that glutamine ameliorates CCl4 induced liver fibrosis and suppresses TGF-β1 induced EMT progression and apoptosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Salidroside mediates apoptosis and autophagy inhibition in concanavalin A-induced liver injury

    PubMed Central

    Feng, Jiao; Niu, Peiqin; Chen, Kan; Wu, Liwei; Liu, Tong; Xu, Shizan; Li, Jingjing; Li, Sainan; Wang, Wenwen; Lu, Xiya; Yu, Qiang; Liu, Ning; Xu, Ling; Wang, Fan; Dai, Weiqi; Xia, Yujing; Fan, Xiaoming; Guo, Chuanyong

    2018-01-01

    Salidroside (Sal) is a glycoside extract from Rhodiola rosea L. with anti-inflammatory, antioxidant, anticancer and cardioprotective properties. The present study explored the protective effects and the possible mechanisms of Sal on concanavalin A (ConA)-induced liver injury in mice. Balb/C mice were divided into five groups: Normal control (injected with normal saline), ConA (25 mg/kg), Sal (10 mg/kg) +ConA, Sal (20 mg/kg) + ConA (Sal injected 2 h prior to ConA injection) and Sal (20 mg/kg) only. The serum levels of liver enzymes, pro-inflammatory cytokines, and apoptosis- and autophagy-associated marker proteins were determined at 2, 8 and 24 h after ConA injection. LY294002 was further used to verify whether the phosphoinositide 3-kinase (PI3K)/Akt pathway was activated. Primary hepatocytes were isolated to verify the effect of Sal in vitro. The results indicated that Sal was a safe agent to reduce pathological damage and serum liver enzymes in ConA-induced liver injury. Sal suppressed inflammatory reactions in serum and liver tissues, and activated the PI3K/Akt signaling pathway to inhibit apoptosis and autophagy in vivo and in vitro, which could be reversed by LY294002. In conclusion, Sal attenuated ConA-induced liver injury by modulating PI3K/Akt pathway-mediated apoptosis and autophagy in mice.

  12. Acute liver injury induced by weight-loss herbal supplements.

    PubMed

    Chen, Gary C; Ramanathan, Vivek S; Law, David; Funchain, Pauline; Chen, George C; French, Samuel; Shlopov, Boris; Eysselein, Viktor; Chung, David; Reicher, Sonya; Pham, Binh V

    2010-11-27

    We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss.

  13. Acute liver injury induced by weight-loss herbal supplements

    PubMed Central

    Chen, Gary C; Ramanathan, Vivek S; Law, David; Funchain, Pauline; Chen, George C; French, Samuel; Shlopov, Boris; Eysselein, Viktor; Chung, David; Reicher, Sonya; Pham, Binh V

    2010-01-01

    We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss. PMID:21173910

  14. Assessment of amiodarone-induced phospholipidosis in chimeric mice with a humanized liver.

    PubMed

    Sanoh, Seigo; Yamachika, Yuto; Tamura, Yuka; Kotake, Yaichiro; Yoshizane, Yasumi; Ishida, Yuji; Tateno, Chise; Ohta, Shigeru

    2017-01-01

    It is important to consider susceptibility to drug-induced toxicity between animals and humans. Chimeric mice with a humanized liver are expected to predict hepatotoxicity in humans. Drug-induced phospholipidosis (DIPL), in which phospholipids accumulate, is a known entity. In this study, we examined whether chimeric mice can reveal species differences in DIPL. Changes in various phosphatidylcholine (PhC) molecules were investigated in the liver of chimeric mice after administering amiodarone, which induces phospholipidosis. Liquid chromatography-tandem mass spectrometry revealed that levels of PhCs tended to increase in the liver after administration of amiodarone. The liver of chimeric mice consists of human hepatocytes and residual mouse hepatocytes. We used imaging mass spectrometry (IMS) to evaluate the increase of PhCs in human and mouse hepatocytes after administration of amiodarone. IMS visualizes localization of endogenous and exogenous molecules in tissues. The IMS analysis suggested that the localized levels of several PhCs tended to be higher in the human hepatocytes than those in mouse hepatocytes, and PhC levels changed in response to amiodarone. Chimeric mice with a humanized liver will be useful to evaluate species differences in DIPL between mice and humans.

  15. An increase in liver PPARγ2 is an initial event to induce fatty liver in response to a diet high in butter: PPARγ2 knockdown improves fatty liver induced by high-saturated fat.

    PubMed

    Yamazaki, Tomomi; Shiraishi, Sayaka; Kishimoto, Kyoko; Miura, Shinji; Ezaki, Osamu

    2011-06-01

    The effects of a diet rich in saturated fat on fatty liver formation and the related mechanisms that induce fatty liver were examined. C57BL/6J mice were fed butter or safflower oil as a high-fat (HF) diet (40% fat calories) for 2, 4, 10, or 17 weeks. Although both HF diets induced similar levels of obesity, HF butter-fed mice showed a two to threefold increase in liver triacylglycerol (TG) concentration compared to HF safflower oil-fed mice at 4 or 10 weeks without hyperinsulinemia. At 4 weeks, increases in peroxisome proliferator-activated receptor γ2 (PPARγ2), CD36, and adipose differentiation-related protein (ADRP) mRNAs were observed in HF butter-fed mice; at 10 weeks, an increase in sterol regulatory element-binding protein-1c (SREBP-1c) was observed; at 17 weeks, these increases were attenuated. At 4 weeks, a single injection of adenoviral vector-based short hairpin interfering RNA against PPARγ2 in HF butter-fed mice reduced PPARγ protein and mRNA of its target genes (CD36 and ADRP) by 43%, 43%, and 39%, respectively, with a reduction in liver TG concentration by 38% in 5 days. PPARγ2 knockdown also reduced mRNAs in lipogenic genes (fatty-acid-synthase, stearoyl-CoA desaturase 1, acetyl-CoA carboxylase 1) without alteration of SREBP-1c mRNA. PPARγ2 knockdown reduced mRNAs in genes related to inflammation (CD68, interleukin-1β, tumor necrosis factor-α, and monocyte chemoattractant protein-1). In conclusion, saturated fatty acid-rich oil induced fatty liver in mice, and this was triggered initially by an increase in PPARγ2 protein in the liver, which led to increased expression of lipogenic genes. Inactivation of PPARγ2 may improve fatty liver induced by HF saturated fat. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. Blockade of CCN4 attenuates CCl4-induced liver fibrosis.

    PubMed

    Li, Xiaofei; Chen, Yongxin; Ye, Weiwei; Tao, Xingfei; Zhu, Jinhong; Wu, Shuang; Lou, Lianqing

    2015-06-19

    CCN4, also termed WNT-inducible signaling pathway protein-1 (WISP-1), has important roles in inflammation and tissue injury. This study aimed to investigate the effect of CCN4 inhibition using monoclonal anti-CCN4 antibody (CCN4mAb) on the liver injury and fibrosis in a mouse model of liver fibrosis. The mouse liver fibrosis model was induced by carbon tetrachloride (CCl4). Mice received vehicle (saline/olive oil) by subcutaneous injection, CCl4 by subcutaneous injection or CCl4 (subcutaneous) plus CCN4mAb by subcutaneous injection. The pro-inflammatory and pro-fibrotic factors were determined by Western blot. The biochemistry and histopathology, collagen deposition and nuclear factor (NF)-κB activity were also assessed. Chronic CCl4 treatment caused liver injury and collagen accumulation. The expression levels of CCN4, pro-inflammatory and pro-fibrotic mediators as well as the activity of NF-κB were markedly increased. Treatment with CCN4mAb significantly inhibited CCl4-induced CCN4 expression, leading to attenuated CCl4-induced liver injury and the inflammatory response. CCN4 blockade also significantly reduced the formation of collagen in the liver and the expression of α-smooth muscle actin and transforming growth factor β1. CCN4 inhibition by CCN4mAb in vivo significantly attenuated the CCl4-induced liver injury and the progression of liver fibrosis. CCN4 may represent a novel therapeutic target for liver injury and fibrosis.

  17. Oxidative stress and genotoxicity induced by ketorolac on the common carp Cyprinus carpio.

    PubMed

    Galar-Martínez, M; García-Medina, S; Gómez-Olivan, L M; Pérez-Coyotl, I; Mendoza-Monroy, D J; Arrazola-Morgain, R E

    2016-09-01

    The nonsteroidal anti-inflammatory drug ketorolac is extensively used in the treatment of acute postoperative pain. This pharmaceutical has been found at concentrations of 0.2-60 µg/L in diverse water bodies around the world; however, its effects on aquatic organisms remain unknown. The present study, evaluated the oxidative stress and genotoxicity induced by sublethal concentrations of ketorolac (1 and 60 µg/L) on liver, brain, and blood of the common carp Cyprinus carpio. This toxicant induced oxidative damage (increased lipid peroxidation, hydroperoxide content, and protein carbonyl content) as well as changes in antioxidant status (superoxide dismutase, catalase, and glutathione peroxidase activity) in liver and brain of carp. In blood, ketorolac increased the frequency of micronuclei and is therefore genotoxic for the test species. The effects observed were time and concentration dependent. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1035-1043, 2016. © 2015 Wiley Periodicals, Inc.

  18. Ascorbate oxidation is a prerequisite for its transport into rat liver microsomal vesicles.

    PubMed Central

    Csala, M; Mile, V; Benedetti, A; Mandl, J; Bánhegyi, G

    2000-01-01

    Oxidation and uptake of ascorbate show similar time courses in rat liver microsomal vesicles: a rapid burst phase is followed by a slower process. Inhibitors of ascorbate oxidation (proadifen, econazole or quercetin) also effectively decreased the uptake of ascorbate. The results show that dehydroascorbate is the transport form of ascorbate at the membrane of the endoplasmic reticulum. PMID:10880339

  19. Activation of p62-keap1-Nrf2 antioxidant pathway in the early stage of acetaminophen-induced acute liver injury in mice.

    PubMed

    Shen, Zhenyu; Wang, Yu; Su, Zhenhui; Kou, Ruirui; Xie, Keqin; Song, Fuyong

    2018-02-25

    Acetaminophen (APAP) overdose can cause severe liver failure even death. Nearly half of drug-induced liver injury is attributed to APAP in the US and many European countries. Oxidative stress has been validated as a critical event involved in APAP-induced liver failure. p62/SQSTM1, a selective autophagy adaptor protein, is reported to regulate Nrf2-ARE antioxidant pathway in response to oxidative stress. However, the exact role of p62-keap1-Nrf2 antioxidant pathway in APAP-induced hepatotoxicity remains unknown. In the present study, the dose-response and time-course model in C57/BL6 mice were established by intraperitoneal injection of APAP. The results of serum alanine/aspartate aminotransferases (ALT/AST) and histological examination demonstrated that APAP overdose resulted in the severe liver injury. In the meantime, the levels of p62, phospho-p62 and nuclear Nrf2 were significantly increased by APAP in mice liver, suggesting an activation of p62-keap1-Nrf2 pathway. In addition, the expression of GSTA1 mRNA was increased in a dose-dependent manner, while the mRNA levels of HO-1 and GCLC were decreased with the increase of APAP dose. Our further investigation found that expression of HO-1 and GCLC peaked at 3 h∼6 h, and then were decreased gradually. Taken together, these results indicated that p62-keap1-Nrf2 antioxidant pathway was primarily activated in the early stage of APAP hepatotoxicity, which might play a protective role in the process of APAP-induced acute liver injury. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. Protective Effects of Ethanolic Extracts from Artichoke, an Edible Herbal Medicine, against Acute Alcohol-Induced Liver Injury in Mice

    PubMed Central

    Tang, Xuchong; Wei, Ruofan; Deng, Aihua; Lei, Tingping

    2017-01-01

    Oxidative stress and inflammation are well-documented pathological factors in alcoholic liver disease (ALD). Artichoke (Cynara scolymus L.) is a healthy food and folk medicine with anti-oxidative and anti-inflammatory properties. This study aimed to evaluate the preventive effects of ethanolic extract from artichoke against acute alcohol-induced liver injury in mice. Male Institute of Cancer Research mice were treated with an ethanolic extract of artichoke (0.4, 0.8, and 1.6 g/kg body weight) by gavage once daily. Up to 40% alcohol (12 mL/kg body weight) was administered orally 1 h after artichoke treatment. All mice were fed for 10 consecutive days. Results showed that artichoke extract significantly prevented elevated levels of aspartate aminotransferase, alanine aminotransferase, triglyceride, total cholesterol, and malondialdehyde. Meanwhile, the decreased levels of superoxide dismutase and glutathione were elevated by artichoke administration. Histopathological examination showed that artichoke attenuated degeneration, inflammatory infiltration and necrosis of hepatocytes. Immunohistochemical analysis revealed that expression levels of toll-like receptor (TLR) 4 and nuclear factor-kappa B (NF-κB) in liver tissues were significantly suppressed by artichoke treatment. Results obtained demonstrated that artichoke extract exhibited significant preventive protective effect against acute alcohol-induced liver injury. This finding is mainly attributed to its ability to attenuate oxidative stress and suppress the TLR4/NF-κB inflammatory pathway. To the best of our knowledge, the underlying mechanisms of artichoke on acute ALD have been rarely reported. PMID:28891983

  1. Protective Effects of Ethanolic Extracts from Artichoke, an Edible Herbal Medicine, against Acute Alcohol-Induced Liver Injury in Mice.

    PubMed

    Tang, Xuchong; Wei, Ruofan; Deng, Aihua; Lei, Tingping

    2017-09-11

    Oxidative stress and inflammation are well-documented pathological factors in alcoholic liver disease (ALD). Artichoke ( Cynara scolymus L.) is a healthy food and folk medicine with anti-oxidative and anti-inflammatory properties. This study aimed to evaluate the preventive effects of ethanolic extract from artichoke against acute alcohol-induced liver injury in mice. Male Institute of Cancer Research mice were treated with an ethanolic extract of artichoke (0.4, 0.8, and 1.6 g/kg body weight) by gavage once daily. Up to 40% alcohol (12 mL/kg body weight) was administered orally 1 h after artichoke treatment. All mice were fed for 10 consecutive days. Results showed that artichoke extract significantly prevented elevated levels of aspartate aminotransferase, alanine aminotransferase, triglyceride, total cholesterol, and malondialdehyde. Meanwhile, the decreased levels of superoxide dismutase and glutathione were elevated by artichoke administration. Histopathological examination showed that artichoke attenuated degeneration, inflammatory infiltration and necrosis of hepatocytes. Immunohistochemical analysis revealed that expression levels of toll-like receptor (TLR) 4 and nuclear factor-kappa B (NF-κB) in liver tissues were significantly suppressed by artichoke treatment. Results obtained demonstrated that artichoke extract exhibited significant preventive protective effect against acute alcohol-induced liver injury. This finding is mainly attributed to its ability to attenuate oxidative stress and suppress the TLR4/NF-κB inflammatory pathway. To the best of our knowledge, the underlying mechanisms of artichoke on acute ALD have been rarely reported.

  2. Hepatoprotective Effects of Sophoricoside against Fructose-Induced Liver Injury via Regulating Lipid Metabolism, Oxidation, and Inflammation in Mice.

    PubMed

    Li, Wenfeng; Lu, Yalong

    2018-02-01

    The dried fruit of Sophora japonica L. is a traditional Chinese herb tea rich in sophoricoside that is an isoflavone glycoside. The aim of current study was to investigate the hepatic protective effect of sophoricoside in high fructose (HF) diet fed mice. Healthy male mice were fed 30% fructose water and treated 80 and 160 mg/kg·bw sophoricoside continuously for 8 wk. Our data showed that administration of sophoricoside at 80 and 160 mg/kg·bw observably decreased the body weight and liver weight in HF-fed mice. It was found that the treatment of sophoricoside decreased the hepatic cholesterol and triglyceride levels, and serum low-density lipoprotein-cholesterol and apolipoprotein-B levels, and elevated the serum high-density lipoprotein-cholesterol and apolipoprotein-A1 levels. Moreover, the administration of sophoricoside decreased the HF-caused elevations of hepatic malonaldehyde, interleukin-1 and tumor necrosis factor-α levels, while increased the HF-induced decreases of hepatic superoxide dismutase and glutathione peroxidase activities. Meanwhile, serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activities were reduced by treatment of sophoricoside in HF-fed mice. Histopathology of hematoxylin and eosin (H&E) and oil red O staining of liver tissues also confirmed the beneficial effects of sophoricoside against liver injury induced by HF-diet in mice. These findings indicated that sophoricoside may be a novel natural isoflavone for alleviating HF-induced liver injury. Fruit of Sophora japonica L. is a traditional herb tea and it recently becomes popular in China. Sophoricoside is an isoflavone glycoside (Genistein-4'-O-β-d-glucopyranoside) isolated from S. japonical L, and it possessed differential effects on the body health. The ingestion of sophoricoside or sophora fruit tea may be a novel strategy to prevent non-alcoholic fatty liver disease. © 2018 Institute of Food Technologists®.

  3. 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.

  4. Role of activin A in carbon tetrachloride-induced acute liver injury.

    PubMed

    Wang, Dong-Hui; Wang, Yi-Nan; Ge, Jing-Yan; Liu, Hai-Yan; Zhang, Hong-Jun; Qi, Yan; Liu, Zhong-Hui; Cui, Xue-Ling

    2013-06-28

    To investigate the expression and role of activin A in a mouse model of acute chemical liver injury. Acute liver injury in C57BL/6 male mice was induced by intraperitoneal injection with carbon tetrachloride (CCl4) (0.5 mL/kg, body weight) dissolved in olive oil (1:19 v/v). Mice were sacrificed 1, 3, 5 and 7 d after the treatment. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum were examined and pathological changes of liver observed by hematoxylin and eosin staining to evaluate the liver injury. Activin A protein levels in serum and hepatic tissue homogenate of mice were detected by enzyme-linked immunosorbent assay, and the expression pattern of activin A protein in livers of mice was examined by immunohistochemistry. Activin type IIA receptor (ActRIIA) and Smad3 expressions in the liver were analyzed by real-time quantitative reverse transcription-polymerase chain reaction. In order to further investigate the role of activin A, we also utilized activin A blocking experiment by anti-activin A antibody (500 μg/kg, body weight) injection into mouse tail vein. In CCl4-treated mice, serum ALT and AST levels were significantly increased, compared with that in control mice (P < 0.01). Furthermore, the serious necrosis was observed around hepatic portal areas in CCl4-treated mice. Simultaneously, activin A levels in serum and hepatic tissue homogenate of mice treated with CCl4 for 1, 3 and 5 d increased significantly, compared with that in control mice (P < 0.01). Activin A protein expression in hepatocytes not within the necrotic area was also upregulated in mice following CCl4 treatment. Not only activin A, but also ActRIIA and activin signaling molecule Smad3 mRNA expressions in injury liver induced by CCl4 were significantly higher than that in control liver. In addition, levels of serum ALT and AST in CCl4-treated mice were significantly decreased by injection of anti-activin A antibody to block endogenous activin A

  5. Antioxidant Properties of Proanthocyanidins Attenuate Carbon Tetrachloride (CCl4)–Induced Steatosis and Liver Injury in Rats via CYP2E1 Regulation

    PubMed Central

    Zou, Yuan; Zhu, Lei; Wang, Hui-Fang; Dai, Mu-Gen

    2014-01-01

    Abstract Liver steatosis is characterized by lipid dysregulation and fat accumulation in the liver and can lead to oxidative stress in liver. Since proanthocyanidins are present in plant-based foods and have powerful antioxidant properties, we investigated whether proanthocyanidins can prevent oxidative stress and subsequent liver injury. Carbon tetrachloride (CCl4) treatment can cause steatosis in rats that models both alcoholic and non-alcoholic fatty liver disease in humans. We pre-treated rats by oral administration of proanthocyanidins extracted from grape seeds 7 days prior to intragastrically administering CCl4. Proanthocyanidin treatment continued for an additional 2 weeks, after which time liver and serum were harvested, and mediators of liver injury, oxidative stress, and histological features were evaluated. CCl4-treated rats exhibited significant increases in the following parameters as compared to non-treated rats: fat droplets in the liver, liver injury (ALT, AST), and DNA damage (8-OHdG). Additionally, CCl4 treatment decreased antioxidant enzymes SOD, GSH, GPX, and CAT in the liver due to their rapid depletion after battling against oxidative stress. Compared to CCl4-treated rats, treatment with proanthocyanidins effectively suppressed lipid accumulation, liver injury, DNA damage, as well as restored antioxidant enzyme levels. Further investigation revealed that proanthocyanidins treatment also inhibited expression of CYP2E1 in liver, which prevented the initial step of generating free radicals from CCl4. The data presented here show that treatment with orally administered proanthocyanidins prevented liver injury in the CCl4-induced steatosis model, likely through exerting antioxidant actions to suppress oxidative stress and inhibiting the free radical–generating CYP2E1 enzyme. PMID:24712752

  6. Risk assessment of silica nanoparticles on liver injury in metabolic syndrome mice induced by fructose.

    PubMed

    Li, Jianmei; He, Xiwei; Yang, Yang; Li, Mei; Xu, Chenke; Yu, Rong

    2018-07-01

    This study aims to assess the effects and the mechanisms of silica nanoparticles (SiNPs) on hepatotoxicity in both normal and metabolic syndrome mouse models induced by fructose. Here, we found that SiNPs exposure lead to improved insulin resistance in metabolic syndrome mice, but markedly worsened hepatic ballooning, inflammation infiltration, and fibrosis. Moreover, SiNPs exposure aggravated liver injury in metabolic syndrome mice by causing serious DNA damage. Following SiNPs exposure, liver superoxide dismutase and catalase activities in metabolic syndrome mice were stimulated, which is accompanied by significantly increased malondialdehyde and 8-hydroxy-2-deoxyguanosine levels as compared to normal mice. Scanning electron microscope (SEM) revealed that SiNPs were more readily deposited in the liver mitochondria of metabolic syndrome mice, resulting in more severe mitochondrial injury as compared to normal mice. We speculated that SiNPs-induced mitochondrial injury might be the cause of hepatic oxidative stress, which further lead to a series of liver lesions as observed in mice following SiNPs exposure. Based on these results, it is likely that SiNPs will increase the risk and severity of liver disease in individuals with metabolic syndrome. Therefore, SiNPs should be used cautiously in food additives and clinical settings. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Fly ash leachate induces oxidative stress in freshwater fish Channa punctata (Bloch).

    PubMed

    Ali, M; Parvez, S; Pandey, S; Atif, F; Kaur, M; Rehman, H; Raisuddin, S

    2004-09-01

    Oxidative stress inducing potential of fly ash leachate (FAL) was studied in a freshwater fish, Channa punctata (Bloch). Fish were exposed to fly ash leachate for 24 h and lipid peroxidation (LPO) was studied as a marker of oxidative stress. Catalase (CAT), glutathione S-transferase (GST) activities and levels of reduced glutathione (GSH) were also estimated in the exposed fish. FAL (1 ml/l) induced LPO in all the organs and most prominent response was in the gill. It also caused induction of enzymes and glutathione. Liver showed highest level of induction of enzyme activities. The results of this study demonstrate that fly ash constituents have potential to induce oxidative stress in fish and gills are the most vulnerable organs. It is also suggested that in case of exposure to FAL, along with LPO antioxidant defense is also activated to counteract the reactive oxygen species (ROS) at least partly in the initial stages of exposure.

  8. Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure.

    PubMed

    Woolbright, Benjamin L; Jaeschke, Hartmut

    2017-04-01

    Drug-induced acute liver failure carries a high morbidity and mortality rate. Acetaminophen overdose is the number one cause of acute liver failure and remains a major problem in Western medicine. Administration of N-acetyl cysteine is an effective antidote when given before the initial rise in toxicity; however, many patients present to the hospital after this stage occurs. As such, treatments which can alleviate late-stage acetaminophen-induced acute liver failure are imperative. While the initial mechanisms of toxicity are well described, a debate has recently occurred in the literature over whether there is a second phase of injury, mediated by inflammatory processes. Critical to this potential inflammatory process is the activation of caspase-1 and interleukin-1β by a molecular complex known as the inflammasome. Several different stimuli for the formation of multiple different inflammasome complexes have been identified. Formation of the NACHT, leucine-rich repeat (LRR) and pyrin (PYD) domains-containing protein 3 (Nalp3) inflammasome in particular, has directly been attributed to late-stage acetaminophen toxicity. In this review, we will discuss the mechanisms of acetaminophen-induced liver injury in mice and man with a particular focus on the role of inflammation and the inflammasome. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  9. Ginger extract modulates Pb-induced hepatic oxidative stress and expression of antioxidant gene transcripts in rat liver.

    PubMed

    Mohamed, Omnia Ismail; El-Nahas, Abeer Fekry; El-Sayed, Yasser Said; Ashry, Khaled Mohamed

    2016-07-01

    Spices and herbs are recognized sources of natural antioxidants that can protect from oxidative stress, thus play an important role in chemoprevention of liver diseases. Ginger is used worldwide primarily as a spicy condiment. This study evaluated the ability of ginger extract (GE) to ameliorate oxidative-hepatic toxicity induced by lead acetate (PbAc) in rats. Five groups of animals were used: group I kept as control; groups II, IV, and V received PbAc (1 ppm in drinking water daily for 6 weeks, and kept for an additional 2 weeks without PbAc exposure); group III treated orally with GE (350 mg/kg body weight, 4 d per week) for 6 weeks; group IV (protective) received GE for 2 weeks before and simultaneously with PbAc; and group V (treatment) received GE for 2 weeks after PbAc exposure. GC-MS analysis of GE revealed its content of gingerol (7.09%), quercetin (3.20%), dl-limonene (0.96%), and zingiberene (0.18%). Treatment of PbAc-treated rats with GE has no effect on hepatic Pb concentrations. However, it maintained serum aspartate aminotransferase level, increased hepatic glutathione (157%), glutathione S-transferase (GST) (228%), glutathione peroxidase (GPx) (138%) and catalase (CAT) (112%) levels, and reduced hepatic malondialdehyde (80%). Co-treatment of PbAc group with GE upregulated mRNA expression of antioxidant genes: GST-α1 (1.4-fold), GPx1 (1.8-fold), and CAT (8-fold), while post-treatment with GE upregulated only mRNA expression of GPx1 (1.5-fold). GE has an antioxidant protective efficacy against PbAc-induced hepatotoxicity, which appears more effective than its therapeutic application. However, the changes in antioxidant gene expression were not reflected at the protein level.

  10. Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori

    Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxicmore » compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 m

  11. Ethanol-induced oxidant stress modulates hepatic autophagy and proteasome activity

    PubMed Central

    Donohue, Jr., Terrence M.; Thomes, Paul G.

    2014-01-01

    In this review, we describe research findings on the effects of alcohol exposure on two major catabolic systems in liver cells: the ubiquitin–proteasome system (UPS) and autophagy. These hydrolytic systems are not unique to liver cells; they exist in all eukaryotic tissues and cells. However, because the liver is the principal site of ethanol metabolism, it sustains the greatest damage from heavy drinking. Thus, the focus of this review is to specifically describe how ethanol oxidation modulates the activities of the UPS and autophagy and the mechanisms by which these changes contribute to the pathogenesis of alcohol-induced liver injury. Here, we describe the history and the importance of cellular hydrolytic systems, followed by a description of each catabolic pathway and the differential modulation of each by ethanol exposure. Overall, the evidence for an involvement of these catabolic systems in the pathogenesis of alcoholic liver disease is quite strong. It underscores their importance, not only as effective means of cellular recycling and eventual energy generation, but also as essential components of cellular defense. PMID:25462063

  12. Protective effect of artemisinin on chronic alcohol induced-liver damage in mice.

    PubMed

    Zhao, Xiaoyan; Wang, Liqing; Zhang, Hao; Zhang, Duoduo; Zhang, Zhihao; Zhang, Jie

    2017-06-01

    The liver disease related to chronic alcohol consumption is one of the leading causes of death for alcoholics. The efficient drug to ameliorate the alcoholic liver injury was needed urgently. The present study was performed to investigate whether artemisinin possessed the protective effect against chronic alcohol consumption. 50 male Kunming mice were divided into 5 groups: control group (C): 10ml/kg saline+10ml/kg saline, alcohol group (A): 10ml/kg 56%(v/v) alcohol+10ml/kg saline, low dose group of artemisinin (L): 10ml/kg 56%(v/v) alcohol+30mg/kg/day artemisinin, medium dose group of artemisinin (M): 10ml/kg 56%(v/v) alcohol+60mg/kg/day artemisinin, high dose group of artemisinin (H): 10ml/kg 56%(v/v) alcohol+120mg/kg/day artemisinin. Drugs were given orally every day. The general state of mice was observed and the levels of serum activities of AST and ALT were detected after treatment with drugs for 30days. Besides, the liver weight index was calculated and histopathological analysis was performed. We successfully demonstrated that treatment with high dose of artemisinin significantly decreased the elevated levels of AST (p<0.05) and ALT (p<0.01) in plasma, as well as the liver weight index (p<0.01). The loss of body weight, tissue injury, oedema and inflammatory cell infiltration in the hepatocytes were found in the A group. These symptoms were remarkably alleviated in animals treated with artemisinin. Artemisinin can inhibit the activation of NF-кB and the expression of inflammatory cytokines inducible nitric oxide synthase. Besides, it can also enhance the stability of liver cell membrane, and reduce the damage of liver cell membrane and liver cell. Artemisinin showed a protective effect against chronic alcohol poisoning and it has a great potential for the clinical application to treat the liver injury induced by alcohol. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Preventive effects of Ophiocordyceps sinensis mycelium on the liver fibrosis induced by thioacetamide.

    PubMed

    Wu, Yi-Hsieng Samuel; Tseng, Jung-Kai; Chou, Chung-Hsi; Chiu, Chih-Hsien; Lin, Yi-Ling; Chen, Yi-Chen

    2017-06-01

    Thioacetamide (TAA), usually used as a fungicide to control the decay of citrus products, itself is not toxic to the liver, but its intermediates are able to increase oxidative stress in livers and further cause fibrosis. Ophiocordyceps sinensis mycelium (OSM) which contains 10% polysaccharides and 0.25% adenosine decreased (P < 0.05) the lipid accumulation and increased (P < 0.05) antioxidative capacity in livers of thioacetamide (TAA) injected rats. Meanwhile, the increased (P < 0.05) liver sizes, serum alanine transaminase (AST) and aspartate transaminase (ALT) values in thioacetamide (TAA)-injected rats were ameliorated (P < 0.05) by OSM supplementation. Moreover, the levels of proinflammatory cytokines, such as the tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), were also reduced (P < 0.05). The fibrosis phenomena in pathological (Masson's trichrome and H&E stainings) and immunohistochemical [α-smooth actin (αSMA) and CD86/ED1] observations in TAA-treated rats were reduced (P < 0.05) by OSM cotreatment. The protective effect of OSM against TAA-induced liver inflammation/fibrosis may be via downregulations (P < 0.05) of TGF-β pathways and NFκB which further influenced (P < 0.05) the expressions of fibrotic and inflammatory genes (i. e., αSMA, Col1α, COX2). Therefore, OSM shows preventive effects on the development of TAA-induced hepatic fibrosis. © 2017 Wiley Periodicals, Inc.

  14. Evaluation of the bioactive extract of actinomyces isolated from the Egyptian environment against aflatoxin B1-induce cytotoxicity, genotoxicity and oxidative stress in the liver of rats.

    PubMed

    El-Nekeety, Aziza A; Salman, Asmaa S; Hathout, Amal S; Sabry, Bassem A; Abdel-Aziem, Sekena H; Hassan, Nabila S; Abdel-Wahhab, Mosaad A

    2017-07-01

    This study aimed to determine the bioactive compounds of actinomyces (ACT) isolated from the Egyptian environment (D-EGY) and to evaluate their protective activity against AFB 1 in female Sprague-Dawley rats. Six groups of animals were treated orally for 3 weeks included: C, the control group, T1, AFB 1 -treated group (80 μg/kg b.w), T2 and T3, the groups received ACT extract at low (25 mg/kg b.w) or high (50 mg/kg b.w) doses, T4 and T5, the groups received AFB 1 plus the low or high dose of ACT extract. Blood, bone marrow and tissue samples were collected for different analyses and histological examination. The results revealed the identification of 40 components, representing 99.98%. Treatment with AFB 1 disturbs liver function parameters, oxidative stress markers, antioxidant gene expressions, DNA fragmentation and induced severe histological changes. ACT extract at the low or high doses did not induce significant changes in all the tested parameters or histological picture of the liver. Moreover, ACT extract succeeded to induce a significant protection against the toxicity of AFB 1 . It could be concluded that the bioactive compounds in ACT are promise candidate for the development of food additive or drugs for the protection and treatment of liver disorders in the endemic area. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Nicotinamide riboside attenuates alcohol induced liver injuries via activation of SirT1/PGC-1α/mitochondrial biosynthesis pathway.

    PubMed

    Wang, Sufan; Wan, Ting; Ye, Mingtong; Qiu, Yun; Pei, Lei; Jiang, Rui; Pang, Nengzhi; Huang, Yuanling; Liang, Baoxia; Ling, Wenhua; Lin, Xiaojun; Zhang, Zhenfeng; Yang, Lili

    2018-07-01

    Nicotinamide riboside (NR) is a nicotinamide adenine dinucleotide (NAD + ) precursor which is present in foods such as milk and beer. It was reported that NR can prevent obesity, increase longevity, and promote liver regeneration. However, whether NR can prevent ethanol-induced liver injuries is not known. This study aimed to explore the effect of NR on ethanol induced liver injuries and the underlying mechanisms. We fed C57BL/6 J mice with Lieber-DeCarli ethanol liquid diet with or without 400 mg/kg·bw NR for 16 days. Liver injuries and SirT1-PGC-1α-mitochondrial function were analyzed. In in vitro experiments, HepG2 cells (CYP2E1 over-expressing cells) were incubated with ethanol ± 0.5 mmol/L NR. Lipid accumulation and mitochondrial function were compared. SirT1 knockdown in HepG2 cells were further applied to confirm the role of SirT1 in the protection of NR on lipid accumulation. We found that ethanol significantly decreased the expression and activity of hepatic SirT1 and induced abnormal expression of enzymes of lipid metabolism in mice. Both in vivo and in vitro experiments showed that NR activated SirT1 through increasing NAD + levels, decreased oxidative stress, increased deacetylation of PGC-1α and mitochondrial function. In SirT1 knockdown HepG2 cells, NR lost its ability in enhancing mitochondrial function, and its protection against lipid accumulation induced by ethanol. NR can protect against ethanol induced liver injuries via replenishing NAD + , reducing oxidative stress, and activating SirT1-PGC-1α-mitochondrial biosynthesis. Our data indicate that SirT1 plays an important role in the protection of NR against lipid accumulation and mitochondrial dysfunctions induced by ethanol. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  16. Protective effect of boswellic acids versus pioglitazone in a rat model of diet-induced non-alcoholic fatty liver disease: influence on insulin resistance and energy expenditure.

    PubMed

    Zaitone, Sawsan A; Barakat, Bassant M; Bilasy, Shymaa E; Fawzy, Manal S; Abdelaziz, Eman Z; Farag, Noha E

    2015-06-01

    Non-alcoholic fatty liver disease (NAFLD) is closely linked to insulin resistance, oxidative stress, and cytokine imbalance. Boswellic acids, a series of pentacyclic triterpene molecules that are produced by plants in the genus Boswellia, has been traditionally used for the treatment of a variety of diseases. This study aimed at evaluating the protective effect of boswellic acids in a model of diet-induced NAFLD in rats in comparison to the standard insulin sensitizer, pioglitazone. Rats were fed with a high-fat diet (HFD) for 12 weeks to induce NAFLD. Starting from week 5, rats received boswellic acids (125 or 250 mg/kg) or pioglitazone parallel to the HFD. Feeding with HFD induced hepatic steatosis and inflammation in rats. In addition, liver index, insulin resistance index, activities of liver enzymes, and serum lipids deviated from normal. Further, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and cyclooxygenase 2 were elevated; this was associated with an increase in hepatic expression of inducible nitric oxide synthase (iNOS) and formation of 4-hydroxy-2-nonenal (HNE). Rats treated with boswellic acids (125 or 250 mg/kg) or pioglitazone showed improved insulin sensitivity and a reduction in liver index, activities of liver enzymes, serum TNF-α and IL-6 as well as hepatic iNOS expression and HNE formation compared to HFD group. Furthermore, at the cellular level, boswellic acids (250 mg/kg) ameliorated the expression of thermogenesis-related mitochondrial uncoupling protein-1 and carnitine palmitoyl transferase-1 in white adipose tissues. Data from this study indicated that boswellic acids might be a promising therapy in the clinical management of NAFLD if appropriate safety and efficacy data are available.

  17. Protective Effects of Selenium, Vitamin E, and Purple Carrot Anthocyanins on D-Galactose-Induced Oxidative Damage in Blood, Liver, Heart and Kidney Rats.

    PubMed

    Li, Xia; Zhang, Yunlong; Yuan, Yuan; Sun, Yong; Qin, Yan; Deng, Zeyuan; Li, Hongyan

    2016-10-01

    The present study was performed to investigate the protective effects of selenium (Se), vitamin E (Vit E) and anthocyanins from purple carrots and their combination against the oxidative stress induced by D-galactose in rats. A total of 80 male rats were equally divided into 11 groups, one of which acted as control (I) just receiving intraperitoneal injections of physiological saline. The remaining ten groups (II-XI) were intraperitoneally injected with D-galactose at a dose of 400 mg kg(-1) body weight (BW) per day for 42 consecutive days. Rats in groups III-XI were treated with antioxidants via gavage per day as follows: group III: Se-methylselenocysteine (SeMSC), IV: Se as sodium selenite (Na2SeO3), V: Se-enriched yeast (SeY), VI: Vit E as α-tocopherol acetate, VII: anthocyanin from purple carrots (APC), VIII: APC + Vit E, IX: SeMSC + APC+ Vit E, X: Na2SeO3 + APC + Vit E, XI: SeY + Ant + Vit E. The results showed that the rats treated with antioxidants (III-XI) showed significant decreases in the levels of malondialdehyde (MDA) and carbonyl protein (PCO) compared with the D-galactose-treated group (II) in the heart, liver, kidneys, and blood. Moreover, there were significant increases in the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), glutathione (GSH) concentration, and total antioxidant capacity (T-AOC) in the heart, liver, kidneys, and blood of antioxidant-treated animals (III-XI) than those in control group (I). In addition, the combined treatments of two or three antioxidants showed greater antioxidant activities than those of individual treatments, suggesting the synergistic antioxidant effects of Se, Vit E, and APC. In conclusion, all the antioxidants exhibited protective effects against D-galactose-induced oxidative damage in rats, and these antioxidants showed a synergistic effect.

  18. Protective effect of Schisandra chinensis bee pollen extract on liver and kidney injury induced by cisplatin in rats.

    PubMed

    Huang, Haibo; Shen, Zhenhuang; Geng, Qianqian; Wu, Zhenhong; Shi, Peiying; Miao, Xiaoqing

    2017-11-01

    Cisplatin (CP) has been used to cure numerous forms of cancers effectively in clinics, however, it could induce some toxic effects. Bee pollen is a natural compound, produced by honey bees. It is obtained from collected flower pollen and nectar, mixed with bee saliva. Bee pollen produced from Schisandra chinensis plants is described to exert potent antioxidant effects and to be a free radical scavenger. The purpose of this study was to investigate the effects of therapeutic treatment with Schisandra chinensis bee pollen extract (SCBPE) on liver and kidney injury induced by CP. The rats were intragastrically administrated with different doses of SCBPE (400mg/kg/day, 800mg/kg/day, 1200mg/kg/day) and vitamin C (400mg/kg/day, positive control group) for 12days, and the liver and kidney injury models were established by single intraperitoneal injection of CP (8mg/kg) at seventh day. The effect of SCBPE on CP toxicity was evaluated by measuring markers of liver and kidney injury in serum, levels of lipid peroxidation and antioxidants in liver and kidney, observing pathological changes of tissue, and quantified expression of NFκB, IL-1β, IL-6, cytochrome C, caspase3, caspase9, p53 and Bax in liver and kidney. Compared with the model group, the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and the content of blood urea nitrogen (BUN), creatinine (Cr) in serum all decreased in SCBPE high dose group. Meanwhile, the activities of superoxide dismutase (SOD), catalase (CAT) and the content of reduced glutathione (GSH) in liver and kidney increased, and the content of malondialdehyde (MDA) and inducible nitric oxide synthase (iNOS) decreased. In addition, the histopathologic aspects showed that the pathological changes of liver and kidney were found in the model group, and SCBPE group reduced to varying degrees. Moreover, the expression of NFκB, IL-1β, IL-6, cytochrome C, caspase3, caspase9, p53 and Bax in liver and kidney decreased

  19. Supplementation of Nigella sativa fixed and essential oil mediates potassium bromate induced oxidative stress and multiple organ toxicity.

    PubMed

    Sultan, Muhammad Tauseef; Butt, Masood Sadiq; Ahmad, Rabia Shabeer; Pasha, Imran; Ahmad, Atif Nisar; Qayyum, Mir Muhammad Nasir

    2012-01-01

    The plants and their functional ingredients hold potential to cure various maladies and number of plants hold therapeutic potential. The present research was designed study the health promoting potential of black cumin (Nigella sativa) fixed oil (BCFO) and essential oil (BCEO) against oxidative stress with special reference to multiple organ toxicity. For the purpose, thirty rats (Strain: Sprague Dawley) were procured and divided into three groups (10 rats/group). The groups were fed on their respective diets i.e. D1 (control), D2 (BCFO @ 4.0%) and D3 (BCEO @ 0.30%) for a period of 56 days. Mild oxidative stress was induced with the help of potassium bromate injection @ 45 mg/Kg body weight. Furthermore, the levels of cardiac and liver enzymes were assayed. The results indicated that oxidative stress increased the activities of cardiac and liver enzymes. However, supplementation of BCFO and BCEO was effective in reducing the abnormal values of enzymes. Elevated levels of lactate dehydrogenase (LDH), CPK and CPK-MB were reduced from 456 to 231, 176 to 122 and 45 to 36mg/dL, respectively. Similarly, liver enzymes were also reduced. However, the results revealed that BCEO supplementation @ 0.30% is more effectual in ameliorating the multiple organ toxicity in oxidative stressed animal modelling. In the nutshell, it can be assumed that black cumin essential oil is more effective in reducing the extent of potassium bromate induced multiple organ toxicity (cardiac and liver enzymes imbalance) that will ultimately helpful in reducing the extent of myocardial and liver necrosis.

  20. Beneficial Effects of Silymarin After the Discontinuation of CCl4-Induced Liver Fibrosis.

    PubMed

    Clichici, Simona; Olteanu, Diana; Filip, Adriana; Nagy, Andras-Laszlo; Oros, Adrian; Mircea, Petru A

    2016-08-01

    Silymarin (Si) is a herbal product with hepatoprotective potential, well-known for its antioxidant, anti-inflammatory, and immunomodulatory properties. We have recently demonstrated that the usual therapeutic doses of Si are capable of inhibiting the progression of incipient liver fibrosis. We aimed at further investigating the benefits of Si administration upon liver alterations after the hepatotoxin discontinuation, using CCl4 to induce liver injuries on rats. CCl4 administration induces first of all oxidative stress, but other mechanisms, such as inflammation and liver fibrosis are also triggered. Fifty Wistar rats were randomly divided into five groups (n = 10). The control group received sunflower oil twice a week for 8 weeks. Carboxymethyl cellulose group received sunflower oil twice a week, for 8 weeks and CMC daily, for the next 2 weeks. CCl4 group received CCl4 in sunflower oil, by gavage, twice a week, for 8 weeks. CCl4 + Si 50 group received CCl4 twice a week, for 8 weeks, and then 50 mg/body weight (b.w.) Silymarin for the next 2 weeks. CCl4 + Si 200 group was similar to the previous group, but with Si 200 mg/b.w. Ten weeks after the experiment had begun, we assessed inflammation (IL-6, MAPK, NF-κB, pNF-κB), fibrosis (hyaluronic acid), TGF-β1, MMP-9, markers of hepatic stellate cell activation (α-SMA expression), and proliferative capacity (proliferating cell nuclear antigen). Our data showed that Silymarin administered after the toxic liver injury is capable of reducing inflammation and liver fibrosis. The benefits were more important for the higher dose than for the usual therapeutic dose.

  1. Acetaminophen-induced liver injury is attenuated in transgenic fat-1 mice endogenously synthesizing long-chain n-3 fatty acids.

    PubMed

    Feng, Ruibing; Wang, Yang; Liu, Conghui; Yan, Chunyan; Zhang, Hang; Su, Huanxing; Kang, Jing X; Shang, Chang-Zhen; Wan, Jian-Bo

    2018-04-18

    Acetaminophen (APAP) overdose-induced hepatotoxicity is the most commonly cause of drug-induced liver failure characterized by oxidative stress, mitochondrial dysfunction, and cell damage. Therapeutic efficacy of omega-3 polyunsaturated fatty acids (n-3 PUFA) in several models of liver disease is well documented. However, the impacts of n-3 PUFA on APAP hepatotoxicity are not adequately addressed. In this study, the fat-1 transgenic mice that synthesize endogenous n-3 PUFA and wild type (WT) littermates were injected intraperitoneally with APAP at the dose of 400 mg/kg to induce liver injury, and euthanized at 0 h, 2 h, 4 h and 6 h post APAP injection for sampling. APAP overdose caused severe liver injury in WT mice as indicated by serum parameters, histopathological changes and hepatocyte apoptosis, which were remarkably ameliorated in fat-1 mice. These protective effects of n-3 PUFA were associated with regulation of the prolonged JNK activation via inhibition of apoptosis signal-regulating kinase 1 (ASK1)/mitogen-activated protein kinase kinase 4 (MKK4) pathway. Additionally, the augment of endogenous n-3 PUFA reduced nuclear factor kappa B (NF-κB) - mediated inflammation response induced by APAP treatment in the liver. These findings indicate that n-3 PUFA has potent protective effects against APAP-induced acute liver injury, suggesting that n-3 dietary supplement with n-3 PUFA may be a potential therapeutic strategy for the treatment of hepatotoxicity induced by APAP overdose. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. A Bioenergetics Systems Evaluation of Ketogenic Diet Liver Effects

    PubMed Central

    Hutfles, Lewis J.; Wilkins, Heather M.; Koppel, Scott J.; Weidling, Ian W.; Selfridge, J. Eva; Tan, Eephie; Thyfault, John P.; Slawson, Chad; Fenton, Aron W.; Zhu, Hao; Swerdlow, Russell H.

    2018-01-01

    Ketogenic diets induce hepatocyte fatty acid oxidation and ketone body production. To further evaluate how ketogenic diets affect hepatocyte bioenergetic infrastructure, we analyzed livers from C57Bl/6J male mice maintained for one month on a ketogenic or standard chow diet. Compared to the standard diet, the ketogenic diet increased cytosolic and mitochondrial protein acetylation and also altered protein succinylation patterns. SIRT3 protein decreased while SIRT5 protein increased, and gluconeogenesis, oxidative phosphorylation, and mitochondrial biogenesis pathway proteins were variably and likely strategically altered. The pattern of changes observed can be used to inform a broader systems overview of how ketogenic diets affect liver bioenergetics. PMID:28514599

  3. A bioenergetics systems evaluation of ketogenic diet liver effects.

    PubMed

    Hutfles, Lewis J; Wilkins, Heather M; Koppel, Scott J; Weidling, Ian W; Selfridge, J Eva; Tan, Eephie; Thyfault, John P; Slawson, Chad; Fenton, Aron W; Zhu, Hao; Swerdlow, Russell H

    2017-09-01

    Ketogenic diets induce hepatocyte fatty acid oxidation and ketone body production. To further evaluate how ketogenic diets affect hepatocyte bioenergetic infrastructure, we analyzed livers from C57Bl/6J male mice maintained for 1 month on a ketogenic or standard chow diet. Compared with the standard diet, the ketogenic diet increased cytosolic and mitochondrial protein acetylation and also altered protein succinylation patterns. SIRT3 protein decreased while SIRT5 protein increased, and gluconeogenesis, oxidative phosphorylation, and mitochondrial biogenesis pathway proteins were variably and likely strategically altered. The pattern of changes observed can be used to inform a broader systems overview of how ketogenic diets affect liver bioenergetics.

  4. Protective effects of Sesamum indicum extract against oxidative stress induced by vanadium on isolated rat hepatocytes.

    PubMed

    Hosseini, Mir-Jamal; Shahraki, Jafar; Tafreshian, Saman; Salimi, Ahmad; Kamalinejad, Mohammad; Pourahmad, Jalal

    2016-08-01

    Vanadium toxicity is a challenging problem to human and animal health with no entirely understanding cytotoxic mechanisms. Previous studies in vanadium toxicity showed involvement of oxidative stress in isolated liver hepatocytes and mitochondria via increasing of ROS formation, release of cytochrome c and ATP depletion after incubation with different concentrations (25-200 µM). Therefore, we aimed to investigate the protective effects of Sesamum indicum seed extract (100-300 μg/mL) against oxidative stress induced by vanadium on isolated rat hepatocytes. Our results showed that quite similar to Alpha-tocopherol (100 µM), different concentrations of extract (100-300 μg/mL) protected the isolated hepatocyte against all oxidative stress/cytotoxicity markers induced by vanadium in including cell lysis, ROS generation, mitochondrial membrane potential decrease and lysosomal membrane damage. Besides, vanadium induced mitochondrial/lysosomal toxic interaction and vanadium reductive activation mediated by glutathione in vanadium toxicity was significantly (P < 0.05) ameliorated by Sesamum indicum extracts. These findings suggested a hepato-protective role for extracts against liver injury resulted from vanadium toxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 979-985, 2016. © 2015 Wiley Periodicals, Inc.

  5. Cobalt iron oxide nanoparticles induce cytotoxicity and regulate the apoptotic genes through ROS in human liver cells (HepG2).

    PubMed

    Ahamed, Maqusood; Akhtar, Mohd Javed; Khan, M A Majeed; Alhadlaq, Hisham A; Alshamsan, Aws

    2016-12-01

    Cobalt iron oxide (CoFe 2 O 4 ) nanoparticles (CIO NPs) have been one of the most widely explored magnetic NPs because of their excellent chemical stability, mechanical hardness and heat generating potential. However, there is limited information concerning the interaction of CIO NPs with biological systems. In this study, we investigated the reactive oxygen species (ROS) mediated cytotoxicity and apoptotic response of CIO NPs in human liver cells (HepG2). Diameter of crystalline CIO NPs was found to be 23nm with a band gap of 1.97eV. CIO NPs induced cell viability reduction and membrane damage, and degree of induction was dose- and time-dependent. CIO NPs were also found to induce oxidative stress revealed by induction of ROS, depletion of glutathione and lower activity of superoxide dismutase enzyme. Real-time PCR data has shown that mRNA level of tumor suppressor gene p53 and apoptotic genes (bax, CASP3 and CASP9) were higher, while the expression level of anti-apoptotic gene bcl-2 was lower in cells following exposure to CIO NPs. Activity of caspase-3 and caspase-9 enzymes was also higher in CIO NPs exposed cells. Furthermore, co-exposure of N-acetyl-cysteine (ROS scavenger) efficiently abrogated the modulation of apoptotic genes along with the prevention of cytotoxicity caused by CIO NPs. Overall, we observed that CIO NPs induced cytotoxicity and apoptosis in HepG2 cells through ROS via p53 pathway. This study suggests that toxicity mechanisms of CIO NPs should be further investigated in animal models. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Antioxidant and hepatoprotective activity of vitex honey against paracetamol induced liver damage in mice.

    PubMed

    Wang, Yuan; Li, Dan; Cheng, Ni; Gao, Hui; Xue, Xiaofeng; Cao, Wei; Sun, Liping

    2015-07-01

    Fourteen vitex honeys from China were investigated to evaluate its antioxidant and hepatoprotective activity against paracetamol-induced liver damage. All honey samples exhibited high total phenolic content (344-520 mg GAE per kg), total flavonoid content (19-31 mg Rutin per kg), and strong antioxidant activity in DPPH radical scavenging, ferric reducing antioxidant power and Ferrous ion-chelating ability. Nine phenolic acids were detected in vitex honey samples, in which caffeic acid was the main compound. Honey from Heibei Zanhuang (S2) ranked the highest antioxidant activity was orally administered to mice (5 g kg(-1), 20 g kg(-1)) for 70 days. In high-dose (20 g kg(-1)), vitex honey pretreatment resulting in significant increase in serum oxygen radical absorbance capacity (15.07%) and decrease in Cu(2+)-mediate lipoprotein oxidation (80.07%), and suppression in alanine aminotransferase (75.79%) and aspartate aminotransferase (74.52%), enhancement in the superoxide dismutase and glutathione peroxidase activities and reduction in malondialdehyde (36.15%) and 8-hydroxy-2'-deoxyguanosine (19.6%) formation compared with paracetamol-intoxicated group. The results demonstrated the hepatoprotection of vitex honey against paracetamol-induced liver damage might attribute to its antioxidant and/or perhaps pro-oxidative property.

  7. Ethylenediaminetetraacetic acid induces antioxidant and anti-inflammatory activities in experimental liver fibrosis.

    PubMed

    González-Cuevas, J; Navarro-Partida, J; Marquez-Aguirre, A L; Bueno-Topete, M R; Beas-Zarate, C; Armendáriz-Borunda, J

    2011-01-01

    Experimental liver fibrosis induced by carbon tetrachloride (CCl(4)) is associated with oxidative stress, lipid peroxidation, and inflammation. This work was focused on elucidating the anti-inflammatory and antioxidant effects of ethylenediaminetetraacetic acid (EDTA) in this model of hepatotoxicity. Wistar male rats were treated with CCl(4) and EDTA (60, 120, or 240 mg/kg). Morphometric analyses were carried out in Masson's stained liver sections to determine fibrosis index. Coagulation tests prothrombin time (PT) and partial thromboplastin time (PTT) were also determined. Gene expression for transforming growth factor beta (TGF-beta1), alpha1(I) procollagen gene (alpha1 Col I), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and superoxide dismutase (SOD) was monitored by real-time PCR. Antioxidant effect of EDTA was measured by its effects on lipid peroxidation; biological activity of ceruloplasmin (Cp), SOD, and catalase (Cat) were analyzed by zymography assays. Animals with CCl(4)-hepatic injury that received EDTA showed a decrement in fibrosis (20%) and lipid peroxidation (22%). The mRNA expression for TNF-alpha (55%), TGF-beta1 (50%), IL-6 (52%), and alpha1 Col I (60%) was also decreased. This group of animals showed increased Cp (62%) and SOD (25%) biological activities. Coagulation blood tests, Cat activity, and gene expression for SOD were not modified by EDTA treatment. This study demonstrates that EDTA treatment induces the activity of antioxidant enzymes, decreases lipid peroxidation, hepatic inflammation, and fibrosis in experimental liver fibrosis induced by CCl(4).

  8. Aloe vera attenuated liver injury in mice with acetaminophen-induced hepatitis

    PubMed Central

    2014-01-01

    Background An overdose of the acetaminophen causes liver injury. This study aims to examine the anti-oxidative, anti-inflammatory effects of Aloe vera in mice with acetaminophen induced hepatitis. Methods Male mice were randomly divided into three groups (n = 8 each). Control group were given orally distilled water (DW). APAP group were given orally N-acetyl-P-aminophenol (APAP) 400 mg/kg suspended in DW. Aloe vera-treated group were given orally APAP and Aloe vera (150 mg/kg) suspended in DW. Twenty-four hours later, the liver was removed to determine hepatic malondialdehyde (MDA), hepatic glutathione (GSH), the number of interleukin (IL)-12 and IL-18 positive stained cells (%) by immunohistochemistry method, and histopathological examination. Then, the serum was collected to determine transaminase (ALT). Results In APAP group, ALT, hepatic MDA and the number of IL-12 and IL-18 positive stained cells were significantly increased when compared to control group (1210.50 ± 533.86 vs 85.28 ± 28.27 U/L, 3.60 ± 1.50 vs 1.38 ± 0.15 nmol/mg protein, 12.18 ± 1.10 vs 1.84 ± 1.29%, and 13.26 ± 0.90 vs 2.54 ± 1.29%, P = 0.000, respectively), whereas hepatic GSH was significantly decreased when compared to control group (5.98 ± 0.30 vs 11.65 ± 0.43 nmol/mg protein, P = 0.000). The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive stained cells, and hepatic GSH in Aloe vera-treated group were improved as compared with APAP group (606.38 ± 495.45 vs 1210.50 ± 533.86 U/L, P = 0.024; 1.49 ± 0.64 vs 3.60 ± 1.50 nmol/mg protein, P = 0.001; 5.56 ± 1.25 vs 12.18 ± 1.10%, P = 0.000; 6.23 ± 0.94 vs 13.26 ± 0.90%, P = 0.000; and 10.02 ± 0.20 vs 5.98 ± 0.30 nmol/mg protein, P = 0.000, respectively). Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in Aloe vera-treated group, the liver architecture was improved histopathology. Conclusions APAP overdose can cause liver injury. Our result indicate

  9. Acute Liver Injury Induces Nucleocytoplasmic Redistribution of Hepatic Methionine Metabolism Enzymes

    PubMed Central

    Delgado, Miguel; Garrido, Francisco; Pérez-Miguelsanz, Juliana; Pacheco, María; Partearroyo, Teresa; Pérez-Sala, Dolores

    2014-01-01

    Abstract Aims: The discovery of methionine metabolism enzymes in the cell nucleus, together with their association with key nuclear processes, suggested a putative relationship between alterations in their subcellular distribution and disease. Results: Using the rat model of d-galactosamine intoxication, severe changes in hepatic steady-state mRNA levels were found; the largest decreases corresponded to enzymes exhibiting the highest expression in normal tissue. Cytoplasmic protein levels, activities, and metabolite concentrations suffered more moderate changes following a similar trend. Interestingly, galactosamine treatment induced hepatic nuclear accumulation of methionine adenosyltransferase (MAT) α1 and S-adenosylhomocysteine hydrolase tetramers, their active assemblies. In fact, galactosamine-treated livers showed enhanced nuclear MAT activity. Acetaminophen (APAP) intoxication mimicked most galactosamine effects on hepatic MATα1, including accumulation of nuclear tetramers. H35 cells that overexpress tagged-MATα1 reproduced the subcellular distribution observed in liver, and the changes induced by galactosamine and APAP that were also observed upon glutathione depletion by buthionine sulfoximine. The H35 nuclear accumulation of tagged-MATα1 induced by these agents correlated with decreased glutathione reduced form/glutathione oxidized form ratios and was prevented by N-acetylcysteine (NAC) and glutathione ethyl ester. However, the changes in epigenetic modifications associated with tagged-MATα1 nuclear accumulation were only prevented by NAC in galactosamine-treated cells. Innovation: Cytoplasmic and nuclear changes in proteins that regulate the methylation index follow opposite trends in acute liver injury, their nuclear accumulation showing potential as disease marker. Conclusion: Altogether these results demonstrate galactosamine- and APAP-induced nuclear accumulation of methionine metabolism enzymes as active oligomers and unveil the implication of

  10. Selenium ameliorates isotretinoin-induced liver injury and dyslipidemia via antioxidant effect in rats.

    PubMed

    Saied, Nashwa Mostafa; Hamza, Alaaeldin Ahmed

    2014-09-01

    Isotretinoin (Iso) is a widely used retinoid for the treatment of dermatologic conditions. Although it has broad side effects, there is no well-designed study about preventive effects against its hepatic toxicity. This study was undertaken to evaluate the protective effect of selenium (Se) against Iso-induced hepatotoxicity in Wistar rats. Animals were divided into four groups. The first group served as control. The second, third and fourth groups received Se, Iso and Se & Iso, respectively, for 28 days. Se was administered daily orally at a dose of 50 µg / 100 g body weight. Iso was given daily orally at a dose of 0.75 mg/ 100 g /day in olive oil. Iso caused significant increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, cholesterol, triglycerides, and high-density lipids content. Animals also showed significant rise in thiobarbituric acid reacting substance and nitric oxide content with concomitant decrease in reduced glutathione content and the antioxidant enzyme activities of superoxide dismutase and catalase in liver tissue after Iso exposure. Se administration produced a significant protection against the hepatotoxic effects of Iso and markedly alleviated alterations in these parameters. The results obtained herein clearly indicate that Iso causes induction of oxidative stress and the co-administration of Iso and Se provides protection against Iso-induced liver injury.

  11. TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner

    PubMed Central

    Badmann, A; Langsch, S; Keogh, A; Brunner, T; Kaufmann, T; Corazza, N

    2012-01-01

    Paracetamol (acetaminophen, APAP) is a universally used analgesic and antipyretic agent. Considered safe at therapeutic doses, overdoses cause acute liver damage characterized by centrilobular hepatic necrosis. One of the major clinical problems of paracetamol-induced liver disease is the development of hemorrhagic alterations. Although hepatocytes represent the main target of the cytotoxic effect of paracetamol overdose, perturbations within the endothelium involving morphological changes of liver sinusoidal endothelial cells (LSECs) have also been described in paracetamol-induced liver disease. Recently, we have shown that paracetamol-induced liver damage is synergistically enhanced by the TRAIL signaling pathway. As LSECs are constantly exposed to activated immune cells expressing death ligands, including TRAIL, we investigated the effect of TRAIL on paracetamol-induced LSEC death. We here demonstrate for the first time that TRAIL strongly enhances paracetamol-mediated LSEC death with typical features of apoptosis. Inhibition of caspases using specific inhibitors resulted in a strong reduction of cell death. TRAIL appears to enhance paracetamol-induced LSEC death via the activation of the pro-apoptotic BH3-only proteins Bid and Bim, which initiate the mitochondrial apoptotic pathway. Taken together this study shows that the liver endothelial layer, mainly LSECs, represent a direct target of the cytotoxic effect of paracetamol and that activation of TRAIL receptor synergistically enhances paracetamol-induced LSEC death via the mitochondrial apoptotic pathway. TRAIL-mediated acceleration of paracetamol-induced cell death may thus contribute to the pathogenesis of paracetamol-induced liver damage. PMID:23254290

  12. Nitroaryl-1,4-dihydropyridines as antioxidants against rat liver microsomes oxidation induced by iron/ascorbate, nitrofurantoin and naphthalene.

    PubMed

    Letelier, María Eugenia; Entrala, Paz; López-Alarcón, Camilo; González-Lira, Víctor; Molina-Berríos, Alfredo; Cortés-Troncoso, Juan; Jara-Sandoval, José; Santander, Paola; Núñez-Vergara, Luis

    2007-12-01

    1,4-Dihydropyridines (DHPs) used in the treatment of cardiovascular diseases, are calcium channel antagonists and also antioxidant agents. These drugs are metabolized through cytochrome P(450) oxidative system, majority localized in the hepatic endoplasmic reticulum. Several lipophilic drugs generate oxidative stress to be metabolized by this cellular system. Thus, DHP antioxidant properties may prevent the oxidative stress associated with hepatic biotransformation of drugs. In this work, we tested the antioxidant capacity of several synthetic nitro-phenyl-DHPs. These compounds (I-IV) inhibited the microsomal lipid peroxidation, UDPGT oxidative activation and microsomal thiols oxidation; all phenomena induced by Fe(3+)/ascorbate, a generator system of oxygen free radicals. As the same manner, these compounds inhibited the oxygen consumption induced by Cu(2+)/ascorbate in the absence of microsomes. Furthermore, compound III (2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridin-3,5-ethyl-dicarboxylate) and compound V (N-ethyl-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridin-3,5-methyl-dicarboxylate) inhibited the microsomal lipid peroxidation induced by Nitrofurantoin and naphthalene in the presence of NADPH. Oxidative stress induced on endoplasmic reticulum may alter the biotransformation of drugs, so, modifying their plasmatic concentrations and therapeutic effects. When drugs which are activated by biotransformation are administered together with antioxidant drugs, such as DHPs, oxidative stress induced in situ may be prevented.

  13. Ameliorating role of rutin on oxidative stress induced by iron overload in hepatic tissue of rats.

    PubMed

    Aziza, Samy Ali Hussein; Azab, Mohammed El-Said; El-Shall, Soheir Kamal

    2014-08-01

    Iron is an essential element that participates in several metabolic activities of cells; however, excess iron is a major cause of iron-induced oxidative stress and several human diseases. Natural flavonoids, as rutin, are well-known antioxidants and could be efficient protective agents. Therefore, the present study was undertaken to evaluate the protective influence of rutin supplementation to improve rat antioxidant systems against IOL-induced hepatic oxidative stress. Sixty male albino rats were randomly divided to three equal groups. The first group, the control, the second group, iron overload group, the third group was used as iron overload+rutin group. Rats received six doses of ferric hydroxide polymaltose (100 mg kg(-1) b.wt.) as one dose every two days, by intraperitoneal injections (IP) and administrated rutin (50 mg kg(-1) b.wt.) as one daily oral dose until the sacrificed day. Blood samples for serum separation and liver tissue specimens were collected three times, after three, four and five weeks from the onset of the experiment. Serum iron profiles total iron, Total Iron Binding Capacity (TIBC), Unsaturated Iron Binding Capacity (UIBC), transferrin (Tf) and Transferrin Saturation% (TS%)}, ferritin, albumin, total Protein, total cholesterol, triacylglycerols levels and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were determined. Moreover, total iron in the liver, L-malondialdehyde (L-MDA), glutathione (GSH), Nitric Oxide (NO) and Total Nucleic Acid (TNA) levels and glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) activities were also determined. The obtained results revealed that, iron overload (IOL) resulted in significant increase in serum iron, TIBC, Tf, TS% and ferritin levels and AST and ALT activities and also increased liver iron, L-MDA and NO levels. Meanwhile, it decreased serum UIBC, total cholesterol, triacylglycerols, albumin, total protein and liver GSH, TNA levels and Gpx, CAT

  14. Mitochondria-targeted ubiquinone (MitoQ) enhances acetaldehyde clearance by reversing alcohol-induced posttranslational modification of aldehyde dehydrogenase 2: A molecular mechanism of protection against alcoholic liver disease.

    PubMed

    Hao, Liuyi; Sun, Qian; Zhong, Wei; Zhang, Wenliang; Sun, Xinguo; Zhou, Zhanxiang

    2018-04-01

    Alcohol metabolism in the liver generates highly toxic acetaldehyde. Breakdown of acetaldehyde by aldehyde dehydrogenase 2 (ALDH2) in the mitochondria consumes NAD + and generates reactive oxygen/nitrogen species, which represents a fundamental mechanism in the pathogenesis of alcoholic liver disease (ALD). A mitochondria-targeted lipophilic ubiquinone (MitoQ) has been shown to confer greater protection against oxidative damage in the mitochondria compared to untargeted antioxidants. The present study aimed to investigate if MitoQ could preserve mitochondrial ALDH2 activity and speed up acetaldehyde clearance, thereby protects against ALD. Male C57BL/6J mice were exposed to alcohol for 8 weeks with MitoQ supplementation (5mg/kg/d) for the last 4 weeks. MitoQ ameliorated alcohol-induced oxidative/nitrosative stress and glutathione deficiency. It also reversed alcohol-reduced hepatic ALDH activity and accelerated acetaldehyde clearance through modulating ALDH2 cysteine S-nitrosylation, tyrosine nitration and 4-hydroxynonenol adducts formation. MitoQ ameliorated nitric oxide (NO) donor-mediated ADLH2 S-nitrosylation and nitration in Hepa-1c1c7 cells under glutathion depletion condition. In addition, alcohol-increased circulating acetaldehyde levels were accompanied by reduced intestinal ALDH activity and impaired intestinal barrier. In accordance, MitoQ reversed alcohol-increased plasma endotoxin levels and hepatic toll-like receptor 4 (TLR4)-NF-κB signaling along with subsequent inhibition of inflammatory cell infiltration. MitoQ also reversed alcohol-induced hepatic lipid accumulation through enhancing fatty acid β-oxidation. Alcohol-induced ER stress and apoptotic cell death signaling were reversed by MitoQ. This study demonstrated that speeding up acetaldehyde clearance by preserving ALDH2 activity critically mediates the beneficial effect of MitoQ on alcohol-induced pathogenesis at the gut-liver axis. Copyright © 2017 The Authors. Published by Elsevier B

  15. Protective effects of cassia seed ethanol extract against carbon tetrachloride-induced liver injury in mice.

    PubMed

    Xie, Qing; Guo, Fang-Fang; Zhou, Wen

    2012-01-01

    Oxidative stress has been recognized as a critical pathogenetic mechanism for the initiation and the progression of hepatic injury in a variety of liver disorders. Antioxidants, including many natural compounds or extracts, have been used to cope with liver disorders. The present study was designed to investigate the hepatoprotective effects of cassia seed ethanol extract (CSE) in carbon tetrachloride (CCl(4))-induced liver injury in mice. The animals were pre-treated with different doses of CSE (0.5, 1.0, 2.0 g/kg body weight) or distilled water for 5 days, then were injected intraperitoneally with CCl(4) (0.1% in corn oil, v/v, 20 ml/kg body weight), and sacrificed at 16 hours after CCl(4) exposure. The serum aminotransferase activities, histopathological changes, hepatic and mitochondrial antioxidant indexes, and cytochrome P450 2E1 (CYP2E1) activities were examined. Consistent with previous studies, acute CCl(4) administration caused great lesion to the liver, shown by the elevation of the serum aminotransferase activities, mitochondria membrane permeability transition (MPT), and the ballooning degeneration of hepatocytes. However, these adverse effects were all significantly inhibited by CSE pretreatment. CCl(4)-induced decrease of the CYP2E1 activity was dose-dependently inhibited by CSE pretreatment. Furthermore, CSE dramatically decreased the hepatic and mitochondrial malondialdehyde (MDA) levels, increased the hepatic and mitochondrial glutathione (GSH) levels, and restored the activities of superoxide dismutase (SOD), glutathione reductase (GR), and glutathione S-transferase (GST). These results suggested that CSE could protect mice against CCl(4)-induced liver injury via enhancement of the antioxidant capacity.

  16. Involvement of oxidative stress in subacute toxicity induced by fumonisin B1 in broiler chicks.

    PubMed

    Poersch, A B; Trombetta, F; Braga, A C M; Boeira, S P; Oliveira, M S; Dilkin, P; Mallmann, C A; Fighera, M R; Royes, L F F; Oliveira, M S; Furian, A F

    2014-11-07

    Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium spp. It has been reported to be a potential cause of liver cancer in rats and esophageal cancer in humans. The underlying mechanisms of FB1 toxicity are thought to be related to the inhibition of ceramide synthase, causing an accumulation of sphingosine (SO) and sphinganine (SA), which in turn may cause tissue functional impairment and the development of oxidative stress. Therefore, in this study, we investigate the effects of an FB1-contaminated diet on markers of oxidative stress in chick liver. A total of 24 male broiler chicks (Cobb 500) were fed a standard control diet or a diet contaminated with FB1 (100mg/kg) for 21 days, starting on postnatal day one. The feed and animals were weighed on days 0, 7, 14 and 21 to estimate the feed conversion ratio, and at 21 days, the liver weight and liver relative weight were determined. At the end of the experiment, samples of blood and liver were collected. The blood was used to quantify the SA/SO ratio, and the liver was used to determine the activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST); ascorbic acid levels (VitC), non-protein thiol (NPSH) levels and TBARS content were also determined. The FB1 diet increased the liver weight, liver relative weight, feed conversion and SA/SO ratio. Furthermore, hepatic TBARS levels, Vit C content and CAT activity were also increased. Conversely, the activities of SOD, GST and NPSH levels, in the liver were not altered by the mycotoxin-contaminated diet. In summary, we showed that subacute exposure of broiler chicks to FB1 induced liver oxidative stress concomitantly with SA/SO accumulation. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Agaricus blazei Murill extract abrogates CCl4-induced liver injury in rats.

    PubMed

    Wu, Ming-Fang; Hsu, Yu-Ming; Tang, Ming-Chu; Chen, Hsueh-Chin; Chung, Jing-Gung; Lu, Hsu-Feng; Lin, Jing-Pin; Tang, Nou-Ying; Yeh, Chun; Yeh, Ming-Yang

    2011-01-01

    Agaricus blazei Murill (ABM) is enriched with polysaccharides, lipids, vitamins, fibers and minerals. Many studies have shown that ABM possesses immune-enhancing and anti-tumor effects. However, little is known about its protective effects on liver function. We employed carbon tetrachloride (CCl(4)) to induce hepatic fibrosis in a rat model to examine the protective effects of ABM on the liver in this study. The experiments included non-treatment control, CCl(4)-only control, and treatment with 200 mg and 2,000 mg of ABM extracts (per kilogram rat weight). All groups other than the non-treatment control were treated with intraperitoneal injections of CCl(4) twice a week. Experimental and control rats were tube-fed with experimental ABM extracts or double-distilled water, respectively, on the remaining four days each week. The whole experimental protocol lasted 8 weeks; blood and liver samples were collected for biochemical and tissue histochemical analysis. Plasma alanine aminotransferase and aspartate aminotransferase, and the activities of the anti-oxidative enzymes glutathione peroxidase, superoxide dismutase and catalase in the liver were measured. We found that high-dose ABM treatment reduced hepatic necrosis and fibrosis caused by CCl(4) in comparison with the CCl(4) control group. ALT and AST activities in the sera collected from ABM-treated rats were lower than those in the CCl(4) control rats. These results suggested that ABM extract was capable of either enhancing liver recovering from CCl(4) damage or attenuating CCl(4) toxicity. Results of anti-oxidative enzyme activity analysis showed no apparent differences among ABM-treated groups and CCl(4) control groups, indicating that removal of free radicals does not explain the protective/recovery effects observed in this study.

  18. Protective effects of dietary avocado oil on impaired electron transport chain function and exacerbated oxidative stress in liver mitochondria from diabetic rats.

    PubMed

    Ortiz-Avila, Omar; Gallegos-Corona, Marco Alonso; Sánchez-Briones, Luis Alberto; Calderón-Cortés, Elizabeth; Montoya-Pérez, Rocío; Rodriguez-Orozco, Alain R; Campos-García, Jesús; Saavedra-Molina, Alfredo; Mejía-Zepeda, Ricardo; Cortés-Rojo, Christian

    2015-08-01

    Electron transport chain (ETC) dysfunction, excessive ROS generation and lipid peroxidation are hallmarks of mitochondrial injury in the diabetic liver, with these alterations also playing a role in the development of non-alcoholic fatty liver disease (NAFLD). Enhanced mitochondrial sensitivity to lipid peroxidation during diabetes has been also associated to augmented content of C22:6 in membrane phospholipids. Thus, we aimed to test whether avocado oil, a rich source of C18:1 and antioxidants, attenuates the deleterious effects of diabetes on oxidative status of liver mitochondria by decreasing unsaturation of acyl chains of membrane lipids and/or by improving ETC functionality and decreasing ROS generation. Streptozocin-induced diabetes elicited a noticeable increase in the content of C22:6, leading to augmented mitochondrial peroxidizability index and higher levels of lipid peroxidation. Mitochondrial respiration and complex I activity were impaired in diabetic rats with a concomitant increase in ROS generation using a complex I substrate. This was associated to a more oxidized state of glutathione, All these alterations were prevented by avocado oil except by the changes in mitochondrial fatty acid composition. Avocado oil did not prevented hyperglycemia and polyphagia although did normalized hyperlipidemia. Neither diabetes nor avocado oil induced steatosis. These results suggest that avocado oil improves mitochondrial ETC function by attenuating the deleterious effects of oxidative stress in the liver of diabetic rats independently of a hypoglycemic effect or by modifying the fatty acid composition of mitochondrial membranes. These findings might have also significant implications in the progression of NAFLD in experimental models of steatosis.

  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. 1H NMR-based metabolomics study of liver damage induced by ginkgolic acid (15:1) in mice.

    PubMed

    Jiang, Lei; Si, Zhi-Hong; Li, Ming-Hui; Zhao, He; Fu, Yong-Hong; Xing, Yue-Xiao; Hong, Wei; Ruan, Ling-Yu; Li, Pu-Min; Wang, Jun-Song

    2017-03-20

    Ginkgolic acid (15:1) is a major toxic component in extracts obtained from Ginkgo biloba (EGb) that has allergic and genotoxic effects. This study is the first to explore the hepatotoxicity of ginkgolic acid (15:1) using a NMR (nuclear magnetic resonance)-based metabolomics approach in combination with biochemistry assays. Mice were orally administered two doses of ginkgolic acid (15:1), and mouse livers and serum were then collected for NMR recordings and biochemical assays. The levels of activity of alanine aminotransferase (ALT) and glutamic aspartate transaminase (AST) observed in the ginkgolic acid (15:1)-treated mice suggested that it had induced severe liver damage. An orthogonal signal correction partial least-squares discriminant analysis (OSC-PLSDA) performed to determine the metabolomic profile of mouse liver tissues indicated that many metabolic disturbances, especially oxidative stress and purine metabolism, were induced by ginkgolic acid (15:1). A correlation network analysis combined with information related to structural similarities further confirmed that purine metabolism was disturbed by ginkgolic acid (15:1). This mechanism might represent the link between the antitumour activity and the liver injury-inducing effect of ginkgolic acid (15:1). A SUS (Shared and Unique Structure) plot suggested that a two-dose treatment of ginkgolic acid (15:1) had generally the same effect on metabolic variations but that its effects were dose-dependent, revealing some of the common features of ginkgolic acid (15:1) dosing. This integrated metabolomics approach helped us to characterise ginkgolic acid (15:1)-induced liver damage in mice. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Active form of vitamin D ameliorates non-alcoholic fatty liver disease by alleviating oxidative stress in a high-fat diet rat model.

    PubMed

    Zhu, Chong-Gui; Liu, Ya-Xin; Wang, Hao; Wang, Bao-Ping; Qu, Hui-Qi; Wang, Bao-Li; Zhu, Mei

    2017-07-28

    The purpose of this study was to determine whether treatment using the active form of vitamin D (1,25(OH) 2 D 3 ) could protect against high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in rats and ameliorate oxidative stress. Male Sprague-Dawley rats were divided into three groups and treated with standard chow, HFD, or HFD plus intraperitoneal injection of 1,25(OH) 2 D 3 (5 μg/kg body weight, twice per week), respectively, for 16 weeks. Serum lipid profiles, hepatic function, intrahepatic lipid, and calcium levels were determined. Hepatic histology was examined using hematoxylin/eosin, Masson's trichrome, and Oil Red O staining. Oxidative stress was assessed by measuring hepatic malondialdehyde (MDA) and F2α-isoprostane content. Expression of nuclear factor-erythroid-2-related factor 2 (Nrf2) and downstream target genes was analyzed using quantitative RT-PCR. 1,25(OH) 2 D 3 treatment improved the serum lipid profile, reduced intrahepatic lipid levels, and attenuated hepatic steatosis and inflammation in HFD rats. Furthermore, MDA and F2α-isoprostane levels in liver tissue were reduced by 1,25(OH) 2 D 3 administration. Although 1,25(OH) 2 D 3 did not regulate the expression of Nrf2 mRNA, it did induce Nrf2 nuclear translocation. The expression of Nrf2 target genes, including Gclc, Nqo1, Sod2, and Cat, was up-regulated by 1,25(OH) 2 D 3 . We conclude that 1,25(OH) 2 D 3 protects against HFD-induced NAFLD by attenuating oxidative stress, inducing NRF2 nuclear translocation, and up-regulating the expression of genes encoding antioxidant enzymes.

  2. Ascorbate and low concentrations of FeSO4 induce Ca2+-dependent pore in rat liver mitochondria.

    PubMed

    Brailovskaya, I V; Starkov, A A; Mokhova, E N

    2001-08-01

    Oxidative stress is one of the most frequent causes of tissue and cell injury in various pathologies. The molecular mechanism of mitochondrial damage under conditions of oxidative stress induced in vitro with low concentrations of FeSO4 and ascorbate (vitamin C) was studied. FeSO4 (1-4 microM) added to rat liver mitochondria that were incubated in the presence of 2.3 mM ascorbate induced (with a certain delay) a decrease in membrane potential and high-amplitude swelling. It also significantly decreased the ability of mitochondria to accumulate exogenous Ca2+. All the effects of FeSO4 + ascorbate were essentially prevented by cyclosporin A, a specific inhibitor of the mitochondrial Ca2+-dependent pore (also known as the mitochondrial permeability transition). EGTA restored the membrane potential of mitochondria de-energized with FeSO4 + ascorbate. We hypothesize that oxidative stress induced in vitro with FeSO4 and millimolar concentrations of ascorbate damages mitochondria by inducing the cyclosporin A-sensitive Ca2+-dependent pore in the inner mitochondrial membrane.

  3. 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

  4. Antioxidant Effect of CoQ(10) on N-nitrosodiethylamine-induced Oxidative Stress in Mice.

    PubMed

    Song, Ho Sun; Kim, Hee Rae; Park, Tae Wook; Cho, Bong Jae; Choi, Mi Young; Kim, Chang Jong; Sohn, Uy Dong; Sim, Sang Soo

    2009-08-01

    The antioxidant effect of CoQ(10) on N-nitrosodiethylamine (NDEA)-induced oxidative stress was investigated in mice. Food intake and body weight were similar in both CoQ(10) and control groups during the 3-week experimental period. NDEA significantly increased the activities of typical marker enzymes of liver function (AST, ALT and ALP) both in control and CoQ(10) groups. However, the increase of plasma aminotransferase activity was significantly reduced in the CoQ(10) group. Lipid peroxidation in various tissues, such as heart, lung, liver, kidney, spleen and plasma, was significantly increased by NDEA, but this increase was significantly reduced by 100 mg/kg of CoQ(10). Superoxide dismutase activity increased significantly upon NDEA-induced oxidative stress in both the control and CoQ(10) groups with the effect being less in the CoQ(10) group. Catalase activity decreased significantly in both the control and CoQ(10) groups treated with NDEA, again with the effect being less in the CoQ(10) group. The lesser effect on superoxide dismutase and catalase in the NDEA-treated CoQ(10) group is indicative of the protective effect CoQ(10). Thus, CoQ(10) can offer useful protection against NDEA-induced oxidative stress.

  5. An Animal Model of Abacavir-Induced HLA-Mediated Liver Injury.

    PubMed

    Song, Binbin; Aoki, Shigeki; Liu, Cong; Susukida, Takeshi; Ito, Kousei

    2018-04-01

    Genome-wide association studies indicate that several idiosyncratic adverse drug reactions are highly associated with specific human leukocyte antigen (HLA) alleles. For instance, abacavir, a human immunodeficiency virus reverse transcriptase inhibitor, induces multiorgan toxicity exclusively in patients carrying the HLA-B*57:01 allele. However, the underlying mechanism is unclear due to a lack of appropriate animal models. Previously, we developed HLA-B*57:01 transgenic mice and found that topical application of abacavir to the ears induced proliferation of CD8+ lymphocytes in local lymph nodes. Here, we attempted to reproduce abacavir-induced liver injury in these mice. However, oral administration of abacavir alone to HLA-B*57:01 transgenic mice did not increase levels of the liver injury marker alanine aminotransferase. Considering the importance of innate immune activation in mouse liver, we treated mice with CpG oligodeoxynucleotide, a toll-like receptor 9 agonist, plus abacavir. This resulted in a marked increase in alanine aminotransferase, pathological changes in liver, increased numbers of activated CD8+ T cells, and tissue infiltration by immune cells exclusively in HLA-B*57:01 transgenic mice. These results indicate that CpG oligodeoxynucleotide-induced inflammatory reactions and/or innate immune activation are necessary for abacavir-induced HLA-mediated liver injury characterized by infiltration of CD8+ T cells. Thus, we developed the first mouse model of HLA-mediated abacavir-induced idiosyncratic liver injury. Further investigation will show that the proposed HLA-mediated liver injury model can be applied to other combinations of drugs and HLA types, thereby improving drug development and contributing to the development of personalized medicine.

  6. Hepatoprotective effect of methyl ferulic acid against carbon tetrachloride-induced acute liver injury in rats

    PubMed Central

    Yang, Chengfang; Li, Li; Ma, Zuheng; Zhong, Yujuan; Pang, Wenxiao; Xiong, Meili; Fang, Shuping; Li, Yongwen

    2018-01-01

    The present study aimed to investigate the hepatoprotective effects of methyl ferulic acid (MFA) against oxidative stress and apoptosis in acute liver injury induced by carbon tetrachloride (CCl4) in rats, as well as the underlying mechanisms. Sprague Dawley rats were treated with CCl4 after oral administration of MFA (25, 50, and 100 mg/kg) or dimethyl diphenyl bicarboxylate (200 mg/kg) for 7 days. The hepatoprotective effects of MFA were determined by analyzing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities as well as changes of oxidant parameters. Histopathological analysis was performed to determine the degree of hepatic injury. The mechanisms were investigated by detecting the levels of NADPH oxidase (NOX) trans-membrane subunit NOX4, its ligand p22phox, as well as caspase3, cleaved caspase3, B-cell lymphoma (Bcl)-2, Bcl-2-associated X protein (Bax), tumor necrosis factor (TNF)-α, interleukin (IL)-1, reactive oxygen species (ROS), thiobarbituric acid-reactive substances (TBARS), total anti-oxidant capacity (TAC), phosphorylated J-Jun N-terminal kinase (p-JNK) and p-p38 mitogen-activated protein kinase (MAPK) using semi-quantitative polymerase chain reaction, western blot analysis and colorimetric assays. MFA treatment significantly decreased serum enzymatic activities of ALT and AST. MFA markedly increased activities of liver superoxide dismutase, catalase and glutathione peroxidase, and reduced the malondialdehyde concentration. Histopathological examination demonstrated that MFA reduced lipid degeneration, cytoplasmic vacuolization, necrosis and inflammatory cell infiltration in the liversof CCl4-treated rats. MFA treatment markedly inhibited the expression of inflammatory factors TNF-α and IL-1β. Mechanistic study revealed that MFA decreased the TAC and the levels of ROS and TBARS. Furthermore, MFA treatment led to a reduction of the mRNA and protein expression of NOX4 and p22phox, as well as the protein levels of

  7. Effect of 3-keto-1,5-bisphosphonates on obese-liver's rats.

    PubMed

    Lahbib, Karima; Touil, Soufiane

    2016-10-01

    Obesity is associated with an oxidative stress status, which is defined by an excess of reactive oxygen species (ROS) vs. the antioxidant defense system. We report in this present work, the link between fat deposition and oxidative stress markers using a High Fat Diet-(HFD) induced rat obesity and liver-oxidative stress. We further determined the impact of chronic administration of 3-keto-1, 5-BPs 1 (a & b) (40μg/kg/8 weeks/i.p.) on liver's level. In fact, exposure of rats to HFD during 16 weeks induced body and liver weight gain and metabolic disruption with an increase on liver Alanine amino transférase (ALAT) and Aspartate aminotransférase (ASAT) concentration. HFD increased liver calcium level as well as free iron, whereas, it provoked a decrease on liver lipase activity. HFD also induced liver-oxidative stress status vocalized by an increase in reactive oxygen species (ROS) as superoxide radical (O 2 ), hydroxyl radical (OH) and Hydrogen peroxide (H 2 O 2 ). Consequently, different deleterious damages as an increase on Malon Dialdehyde MDA, Carbonyl protein PC levels with a decrease in non-protein sulfhydryls NPSH concentrations, have been detected. Interestingly, our results demonstrate a decrease in antioxidant enzymes activities such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GPx) and peroxidases (POD). Importantly, 3-keto-1,5-bisphosphonates treatment corrected the majority of the deleterious effects caused by HFD, but it failed to correct some liver's disruptions as mineral profile, oxidative damages (PC and NPSH levels) as well as SOD and lipase activities. Our investigation point that 3-keto-1,5-bisphosphonates could be considered as safe antioxidant agents on the hepatic level that should also find other potential biological applications. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  8. Atypical onset of bicalutamide-induced liver injury.

    PubMed

    Yun, Gee Young; Kim, Seok Hyun; Kim, Seok Won; Joo, Jong Seok; Kim, Ju Seok; Lee, Eaum Seok; Lee, Byung Seok; Kang, Sun Hyoung; Moon, Hee Seok; Sung, Jae Kyu; Lee, Heon Young; Kim, Kyung Hee

    2016-04-21

    Anti-androgen therapy is the leading treatment for advanced prostate cancer and is commonly used for neoadjuvant or adjuvant treatment. Bicalutamide is a non-steroidal anti-androgen, used during the initiation of androgen deprivation therapy along with a luteinizing hormone-releasing hormone agonist to reduce the symptoms of tumor-related flares in patients with advanced prostate cancer. As side effects, bicalutamide can cause fatigue, gynecomastia, and decreased libido through competitive androgen receptor blockade. Additionally, although not as common, drug-induced liver injury has also been reported. Herein, we report a case of hepatotoxicity secondary to bicalutamide use. Typically, bicalutamide-induced hepatotoxicity develops after a few days; however, in this case, hepatic injury occurred 5 mo after treatment initiation. Based on this rare case of delayed liver injury, we recommend careful monitoring of liver function throughout bicalutamide treatment for prostate cancer.

  9. Opposite Expression of SPARC between the Liver and Pancreas in Streptozotocin-Induced Diabetic Rats

    PubMed Central

    Aseer, Kanikkai Raja; Kim, Sang Woo; Choi, Myung-Sook; Yun, Jong Won

    2015-01-01

    Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates several cellular events, including inflammation and tissue remodelling. In this study, we investigated the tissue-specific expression of SPARC in streptozotocin (STZ)-induced diabetes, and found that SPARC was significantly up-regulated in the liver while down-regulated in the pancreas of STZ-induced diabetic rats. Chronic inflammation occurred in the diabetic pancreas accompanied by up-regulation of CCAAT/enhancer-binding protein beta (C/EBPβ) and its targets (TNFα, Il6, CRP, and Fn1) as well as myeloperoxidase (Mpo) and C-X-C chemokine receptor type 2 (Cxcr2). Diabetic liver showed significant up-regulation of Tgfb1 as well as moderately less up-regulated TNFα and reduced Fn1, resulting in elevated fibrogenesis. PARP-1 was not up-regulated during CD95-mediated apoptosis, resulting in restoration of high ATP levels in the diabetic liver. On the contrary, CD95-dependent apoptosis was not observed in the diabetic pancreas due to up-regulation of PARP-1 and ATP depletion, resulting in necrosis. The cytoprotective machinery was damaged by pancreatic inflammation, whereas adequate antioxidant capacity indicates low oxidative stress in the diabetic liver. High and low cellular insulin content was found in the diabetic liver and pancreas, respectively. Furthermore, we identified six novel interacting partner proteins of SPARC by co-immunoprecipitation in the diabetic liver and pancreas, and their interactions with SPARC were predicted by bioinformatics tools. Taken together, opposite expression of SPARC in the diabetic liver and pancreas may be related to inflammation and immune cell infiltration, degrees of apoptosis and fibrosis, cytoprotective machinery, and cellular insulin levels. PMID:26110898

  10. Mesenchymal stem cells restore CCl4-induced liver injury by an antioxidative process.

    PubMed

    Cho, Kyung-Ah; Woo, So-Youn; Seoh, Ju-Young; Han, Ho-Seong; Ryu, Kyung-Ha

    2012-01-01

    We have investigated BM (bone marrow)-derived MSCs (mesenchymal stem cells) for the treatment of liver injury. It was hypothesized that MSC-mediated resolution of liver injury could occur through an antioxidative process. After being injected with CCl4 (carbon tetrachloride), mice were injected with syngenic BM-derived MSCs or normal saline. Oxidative stress activity of the MSCs was determined by the analysis of ROS (reactive oxygen species) and SOD (superoxide dismutase) activity. In addition, cytoprotective genes of the liver tissue were assessed by real-time PCR and ARE (antioxidant-response element) reporter assay. Up-regulated ROS of CCl4-treated liver cells was attenuated by co-culturing with MSCs. Suppression of SOD by adding an SOD inhibitor decreased the effect of MSCs on injured liver cells. MSCs significantly increased SOD activity and inhibited ROS production in the injured liver. The gene expression levels of Hmox-1 (haem oxygenase-1), BI-1 (Bax inhibitor-1), HGF (hepatocyte growth factor), GST (glutathione transferase) and Nrf2 (nuclear factor-erythoid 2 p45 subunit-related factor 20), attenuated by CCl4, were increased up to basal levels after MSC transplantation. In addition, MSCs induced an ARE, shown by luciferase activity, which represented a cytoprotective response in the injured liver. Evidence of a new cytoprotective effect is shown in which MSCs promote an antioxidant response and supports the potential of using MSC transplantation as an effective treatment modality for liver disease.

  11. Baicalin Attenuates IL-17-Mediated Acetaminophen-Induced Liver Injury in a Mouse Model

    PubMed Central

    Liao, Chia-Chih; Day, Yuan-Ji; Lee, Hung-Chen; Liou, Jiin-Tarng; Chou, An-Hsun; Liu, Fu-Chao

    2016-01-01

    Background IL-17 has been shown to be involved in liver inflammatory disorders in both mice and humans. Baicalin (BA), a major compound extracted from traditional herb medicine (Scutellariae radix), has potent hepatoprotective properties. Previous study showed that BA inhibits IL-17-mediated lymphocyte adhesion and downregulates joint inflammation. The aim of this study is to investigate the role of IL-17 in the hepatoprotective effects of BA in an acetaminophen (APAP)-induced liver injury mouse model. Methods Eight weeks male C57BL/6 (B6) mice were used for this study. Mice received intraperitoneal hepatotoxic injection of APAP (300 mg/kg) and after 30 min of injection, the mice were treated with BA at a concentration of 30 mg/kg. After 16 h of treatment, mice were killed. Blood samples and liver tissues were harvested for analysis of liver injury parameters. Results APAP overdose significantly increased the serum alanine transferase (ALT) levels, hepatic activities of myeloperoxidase (MPO), expression of cytokines (TNF-α, IL-6, and IL-17), and malondialdehyde (MDA) activity when compared with the control animals. BA treatment after APAP administration significantly attenuated the elevation of these parameters in APAP-induced liver injury mice. Furthermore, BA treatment could also decrease hepatic IL-17-producing γδT cells recruitment, which was induced after APAP overdose. Conclusion Our data suggested that baicalin treatment could effectively decrease APAP-induced liver injury in part through attenuation of hepatic IL-17 expression. These results indicate that baicalin is a potential hepatoprotective agent. PMID:27855209

  12. Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling.

    PubMed

    Kuijper, Isoude A; Yang, Huan; Van De Water, Bob; Beltman, Joost B

    2017-01-01

    Drug-induced liver injury (DILI) is a significant threat to human health and a major problem in drug development. It is hard to predict due to its idiosyncratic nature and which does not show up in animal trials. Hepatic adaptive stress response pathway activation is generally observed in drug-induced liver injury. Dynamical pathway modeling has the potential to foresee adverse effects of drugs before they go in trial. Ordinary differential equation modeling can offer mechanistic insight, and allows us to study the dynamical behavior of stress pathways involved in DILI. Areas covered: This review provides an overview on the progress of the dynamical modeling of stress and death pathways pertinent to DILI, i.e. pathways relevant for oxidative stress, inflammatory stress, DNA damage, unfolded proteins, heat shock and apoptosis. We also discuss the required steps for applying such modeling to the liver. Expert opinion: Despite the strong progress made since the turn of the century, models of stress pathways have only rarely been specifically applied to describe pathway dynamics for DILI. We argue that with minor changes, in some cases only to parameter values, many of these models can be repurposed for application in DILI research. Combining both dynamical models with in vitro testing might offer novel screening methods for the harmful side-effects of drugs.

  13. Lycium barbarum polysaccharides improve CCl4-induced liver fibrosis, inflammatory response and TLRs/NF-kB signaling pathway expression in wistar rats.

    PubMed

    Gan, Fang; Liu, Qing; Liu, Yunhuan; Huang, Da; Pan, Cuiling; Song, Suquan; Huang, Kehe

    2018-01-01

    Lycium barbarum polysaccharides (LBPs) have multiple biological and pharmacological functions, including antioxidant, anti-inflammatory and anticancer activities. This research was conducted to evaluate whether LBPs could alleviate carbon tetrachloride (CCl 4 )-induced liver fibrosis and the underlying signaling pathway mechanism. Fifty male wistar rats were randomly allocated to five groups (n=10): control, CCl 4 and CCl 4 with 400, 800 or 1600mg/kg LBPs, respectively. Each wistar rat from each group was used for blood and tissue collections at the end of experiment. The results showed that CCl 4 induced liver fibrosis as demonstrated by increasing histopathological damage, α-smooth muscle actin expression, aspartate transaminase activities, alkaline phosphatase activities and alanine aminotransferase activities. LBPs supplementation alleviated CCl 4 -induced liver fibrosis as demonstrated by reversing the above parameters. In addition, CCl 4 treatment induced the oxidative injury, increased the mRNA levels of tumor necrosis factor-α, monocyte chemoattractant protein-1 and interleukin-1β, and up-regulated the protein expressions of toll-like receptor 4 (TLR4), TLR2, myeloid differentiation factor 88, nuclear factor-kappa B (NF-kB) and p-p65. LBPs supplementation alleviated CCl 4 -induced oxidative injury, inflammatory response and TLRs/NF-kB signaling pathway expression by reversing the above some parameters. These results suggest that the alleviating effects of LBPs on CCl 4 -induced liver fibrosis in wistar rats may be through inhibiting the TLRs/NF-kB signaling pathway expression. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Radiation-induced liver disease as a mimic of liver metastases at serial PET/CT during neoadjuvant chemoradiation of distal esophageal cancer.

    PubMed

    Grant, Michael J; Didier, Ryne A; Stevens, Jeffrey S; Beyder, Dmitry D; Hunter, John G; Thomas, Charles R; Coakley, Fergus V

    2014-10-01

    To determine the frequency and appearance of radiation-induced liver disease on PET/CT in patients undergoing serial imaging during neoadjuvant chemoradiation of distal esophageal cancer. In this IRB-approved, HIPAA-compliant retrospective analysis, we identified 112 patients with distal esophageal cancer treated by neoadjuvant chemoradiation who had serial PET/CT imaging available for review. Two readers reviewed all studies in consensus and recorded those cases where new foci of visually detectable increased FDG avidity appeared in the liver during therapy. The etiology of such foci was determined from corresponding findings at CT or MRI, by hepatic biopsy during surgery, by characteristic evolution on post-operative imaging, or by a combination of these methods. New foci of FDG avidity developed in the liver during neoadjuvant therapy in 10 of 112 (9%) patients, of whom nine (8%) were determined to have radiation-induced liver disease based on further imaging and/or biopsy and one of whom had developed interval metastatic disease based on biopsy. In the cases of radiation-induced liver disease, the abnormal foci were found only in the caudate and left hepatic lobes, near the primary tumor, while the patient who developed interval metastatic disease had involvement of the inferior right hepatic lobe, remote from the radiation therapy field. New foci of increased FDG avidity are commonly seen in the caudate and left hepatic lobes of the liver during neoadjuvant chemoradiation of distal esophageal cancer, and these findings generally reflect radiation-induced liver disease rather than metastatic disease.

  15. Investigation of the role of α-lipoic acid on fatty acids profile, some minerals (zinc, copper, iron) and antioxidant activity against aluminum-induced oxidative stress in the liver of male rats.

    PubMed

    Sahin, Zafer; Ozkaya, Ahmet; Yilmaz, Okkes; Yuce, Abdurrauf; Gunes, Mehmet

    2017-07-26

    We have investigated the effects of α-lipoic acid (LA), a powerful antioxidant, on the fatty acid (FA) profiles, aluminum accumulation, antioxidant activity and some minerals such as zinc, copper and iron against aluminum chloride (AlCl3)-induced oxidative stress in rat liver. Twenty-eight male Wistar rats were divided into four groups as control, LA, AlCl3 and LA+AlCl3. For 30 days, LA was intraperitoneally administrated (50 mg/kg) and AlCl3 was given via orogastric gavage (1600 ppm) every other day. AlCl3-treated animals exhibited higher hepatic malondialdehyde concentration and lower glutathione peroxidase and catalase activity, whereas these alterations were restored by the LA supplementation. Total saturated FA of the AlCl3-treated group was higher than the LA supplementation groups. Moreover, total unsaturated FA level of the LA+AlCl3 group was higher than the AlCl3-treated group. Hepatic zinc level of the AlCl3-treated group was lower than the control group, whereas it was higher in the LA and the LA+AlCl3 groups. Hepatic copper levels did not significantly change in the experimental groups. Iron level was lower in the LA and LA+AlCl3 groups compared with the AlCl3-treated group. Moreover, the liver Al concentration was found to be lower in the LA and LA+AlCl3 groups compared to the AlCl3 group. These results indicate that AlCl3 treatment can induce oxidative stress in the liver. LA supplementation has a beneficial effect on the AlCl3-induced alterations such as high lipid peroxidation, Al accumulation, FA profile ratios and mineral concentrations.

  16. Traditional Chinese herbal extracts inducing autophagy as a novel approach in therapy of nonalcoholic fatty liver disease

    PubMed Central

    Liu, Cong; Liao, Jia-Zhi; Li, Pei-Yuan

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver diseases around the world due to the modern sedentary and food-abundant lifestyle, which is characterized by excessive fat accumulation in the liver related with causes other than alcohol abuse. It is widely acknowledged that insulin resistance, dysfunctional lipid metabolism, endoplasmic reticulum stress, oxidative stress, inflammation, and apoptosis/necrosis may all contribute to NAFLD. Autophagy is a protective self-digestion of intracellular organelles, including lipid droplets (lipophagy), in response to stress to maintain homeostasis. Lipophagy is another pathway for lipid degradation besides lipolysis. It is reported that impaired autophagy also contributes to NAFLD. Some studies have suggested that the histological characteristics of NAFLD (steatosis, lobular inflammation, and peri-sinusoid fibrosis) might be improved by treatment with traditional Chinese herbal extracts, while autophagy may be induced. This review will provide insights into the characteristics of autophagy in NAFLD and the related role/mechanisms of autophagy induced by traditional Chinese herbal extracts such as resveratrol, Lycium barbarum polysaccharides, dioscin, bergamot polyphenol fraction, capsaicin, and garlic-derived S-allylmercaptocysteine, which may inhibit the progression of NAFLD. Regulation of autophagy/lipophagy with traditional Chinese herbal extracts may be a novel approach for treating NAFLD, and the molecular mechanisms should be elucidated further in the near future. PMID:28373762

  17. Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease.

    PubMed

    Derdak, Zoltan; Villegas, Kristine A; Harb, Ragheb; Wu, Annie M; Sousa, Aryanna; Wands, Jack R

    2013-04-01

    p53 and its transcriptional target miRNA34a have been implicated in the pathogenesis of fatty liver. We tested the efficacy of a p53 inhibitor, pifithrin-α p-nitro (PFT) in attenuating steatosis, associated oxidative stress and apoptosis in a murine model of non-alcoholic fatty liver disease (NAFLD). C57BL/6 mice were fed a high-fat (HFD) or control diet for 8 weeks; PFT or DMSO (vehicle) was administered three times per week. Markers of oxidative stress and apoptosis as well as mediators of hepatic fatty acid metabolism were assessed by immunohistochemistry, Western blot, real-time PCR, and biochemical assays. PFT administration suppressed HFD-induced weight gain, ALT elevation, steatosis, oxidative stress, and apoptosis. PFT treatment blunted the HFD-induced upregulation of miRNA34a and increased SIRT1 expression. In the livers of HFD-fed, PFT-treated mice, activation of the SIRT1/PGC1α/PPARα axis increased the expression of malonyl-CoA decarboxylase (MLYCD), an enzyme responsible for malonyl-CoA (mCoA) degradation. Additionally, the SIRT1/LKB1/AMPK pathway (upstream activator of MLYCD) was promoted by PFT. Thus, induction of these two pathways by PFT diminished the hepatic mCoA content by enhancing MLYCD expression and function. Since mCoA inhibits carnitine palmitoyltransferase 1 (CPT1), the decrease of hepatic mCoA in the PFT-treated, HFD-fed mice increased CPT1 activity, favored fatty acid oxidation, and decreased steatosis. Additionally, we demonstrated that PFT abrogated steatosis and promoted MLYCD expression in palmitoleic acid-treated human HepaRG cells. The p53 inhibitor PFT diminished hepatic triglyceride accumulation and lipotoxicity in mice fed a HFD, by depleting mCoA and favoring the β-oxidation of fatty acids. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  18. Isothiocyanates induce UGT1A1 in humanized UGT1 mice in a CAR dependent fashion that is highly dependent upon oxidative stress.

    PubMed

    Yoda, Emiko; Paszek, Miles; Konopnicki, Camille; Fujiwara, Ryoichi; Chen, Shujuan; Tukey, Robert H

    2017-04-19

    Isothiocyanates, such as phenethyl isothiocyanate (PEITC), are formed following the consumption of cruciferous vegetables and generate reactive oxygen species (ROS) that lead to the induction of cytoprotective genes such as the UDP-glucuronosyltransferases (UGTs). The induction of ROS activates the Nrf2-Keap 1 pathway leading to the induction of genes through antioxidant response elements (AREs). UGT1A1, the sole enzyme responsible for the metabolism of bilirubin, can be induced following activation of Nrf2. When neonatal humanized UGT1 (hUGT1) mice, which exhibit severe levels of total serum bilirubin (TSB) because of a developmental delay in expression of the UGT1A1 gene, were treated with PEITC, TSB levels were reduced. Liver and intestinal UGT1A1 were induced, along with murine CYP2B10, a consensus CAR target gene. In both neonatal and adult hUGT1/Car -/- mice, PEITC was unable to induce CYP2B10. A similar result was observed following analysis of UGT1A1 expression in liver. However, TSB levels were still reduced in hUGT1/Car -/- neonatal mice because of ROS induction of intestinal UGT1A1. When oxidative stress was blocked by exposing mice to N-acetylcysteine, induction of liver UGT1A1 and CYP2B10 by PEITC was prevented. Thus, new findings in this report link an important role in CAR activation that is dependent upon oxidative stress.

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

    PubMed

    Varady, Juliane; Gessner, Denise K; Most, Erika; Eder, Klaus; Ringseis, Robert

    2012-02-24

    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. 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). 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. 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.

  20. Apigenin protects against alcohol-induced liver injury in mice by regulating hepatic CYP2E1-mediated oxidative stress and PPARα-mediated lipogenic gene expression.

    PubMed

    Wang, Feng; Liu, Jin-Cheng; Zhou, Rui-Jun; Zhao, Xi; Liu, Mei; Ye, Hua; Xie, Mei-Lin

    2017-09-25

    Alcohol is a major cause of liver injury, and there are currently no ideal pharmacological reagents that can prevent or reverse this disease. Apigenin is one of the most common flavonoids present in numerous plants and has many beneficial effects. But whether or not apigenin may protect against alcohol-induced liver injury remains unknown. Our aim was to examine the effect and potential mechanisms. The experimental mice were given 56% erguotou wine or simultaneously given apigenin 150-300 mg/kg by gavage for 30 days. The results showed that in the apigenin-treated mice, the expression of hepatic cytochrome P450 2E1 (CYP2E1) and nuclear factor kappa B proteins as well as contents of hepatic malondialdehyde and tumor necrosis factor-alpha were reduced, while the levels of hepatic reduced glutathione, glutathione reductase, glutathione peroxidase, and glutathione S-transferase were increased, especially in the 300 mg/kg group. A significant change in hepatic steatosis was also observed in the apigenin 300 mg/kg group. Apigenin pretreatment could increase the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase-1 proteins, and decrease the expression of hepatic sterol regulatory element binding protein-1c, fatty acid synthase, and diacylglycerol acyltransferase proteins. These findings demonstrated that apigenin might exert a protective effect on alcohol-induced liver injury, and its mechanisms might be related to the regulations of hepatic CYP2E1-mediated oxidative stress and PPARα-mediated lipogenic gene expression. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Studies of single-walled carbon nanotubes-induced hepatotoxicity by NMR-based metabonomics of rat blood plasma and liver extracts

    NASA Astrophysics Data System (ADS)

    Lin, Bencheng; Zhang, Huashan; Lin, Zhiqing; Fang, Yanjun; Tian, Lei; Yang, Honglian; Yan, Jun; Liu, Huanliang; Zhang, Wei; Xi, Zhuge

    2013-05-01

    The toxicological effects of single-walled carbon nanotubes (SWCNTs) were investigated after intratracheal instillation in male Wistar rats over a 15-day period using metabonomic analysis of 1H (nuclear magnetic resonance) NMR spectra of blood plasma and liver tissue extracts. Concurrent liver histopathology examinations and plasma clinical chemistry analyses were also performed. Significant changes were observed in clinical chemistry features, including alkaline phosphatase, total protein, and total cholesterol, and in liver pathology, suggesting that SWCNTs clearly have hepatotoxicity in the rat. 1H NMR spectra and pattern recognition analyses from nanomaterial-treated rats showed remarkable differences in the excretion of lactate, trimethylamine oxide, bilineurin, phosphocholine, amylaceum, and glycogen. Indications of amino acid metabolism impairment were supported by increased lactate concentrations and decreased alanine concentrations in plasma. The rise in plasma and liver tissue extract concentrations of choline and phosphocholine, together with decreased lipids and lipoproteins, after SWCNTs treatment indicated a disruption of membrane fluidity caused by lipid peroxidation. Energy, amino acid, and fat metabolism appeared to be affected by SWCNTs exposure. Clinical chemistry and metabonomic approaches clearly indicated liver injury, which might have been associated with an indirect mechanism involving nanomaterial-induced oxidative stress.

  2. Hepatoprotective and Renoprotective Effects of Lavender (Lavandula stoechas L.) Essential Oils Against Malathion-Induced Oxidative Stress in Young Male Mice.

    PubMed

    Selmi, Slimen; Jallouli, Manel; Gharbi, Najoua; Marzouki, Lamjed

    2015-10-01

    We aimed in the present study to investigate the hepato- and nephroprotective effects of Lavandula stoechas essential oils (LSEO) against malathion-induced oxidative stress in young male mice as well as the possible mechanism implicated in such protection. Animals were divided into eight groups of 12 each: Control, malathion (200 mg/kg b.w.); Various doses of LSEO (10, 30, and 50 mg/kg b.w.), malathion+various doses of LSEO. Malathion and LSEO were daily per orally (p.o.) administered by intragastric gavage during 30 days. We initially found that malathion treatment induced body weight gain decrease as well as a clear nephro- and hepatotoxicity as assessed by significant relative liver and kidney weight increase and related hemodynamic parameters deregulation. Malathion exposure of mice also induced a considerable perturbation of metabolic parameters. On the other hand, we showed that malathion administration was accompanied by an oxidative stress status assessed by an increase of malondialdehyde (MDA) and hydrogen peroxide (H2O2) levels as well as a depletion of sulfhydril group content (-SH) and antioxidant enzyme activities such as catalase (CAT) and glutathione peroxidase (GPx), total superoxide dismutase (SOD), Cu/Zn-SOD, Mn-SOD, and Fe-SOD in the kidney and liver. More importantly, LSEO treatment abolished all malathion-induced body gain loss, liver and kidney relative weight increase, hemodynamic and metabolic disorders, as well as hepatic and renal oxidative stress. In conclusion, our data suggest that LSEO exerted potential hepato- and nephroprotective effects against malathion-induced oxidative stress in mice. The beneficial effect of LSEO might be related, in part, to its antioxidant properties.

  3. Hepatoprotective and Renoprotective Effects of Lavender (Lavandula stoechas L.) Essential Oils Against Malathion-Induced Oxidative Stress in Young Male Mice

    PubMed Central

    Jallouli, Manel; Gharbi, Najoua; Marzouki, Lamjed

    2015-01-01

    Abstract We aimed in the present study to investigate the hepato- and nephroprotective effects of Lavandula stoechas essential oils (LSEO) against malathion-induced oxidative stress in young male mice as well as the possible mechanism implicated in such protection. Animals were divided into eight groups of 12 each: Control, malathion (200 mg/kg b.w.); Various doses of LSEO (10, 30, and 50 mg/kg b.w.), malathion+various doses of LSEO. Malathion and LSEO were daily per orally (p.o.) administered by intragastric gavage during 30 days. We initially found that malathion treatment induced body weight gain decrease as well as a clear nephro- and hepatotoxicity as assessed by significant relative liver and kidney weight increase and related hemodynamic parameters deregulation. Malathion exposure of mice also induced a considerable perturbation of metabolic parameters. On the other hand, we showed that malathion administration was accompanied by an oxidative stress status assessed by an increase of malondialdehyde (MDA) and hydrogen peroxide (H2O2) levels as well as a depletion of sulfhydril group content (-SH) and antioxidant enzyme activities such as catalase (CAT) and glutathione peroxidase (GPx), total superoxide dismutase (SOD), Cu/Zn-SOD, Mn-SOD, and Fe-SOD in the kidney and liver. More importantly, LSEO treatment abolished all malathion-induced body gain loss, liver and kidney relative weight increase, hemodynamic and metabolic disorders, as well as hepatic and renal oxidative stress. In conclusion, our data suggest that LSEO exerted potential hepato- and nephroprotective effects against malathion-induced oxidative stress in mice. The beneficial effect of LSEO might be related, in part, to its antioxidant properties. PMID:25835641

  4. Protective effects of melatonin against thioacetamide-induced liver fibrosis in rats.

    PubMed

    Czechowska, G; Celinski, K; Korolczuk, A; Wojcicka, G; Dudka, J; Bojarska, A; Reiter, R J

    2015-08-01

    The aim of this study was to determine the effect of melatonin on thioacetamide (TAA) induced liver fibrosis in rats. The antifibrotic effects of melatonin were assessed by determining activity indirect markers of fibrosis: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), and proinflammatory cytokines: interleukin 6 (IL-6), interleukin-1beta (IL-1β), tumour necrosis factor alpha (TNF-α), transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF). Parameters of oxidative stress: oxidised glutathione (GSSG), reduced glutathione (GSH) and presaged activity of paraoxonase 1 (PON-1), an antioxidative enzyme were determined. Inflammatory changes and fibrosis extent were evaluated histologically. Experiments were carried out in Wistar rats. Animals were divided into 4 groups: I - controls, water ad libitum for 12 weeks, group II - TAA, 300 mg/L ad libitum for 12 weeks, III - melatonin, 10 mg/kg b.w. intraperitoneally (i.p.) daily for 4 weeks, IV - TAA, 300 mg/L ad libitum for 12 weeks followed by melatonin, 10 mg/kg/b.w. i.p. daily for 4 weeks. Results of serum determinations demonstrated significantly lower activity of AST, ALT and AP in the group receiving TAA followed by melatonin compared to the group receiving only TAA. Immunoenzymatic findings on effect of melatonin on concentration of proinflammatory cytokines confirmed these data. Biochemical examinations in liver homogenates revealed statistically significant improvement (concentration of GSH increases and concentration of GSSG decreases) in animals with TAA-induced liver damage receiving melatonin. Moreover, the activity of PON-1 toward phenyl acetate and paraoxon was increased in liver homogenates and serum in the group receiving TAA followed by melatonin compared to the TAA group without melatonin treatment. Microscopic evaluation disclosed inhibitory effects of melatonin on inflammatory changes and extent of liver fibrosis.

  5. Combinatorial usage of fungal polysaccharides from Cordyceps sinensis and Ganoderma atrum ameliorate drug-induced liver injury in mice.

    PubMed

    Fan, Songtao; Huang, Xiaojun; Wang, Sunan; Li, Chang; Zhang, Zhihong; Xie, Mingyong; Nie, Shaoping

    2018-05-15

    This study investigated the possible protective effect of combined fungal polysaccharides (CFP), consisting of Cordyceps sinensis polysaccharides (CSP) and Ganoderma atrum polysaccharides (PSG) with well-defined structural characteristics, against cyclophosphamide (CTX)-induced hepatotoxicity in mice. Our results indicated CFP effectively prevented the liver injury by decreasing toxicity markers (aspartate transaminase, alanine aminotransferase and alkaline phosphatase). Further biochemical and molecular analysis indicated CSP particularly inhibited the activation of Toll-like receptor 9 (TLR9) and its related inflammatory signals, including pro-inflammatory cytokines, inducible nitric oxide synthase, and cyclooxygenase-2 to modulate hepatic inflammation response. Relatively, through activation of peroxisome proliferator-activated receptor α (PPARα), PSG increased hepatic glutathione peroxidase and glutathione content depleted by CTX, as well as prevented mitochondria-dependent apoptosis with regulation on Bcl-2 family proteins (Bad, Bax and Bcl-2). In addition, protective effect of CFP was associated with enhanced modulations on cellular oxidant/antioxidant imbalance, mitochondrial apoptotic pathway and pro-inflammatory factors via PPARα upregulation and TLR9 downregulation. Taking together, the combinatorial approach based on CSP and PSG presented a practical option for the management of drug-induced liver injury. Copyright © 2018 Elsevier Ltd. All rights reserved.

  6. Protective effect of metronidazole on uncoupling mitochondrial oxidative phosphorylation induced by NSAID: a new mechanism.

    PubMed

    Leite, A Z; Sipahi, A M; Damião, A O; Coelho, A M; Garcez, A T; Machado, M C; Buchpiguel, C A; Lopasso, F P; Lordello, M L; Agostinho, C L; Laudanna, A A

    2001-02-01

    The pathogenesis of non-steroidal anti-inflammatory drug (NSAID) enteropathy is complex. It involves uncoupling of mitochondrial oxidative phosphorylation which alters the intercellular junction and increases intestinal permeability with consequent intestinal damage. Metronidazole diminishes the inflammation induced by indomethacin but the mechanisms remain speculative. A direct effect on luminal bacteria has traditionally been thought to account for the protective effect of metronidazole. However, a protective effect of metronidazole on mitochondrial oxidative phosphorylation has never been tested. To assess the protective effect of metronidazole on mitochondrial uncoupling induced by indomethacin and also on the increased intestinal permeability and macroscopic damage. The protective effect of metronidazole was evaluated in rats given indomethacin; a macroscopic score was devised to quantify intestinal lesions, and intestinal permeability was measured by means of (51)Cr-ethylenediaminetetraacetic acid. The protective effect of metronidazole against mitochondrial uncoupling induced by indomethacin was assessed using isolated coupled rat liver mitochondria obtained from rats pretreated with metronidazole or saline. Metronidazole significantly reduced the macroscopic intestinal damage and increase in intestinal permeability induced by indomethacin; furthermore, at the mitochondrial level, it significantly reduced the increase in oxygen consumption in state 4 induced by indomethacin and caused less reduction of the respiratory control rate. Our study confirmed the beneficial effects of metronidazole on intestinal damage and intestinal permeability, and demonstrated, for the first time, a direct protective effect of metronidazole on uncoupling of mitochondrial oxidative phosphorylation caused by NSAIDs.

  7. Esculetin ameliorates hepatic fibrosis in high fat diet induced non-alcoholic fatty liver disease by regulation of FoxO1 mediated pathway.

    PubMed

    Pandey, Anuradha; Raj, Priyank; Goru, Santosh Kumar; Kadakol, Almesh; Malek, Vajir; Sharma, Nisha; Gaikwad, Anil Bhanudas

    2017-08-01

    Non-alcoholic fatty liver disease (NAFLD), a chronic metabolic disorder is associated with oxidative stress, inflammation and fibrotic cascades. In this study, we aimed to examine the effects of Esculetin, a well-known anti-oxidant on TGF-β1 mediated liver fibrosis and FoxO1 activity. A non-genetic murine model for NAFLD was developed by chronic high fat diet (HFD) (58% calories from fats) feeding in Wistar rats. The plasma biochemical parameters, liver function tests, oxidative stress, and histopathological alterations were assessed. The alterations in extracellular matrix (ECM) deposition and FoxO1 activity were assessed by immunohistochemistry. The aberrations in plasma parameters, liver functioning, morphometric and microscopic changes in liver structure of HFD fed rats were significantly improved by treatment with Esculetin. Liver fibrosis, identified in the form of collagen deposition and expression of fibrotic proteins like TGF-β1 and fibronectin was also markedly controlled by Esculetin. The expression of phospho-FoxO1 was found to be reduced in HFD fed rats' liver, showing an increase in activation of FoxO1 under insulin resistant and hyperglycemic states. Esculetin treatment could improve phospho-FoxO1 expression, thus showing its ability to act on Akt/PI3K/FoxO1 pathway. As per the previous studies, a potential therapy for NAFLD may be the one with multi-faceted actions on insulin resistance, oxidative stress, inflammation and fibrosis. This study demonstrates the efficiency of Esculetin in improving liver fibrosis in HFD induced NAFLD. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  8. Obeticholic acid protects mice against lipopolysaccharide-induced liver injury and inflammation.

    PubMed

    Xiong, Xi; Ren, Yuqian; Cui, Yun; Li, Rui; Wang, Chunxia; Zhang, Yucai

    2017-12-01

    Cholestasis, as a main manifestation, induces liver injury during sepsis. The farnesoid X receptor (FXR) plays an important role in regulating bile acid homeostasis. Whether FXR activation by its agonist obeticholic acid (OCA) is contributed to improve sepsis-induced liver injury remains unknown. The aim of the present study was to investigate the effect of OCA on lipopolysaccharide (LPS)-induced acute liver injury in mice. 8-week old male C57BL/6J mice were randomly divided into control group, LPS group, oral OCA group and LPS plus oral OCA (LPS + OCA) group. The serum and livers were collected for further analysis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA) and total bilirubin (TBIL) were measured at indicated time after LPS administration. Liver sections were stained with hematoxylin & eosin (H&E). Orally OCA pretreatment stimulated the expression of FXR and BSEP in livers and protected mice from LPS-induced hepatocyte apoptosis and inflammatory infiltration. Consistently, LPS-induced higher serum levels of ALT, AST, TBA and TBIL were significantly reversed by OCA administration. Meanwhile, the mRNA levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α) and IL-6 were decreased in livers of mice in LPS + OCA group compared with LPS group. Further investigation indicated that the higher expression of ATF4 and LC3II/I were associated with the protective effect of OCA on LPS-induced liver injury. Orally OCA pretreatment protects mice from LPS-induced liver injury possibly contributed by improved bile acid homeostasis, decreased inflammatory factors and ATF4-mediated autophagy activity in hepatocytes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. Protective effects of coenzyme q(10) on decreased oxidative stress resistance induced by simvastatin.

    PubMed

    Kettawan, Aikkarach; Takahashi, Takayuki; Kongkachuichai, Ratchanee; Charoenkiatkul, Somsri; Kishi, Takeo; Okamoto, Tadashi

    2007-05-01

    The effects of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), on oxidative stress resistance and the protective effects of coenzyme Q (CoQ) were investigated. When simvastatin was administered orally to mice, the levels of oxidized and reduced CoQ(9) and CoQ(10) in serum, liver, and heart, decreased significantly when compared to those of control. The levels of thiobarbituric acid reactive substances induced by Fe(2+)-ascorbate in liver and heart mitochondria also increased significantly with simvastatin. Furthermore, cultured cardiac myocytes treated with simvastatin exhibited less resistance to oxidative stress, decreased time to the cessation of spontaneous beating in response to H(2)O(2) addition, and decreased responsiveness to electrical field stimulation. These results suggested that oral administration of simvastatin suppresses the biosynthesis of CoQ, which shares the same biosynthesis pathway as cholesterol up to farnesyl pyrophosphate, thus compromising the physiological function of reduced CoQ, which possesses antioxidant activity. However, these undesirable effects induced by simvastatin were alleviated by coadministering CoQ(10) with simvastatin to mice. Simvastatin also reduced the activity of NADPH-CoQ reductase, a biological enzyme that converts oxidized CoQ to the corresponding reduced CoQ, while CoQ(10) administration improved it. These findings may also support the efficacy of coadministering CoQ(10) with statins.

  10. Hepatoprotective activity of Rhus oxyacantha root cortex extract against DDT-induced liver injury in rats.

    PubMed

    Ben Miled, Hanène; Barka, Zaineb Ben; Hallègue, Dorsaf; Lahbib, Karima; Ladjimi, Mohamed; Tlili, Mounira; Sakly, Mohsen; Rhouma, Khémais Ben; Ksouri, Riadh; Tebourbi, Olfa

    2017-06-01

    The present investigation aimed to study the antioxidant activity and hepatoprotective effects of ethyl acetate extract of R. oxyacantha root cortex (RE) against DDT-induced liver injury in male rats. The RE exhibited high total phenolic, flavonoid and condensed tannins contents. The antioxidant activity in vitro systems showed a significant potent free radical scavenging activity of the extract. The HPLC finger print of R. oxyacantha active extract showed the presence of five phenolic compounds with higher amounts of catechol and gallic acid. The in vivo results showed that a single intraperitoneal administration of DDT enhanced levels of hepatic markers (ALT, AST and LDH) in serum of experimental animals. It also increased the oxidative stress markers resulting in increased levels of the lipid peroxidation with a significant induction of SOD and GPx, metallothioneins (MTs) and a concomitant decrease of non protein thiols (NPSH) in liver. However, pretreatment of rats with RE at a dose of 150 and 300mg/kg body weight significantly lowered serum transaminases and LDH in treated rats. A significant reduction in hepatic thiobarbituric reactive substances and a decrease in antioxidant enzymes activities and hepatic MTs levels by treatment with plant extract against DDT, were observed. These biochemical changes were consistent with histopathological observations, suggesting marked hepatoprotective effect of RE with the two doses used. These results strongly suggest that treatment with ethyl acetate extract normalizes various biochemical parameters and protects the liver against DDT-induced oxidative damage in rats and thus help in evaluation of traditional claim on this plant. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. Non-Alcoholic Fatty Liver Disease.

    PubMed

    Engin, Atilla

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is in parallel with the obesity epidemic and it is the most common cause of liver diseases. The development of hepatic steatosis in majority of patients is linked to dietary fat ingestion. NAFLD is characterized by excess accumulation of triglyceride in the hepatocyte due to both increased inflow of free fatty acids and de novo hepatic lipogenesis. Insulin resistance with the deficiency of insulin receptor substrate-2 (IRS-2)-associated phosphatidylinositol 3-kinase (PI3K) activity causes an increase in intracellular fatty acid-derived metabolites such as diacylglycerol, fatty acyl CoA or ceramides. Lipotoxicity-related mechanism of NAFLD could be explained still best by the "double-hit" hypothesis. Insulin resistance is the major mechanism in the development and progression of NAFLD/Non-alcoholic steatohepatitis (NASH). Metabolic oxidative stress, autophagy, and inflammation induce NASH progression. In the "first hit" the hepatic concentrations of diacylglycerol increase with rising saturated liver fat content in human NAFLD. Activities of mitochondrial respiratory chain complexes are decreased in liver tissue of patients with NASH. Furthermore, hepatocyte lipoapoptosis is a critical feature of NASH. In "second hit" reduced glutathione levels due to oxidative stress lead to overactivation of c-Jun N-terminal kinase (JNK)/c-Jun signaling that induces cell death in the steatotic liver. Accumulation of toxic levels of reactive oxygen species (ROS) is caused by the ineffectual cycling of the endoplasmic reticulum (ER) oxidoreductin (Ero1)-protein disulfide isomerase oxidation cycle through the downstream of the inner membrane mitochondrial oxidative metabolism and Kelch like-ECH-associated protein 1 (Keap1)- Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway.

  12. Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice.

    PubMed

    Maes, Michaël; Crespo Yanguas, Sara; Willebrords, Joost; Weemhoff, James L; da Silva, Tereza Cristina; Decrock, Elke; Lebofsky, Margitta; Pereira, Isabel Veloso Alves; Leybaert, Luc; Farhood, Anwar; Jaeschke, Hartmut; Cogliati, Bruno; Vinken, Mathieu

    2017-08-15

    Historically, connexin hemichannels have been considered as structural precursors of gap junctions. However, accumulating evidence points to independent roles for connexin hemichannels in cellular signaling by connecting the intracellular compartment with the extracellular environment. Unlike gap junctions, connexin hemichannels seem to be mainly activated in pathological processes. The present study was set up to test the potential involvement of hemichannels composed of connexin32 and connexin43 in acute hepatotoxicity induced by acetaminophen. Prior to this, in vitro testing was performed to confirm the specificity and efficacy of TAT-Gap24 and TAT-Gap19 in blocking connexin32 and connexin43 hemichannels, respectively. Subsequently, mice were overdosed with acetaminophen followed by treatment with TAT-Gap24 or TAT-Gap19 or a combination of both after 1.5h. Sampling was performed 3, 6, 24 and 48h following acetaminophen administration. Evaluation of the effects of connexin hemichannel inhibition was based on a series of clinically relevant read-outs, measurement of inflammatory cytokines and oxidative stress. Subsequent treatment of acetaminophen-overdosed mice with TAT-Gap19 only marginally affected liver injury. In contrast, a significant reduction in serum alanine aminotransferase activity was found upon administration of TAT-Gap24 to intoxicated animals. Furthermore, co-treatment of acetaminophen-overdosed mice with both peptides revealed an additive effect as even lower serum alanine aminotransferase activity was observed. Blocking of connexin32 or connexin43 hemichannels individually was found to decrease serum quantities of pro-inflammatory cytokines, while no effects were observed on the occurrence of hepatic oxidative stress. This study shows for the first time a role for connexin hemichannels in acetaminophen-induced acute liver failure. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Effects of acetyl salycilic acid and ibuprofen in chronic liver damage induced by CCl4.

    PubMed

    Chávez, Enrique; Castro-Sánchez, Luis; Shibayama, Mineko; Tsutsumi, Victor; Pérez Salazar, Eduardo; Moreno, Mario G; Muriel, Pablo

    2012-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are drugs used primarily to treat inflammation, pain and fever. Their main mechanism of action is cyclooxygenase (COX) inhibition, and this enzyme has been linked to hepatotoxicity. The association of COX and liver injury has been, in part, due to the presence of COX-2 isoform in damaged liver and the possible induction of this enzyme by profibrotic molecules like Transforming Growth Factor-β (TGF-β). The aim of this work was to evaluate the effects of two of the most used NSAIDs, acetyl salicylic acid (ASA) and ibuprofen (IBP), on experimental liver fibrosis. We formed experimental groups of rats including vehicle and drug controls, damage induced by chronic CCl4 (0.4 g kg(-1) , i.p., three times per week, for 8 weeks) administration, and CCl4 plus ASA (100 mg kg(-1) , p.o., daily) or IBP (30 mg kg(-1) , p.o., daily). Both drugs showed important antifibrotic properties. They inhibited COX-2 activity, prevented oxidative stress measured as lipid peroxidation and glutathione content, and ASA inhibited partially and IBP totally increased TGF-β expression and collagen content. ASA and IBP prevented translocation of NFκB to the nucleus and, interestingly, ASA induced MMP-2 and MMP-13 whereas IBP induced MMP-2, MMP-9 and MMP-13. As a whole, these effects explain the beneficial effects of ASA and IBP on experimental liver fibrosis. Copyright © 2011 John Wiley & Sons, Ltd.

  14. Hepatoprotective Effect of Cuscuta campestris Yunck. Whole Plant on Carbon Tetrachloride Induced Chronic Liver Injury in Mice.

    PubMed

    Peng, Wen-Huang; Chen, Yi-Wen; Lee, Meng-Shiou; Chang, Wen-Te; Tsai, Jen-Chieh; Lin, Ying-Chih; Lin, Ming-Kuem

    2016-12-07

    Cuscuta seeds and whole plant have been used to nourish the liver and kidney. This study was aimed to investigate the hepatoprotective activity of the ethanol extract of Cuscuta campestris Yunck. whole plant (CC EtOH ). The hepatoprotective effect of CC EtOH (20, 100 and 500 mg/kg) was evaluated on carbon tetrachloride (CCl₄)-induced chronic liver injury. Serum alanine aminotransferase, aspartate aminotransferase, triglyceride and cholesterol were measured and the fibrosis was histologically examined. CC EtOH exhibited a significant inhibition of the increase of serum alanine aminotransferase, aspartate aminotransferase, triglyceride and cholesterol. Histological analyses showed that fibrosis of liver induced by CCl₄ were significantly reduced by CC EtOH . In addition, 20, 100 and 500 mg/kg of the extract decreased the level of malondialdehyde (MDA) and enhanced the activities of anti-oxidative enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRd) in the liver. We demonstrate that the hepatoprotective mechanisms of CC EtOH were likely to be associated to the decrease in MDA level by increasing the activities of antioxidant enzymes such as SOD, GPx and GRd. In addition, our findings provide evidence that C. campestris Yunck. whole plant possesses a hepatoprotective activity to ameliorate chronic liver injury.

  15. Hepatoprotective Effect of Cuscuta campestris Yunck. Whole Plant on Carbon Tetrachloride Induced Chronic Liver Injury in Mice

    PubMed Central

    Peng, Wen-Huang; Chen, Yi-Wen; Lee, Meng-Shiou; Chang, Wen-Te; Tsai, Jen-Chieh; Lin, Ying-Chih; Lin, Ming-Kuem

    2016-01-01

    Cuscuta seeds and whole plant have been used to nourish the liver and kidney. This study was aimed to investigate the hepatoprotective activity of the ethanol extract of Cuscuta campestris Yunck. whole plant (CCEtOH). The hepatoprotective effect of CCEtOH (20, 100 and 500 mg/kg) was evaluated on carbon tetrachloride (CCl4)-induced chronic liver injury. Serum alanine aminotransferase, aspartate aminotransferase, triglyceride and cholesterol were measured and the fibrosis was histologically examined. CCEtOH exhibited a significant inhibition of the increase of serum alanine aminotransferase, aspartate aminotransferase, triglyceride and cholesterol. Histological analyses showed that fibrosis of liver induced by CCl4 were significantly reduced by CCEtOH. In addition, 20, 100 and 500 mg/kg of the extract decreased the level of malondialdehyde (MDA) and enhanced the activities of anti-oxidative enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRd) in the liver. We demonstrate that the hepatoprotective mechanisms of CCEtOH were likely to be associated to the decrease in MDA level by increasing the activities of antioxidant enzymes such as SOD, GPx and GRd. In addition, our findings provide evidence that C. campestris Yunck. whole plant possesses a hepatoprotective activity to ameliorate chronic liver injury. PMID:27941627

  16. Polysaccharides from Cordyceps sinensis mycelium ameliorate exhaustive swimming exercise-induced oxidative stress.

    PubMed

    Yan, Feng; Wang, Beibei; Zhang, Yan

    2014-02-01

    Cordyceps sinensis (Berk.) Sacc. (Clavicipitaceae) is a famous medicinal fungus (mushroom) in Chinese herbal medicine. Polysaccharides from Cordyceps sinensis (CSP) have been identified as active ingredients responsible for its biological activities. Although many pharmacological actions of CSP have received a great deal of attention, research in this area continues. The current study was designed to investigate the effects of CSP on exhaustive exercise-induced oxidative stress. The mice were divided into four groups: control (C), low-dose CSP treated (LC), intermediate-dose CSP treated (IC) and high-dose CSP treated (HC). The treated groups received CSP (100, 200 and 400 mg/kg, ig), while the control group received drinking water for 28 days, followed by being forced to undergo exhaustive swimming exercise, and some biochemical parameters including superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured using detection kits according to the manufacturers' instructions. Compared with the C group, exhaustive swimming time was significantly prolonged in the LC, IC and HC groups (p < 0.05); SOD activities in serum, liver and muscle were significantly higher in the IC and HC groups (p < 0.05); GPx activities in serum, liver and muscle were significantly higher in the LC, IC and HC groups (p < 0.05); CAT activities in serum, liver and muscle were significantly higher in the HC groups (p < 0.05); MDA and 8-OHdG levels in serum, liver and muscle were significantly lower in the LC, IC and HC groups (p < 0.05). The results obtained herein indicate that CSP could ameliorate exhaustive exercise-induced oxidative stress.

  17. Vitamin D3-induced hypercalcemia increases carbon tetrachloride-induced hepatotoxicity through elevated oxidative stress in mice

    PubMed Central

    Usuda, Haruki; Miura, Nobuhiko; Fukuishi, Nobuyuki; Nonogaki, Tsunemasa; Onosaka, Satomi

    2017-01-01

    The aim of this study was to determine whether calcium potentiates acute carbon tetrachloride (CCl4) -induced toxicity. Elevated calcium levels were induced in mice by pre-treatment with cholecalciferol (vitamin D3; V.D3), a compound that has previously been shown to induce hypercalcemia in human and animal models. As seen previously, mice injected with CCl4 exhibited increased plasma levels of alanine aminotransferase, aspartate aminotransferase, and creatinine; transient body weight loss; and increased lipid peroxidation along with decreased total antioxidant power, glutathione, ATP, and NADPH. Pre-treatment of these animals with V.D3 caused further elevation of the values of these liver functional markers without altering kidney functional markers; continued weight loss; a lower lethal threshold dose of CCl4; and enhanced effects on lipid peroxidation and total antioxidant power. In contrast, exposure to V.D3 alone had no effect on plasma markers of liver or kidney damage or on total antioxidant power or lipid peroxidation. The potentiating effect of V.D3 was positively correlated with elevation of hepatic calcium levels. Furthermore, direct injection of CaCl2 also enhanced CCl4-induced hepatic injury. Since CaCl2 induced hypercalcemia transiently (within 3 h of injection), our results suggest that calcium enhances the CCl4-induced hepatotoxicity at an early stage via potentiation of oxidative stress. PMID:28448545

  18. Toxic metabolites, MAPK and Nrf2/Keap1 signaling pathways involved in oxidative toxicity in mice liver after chronic exposure to Mequindox.

    PubMed

    Liu, Qianying; Lei, Zhixin; Huang, Anxiong; Wu, Qinghua; Xie, Shuyu; Awais, Ihsan; Dai, Menghong; Wang, Xu; Yuan, Zonghui

    2017-02-03

    Mequindox (MEQ) is a synthetic antimicrobial agent of quinoxaline-1,4-dioxide group (QdNOs). The liver is regarded as the toxicity target of QdNOs, and the role of N → O group-associated various toxicities mediated by QdNOs is well recognized. However, the mechanism underlying the in vivo effects of MEQ on the liver, and whether the metabolic pathway of MEQ is altered in response to the pathophysiological conditions still remain unclear. We now provide evidence that MEQ triggers oxidative damage in the liver. Moreover, using LC/MS-ITTOF analysis, two metabolites of MEQ were detected in the liver, which directly confirms the potential connection between N → O group reduction metabolism of MEQ and liver toxicity. The gender difference in MEQ-induced oxidative stress might be due to adrenal toxicity and the generation of M4 (2-isoethanol 1-desoxymequindox). Furthermore, up-regulation of the MAPK and Nrf2-Keap1 family and phase II detoxifying enzymes (HO-1, GCLC and NQO1) were also observed. The present study demonstrated for the first time the protein peroxidation and a proposal metabolic pathway after chronic exposure of MEQ, and illustrated that the MAPK, Nrf2-Keap1 and NF-кB signaling pathways, as well as the altered metabolism of MEQ, were involved in oxidative toxicity mediated by MEQ in vivo.

  19. Toxic metabolites, MAPK and Nrf2/Keap1 signaling pathways involved in oxidative toxicity in mice liver after chronic exposure to Mequindox

    PubMed Central

    Liu, Qianying; Lei, Zhixin; Huang, Anxiong; Wu, Qinghua; Xie, Shuyu; Awais, Ihsan; Dai, Menghong; Wang, Xu; Yuan, Zonghui

    2017-01-01

    Mequindox (MEQ) is a synthetic antimicrobial agent of quinoxaline-1,4-dioxide group (QdNOs). The liver is regarded as the toxicity target of QdNOs, and the role of N → O group-associated various toxicities mediated by QdNOs is well recognized. However, the mechanism underlying the in vivo effects of MEQ on the liver, and whether the metabolic pathway of MEQ is altered in response to the pathophysiological conditions still remain unclear. We now provide evidence that MEQ triggers oxidative damage in the liver. Moreover, using LC/MS-ITTOF analysis, two metabolites of MEQ were detected in the liver, which directly confirms the potential connection between N → O group reduction metabolism of MEQ and liver toxicity. The gender difference in MEQ-induced oxidative stress might be due to adrenal toxicity and the generation of M4 (2-isoethanol 1-desoxymequindox). Furthermore, up-regulation of the MAPK and Nrf2-Keap1 family and phase II detoxifying enzymes (HO-1, GCLC and NQO1) were also observed. The present study demonstrated for the first time the protein peroxidation and a proposal metabolic pathway after chronic exposure of MEQ, and illustrated that the MAPK, Nrf2-Keap1 and NF-кB signaling pathways, as well as the altered metabolism of MEQ, were involved in oxidative toxicity mediated by MEQ in vivo. PMID:28157180

  20. Obstructive Sleep Apnea and Non-Alcoholic Fatty Liver Disease: Is the Liver Another Target?

    PubMed Central

    Mirrakhimov, Aibek E.; Polotsky, Vsevolod Y.

    2012-01-01

    Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH). OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD). NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH), liver fibrosis, and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1) IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA) flux into the liver; (2) IH up-regulates lipid biosynthetic pathways in the liver; (3) IH induces oxidative stress in the liver; (4) IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done. PMID:23087670

  1. N-Acetylcysteine Use in Non-Acetaminophen-Induced Acute Liver Failure.

    PubMed

    McPheeters, Chelsey M; VanArsdale, Vanessa M; Weant, Kyle A

    2016-01-01

    This article will review the available evidence related to the management of non-acetaminophen induced acute liver failure with N-acetylcysteine. Randomized controlled trials and a meta-analysis were included in this review. The efficacy of N-acetylcysteine in the treatment of acute liver failure from causes other than acetaminophen toxicity was evaluated. The efficacy of N-acetylcysteine in non-acetaminophen-induced acute liver failure is limited to specific patient populations. Patients classified as Coma Grade I or II are more likely to benefit from the use of this agent. The use of N-acetylcysteine is associated with improved transplant-free survival, not overall survival, in adults. N-Acetylcysteine does not improve the overall survival of patients with non-acetaminophen-induced acute liver failure but may be beneficial in those patients with Coma Grades I-II. Liver transplantation remains the only definitive therapy in advanced disease.

  2. Protective effect of Piper betle leaf extract against cadmium-induced oxidative stress and hepatic dysfunction in rats

    PubMed Central

    Milton Prabu, S.; Muthumani, M.; Shagirtha, K.

    2012-01-01

    The present study was undertaken to examine the attenuative effect of Piper betle leaf extract (PBE) against cadmium (Cd) induced oxidative hepatic dysfunction in the liver of rats. Pre-oral supplementation of PBE (200 mg/kg BW) treated rats showed the protective efficacy against Cd induced hepatic oxidative stress. Oral administration of Cd (5 mg/kg BW) for four weeks to rats significantly (P > 0.05) elevated the level of serum hepatic markers such as serum aspartate transaminase (AST), serum alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT), bilirubin (TBRNs), oxidative stress markers viz., thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH), protein carbonyls (PC) and conjugated dienes (CD) and significantly (P > 0.05) reduced the enzymatic antioxidants viz., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PD) and non-enzymatic antioxidants Viz., reduced glutathione (GSH), total sulfhydryls (TSH), vitamin C and vitamin E in the liver. Pre-oral supplementation of PBE (200 mg/kg BW) in Cd intoxicated rats, the altered biochemical indices and pathological changes were recovered significantly (P > 0.05) which showed ameliorative effect of PBE against Cd induced hepatic oxidative stress. From the above findings, we suggested that the pre-administration of P. betle leaf extract exhibited remarkable protective effects against cadmium-induced oxidative hepatic injury in rats. PMID:23961183

  3. Protective effect of Piper betle leaf extract against cadmium-induced oxidative stress and hepatic dysfunction in rats.

    PubMed

    Milton Prabu, S; Muthumani, M; Shagirtha, K

    2012-04-01

    The present study was undertaken to examine the attenuative effect of Piper betle leaf extract (PBE) against cadmium (Cd) induced oxidative hepatic dysfunction in the liver of rats. Pre-oral supplementation of PBE (200 mg/kg BW) treated rats showed the protective efficacy against Cd induced hepatic oxidative stress. Oral administration of Cd (5 mg/kg BW) for four weeks to rats significantly (P > 0.05) elevated the level of serum hepatic markers such as serum aspartate transaminase (AST), serum alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT), bilirubin (TBRNs), oxidative stress markers viz., thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH), protein carbonyls (PC) and conjugated dienes (CD) and significantly (P > 0.05) reduced the enzymatic antioxidants viz., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PD) and non-enzymatic antioxidants Viz., reduced glutathione (GSH), total sulfhydryls (TSH), vitamin C and vitamin E in the liver. Pre-oral supplementation of PBE (200 mg/kg BW) in Cd intoxicated rats, the altered biochemical indices and pathological changes were recovered significantly (P > 0.05) which showed ameliorative effect of PBE against Cd induced hepatic oxidative stress. From the above findings, we suggested that the pre-administration of P. betle leaf extract exhibited remarkable protective effects against cadmium-induced oxidative hepatic injury in rats.

  4. Diphenylarsinic acid, a chemical warfare-related neurotoxicant, promotes liver carcinogenesis via activation of aryl hydrocarbon receptor signaling and consequent induction of oxidative DAN damage in rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wei, Min; Yamada, Takanori; Yamano, Shotaro

    2013-11-15

    Diphenylarsinic acid (DPAA), a chemical warfare-related neurotoxic organic arsenical, is present in the groundwater and soil in some regions of Japan due to illegal dumping after World War II. Inorganic arsenic is carcinogenic in humans and its organic arsenic metabolites are carcinogenic in animal studies, raising serious concerns about the carcinogenicity of DPAA. However, the carcinogenic potential of DPAA has not yet been evaluated. In the present study we found that DPAA significantly enhanced the development of diethylnitrosamine-induced preneoplastic lesions in the liver in a medium-term rat liver carcinogenesis assay. Evaluation of the expression of cytochrome P450 (CYP) enzymes inmore » the liver revealed that DPAA induced the expression of CYP1B1, but not any other CYP1, CYP2, or CYP3 enzymes, suggesting that CYP1B1 might be the enzyme responsible for the metabolic activation of DPAA. We also found increased oxidative DNA damage, possibly due to elevated CYP1B1 expression. Induction of CYP1B1 has generally been linked with the activation of AhR, and we found that DPAA activates the aryl hydrocarbon receptor (AhR). Importantly, the promotion effect of DPAA was observed only at a dose that activated the AhR, suggesting that activation of AhR and consequent induction of AhR target genes and oxidative DNA damage plays a vital role in the promotion effects of DPAA. The present study provides, for the first time, evidence regarding the carcinogenicity of DPAA and indicates the necessity of comprehensive evaluation of its carcinogenic potential using long-term carcinogenicity studies. - Highlights: • DPAA, an environmental neurotoxicant, promotes liver carcinogenesis in rats. • DPAA is an activator of AhR signaling pathway. • DPAA promoted oxidative DNA damage in rat livers. • AhR target gene CYP 1B1 might be involved in the metabolism of DPAA.« less

  5. 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.

  6. Protective Effect of Procyanidin B2 against CCl4-Induced Acute Liver Injury in Mice.

    PubMed

    Yang, Bing-Ya; Zhang, Xiang-Yu; Guan, Sheng-Wen; Hua, Zi-Chun

    2015-07-03

    Procyanidin B2 has demonstrated several health benefits and medical properties. However, its protective effects against CCl4-induced hepatotoxicity have not been clarified. The present study aimed to investigate the hepatoprotective effects of procyanidin B2 in CCl4-treated mice. Our data showed that procyanidin B2 significantly decreased the CCl4-induced elevation of serum alanine aminotransferase activities, as well as improved hepatic histopathological abnormalities. Procyanidin B2 also significantly decreased the content of MDA but enhanced the activities of antioxidant enzymes SOD, CAT and GSH-Px. Further research demonstrated that procyanidin B2 decreased the expression of TNF-α, IL-1β, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), as well as inhibited the translocation of nuclear factor-kappa B (NF-κB) p65 from the cytosol to the nuclear fraction in mouse liver. Moreover, CCl4-induced apoptosis in mouse liver was measured by (terminal-deoxynucleotidyl transferase mediated nick end labeling) TUNEL assay and the cleaved caspase-3. Meanwhile, the expression of apoptosis-related proteins Bax and Bcl-xL was analyzed by Western blot. Results showed that procyanidin B2 significantly inhibited CCl4-induced hepatocyte apoptosis, markedly suppressed the upregulation of Bax expression and restored the downregulation of Bcl-xL expression. Overall, the findings indicated that procyanidin B2 exhibited a protective effect on CCl4-induced hepatic injury by elevating the antioxidative defense potential and consequently suppressing the inflammatory response and apoptosis of liver tissues.

  7. Carbon monoxide alleviates ethanol-induced oxidative damage and inflammatory stress through activating p38 MAPK pathway

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Li, Yanyan; Gao, Chao; Shi, Yanru

    2013-11-15

    Stress-inducible protein heme oxygenase-1(HO-1) is well-appreciative to counteract oxidative damage and inflammatory stress involving the pathogenesis of alcoholic liver diseases (ALD). The potential role and signaling pathways of HO-1 metabolite carbon monoxide (CO), however, still remained unclear. To explore the precise mechanisms, ethanol-dosed adult male Balb/c mice (5.0 g/kg.bw.) or ethanol-incubated primary rat hepatocytes (100 mmol/L) were pretreated by tricarbonyldichlororuthenium (II) dimmer (CORM-2, 8 mg/kg for mice or 20 μmol/L for hepatocytes), as well as other pharmacological reagents. Our data showed that CO released from HO-1 induction by quercetin prevented ethanol-derived oxidative injury, which was abolished by CO scavenger hemoglobin.more » The protection was mimicked by CORM-2 with the attenuation of GSH depletion, SOD inactivation, MDA overproduction, and the leakage of AST, ALT or LDH in serum and culture medium induced by ethanol. Moreover, CORM-2 injection or incubation stimulated p38 phosphorylation and suppressed abnormal Tnfa and IL-6, accompanying the alleviation of redox imbalance induced by ethanol and aggravated by inflammatory factors. The protective role of CORM-2 was abolished by SB203580 (p38 inhibitor) but not by PD98059 (ERK inhibitor) or SP600125 (JNK inhibitor). Thus, HO-1 released CO prevented ethanol-elicited hepatic oxidative damage and inflammatory stress through activating p38 MAPK pathway, suggesting a potential therapeutic role of gaseous signal molecule on ALD induced by naturally occurring phytochemicals. - Highlights: • CO alleviated ethanol-derived liver oxidative and inflammatory stress in mice. • CO eased ethanol and inflammatory factor-induced oxidative damage in hepatocytes. • The p38 MAPK is a key signaling mechanism for the protective function of CO in ALD.« less

  8. Melatonin attenuates oxidative stress, liver damage and hepatocyte apoptosis after bile-duct ligation in rats.

    PubMed

    Aktas, Cevat; Kanter, Mehmet; Erboga, Mustafa; Mete, Rafet; Oran, Mustafa

    2014-10-01

    The goal of this study was to evaluate the possible protective effects of melatonin against cholestatic oxidative stress, liver damage and hepatocyte apoptosis in the common rats with bile duct ligation (BDL). A total of 24 male Wistar albino rats were divided into three groups: control, BDL and BDL + received melatonin; each group contains eight animals. Melatonin-treated BDL rats received daily melatonin 100 mg/kg/day via intraperitoneal injection. The application of BDL clearly increased the malondialdehyde (MDA) levels and decreased the superoxide dismutase (SOD) and glutathione (GSH) activities. Melatonin treatment significantly decreased the elevated tissue MDA levels and increased the reduced SOD and GSH enzyme levels in the tissues. The changes demonstrate that the bile duct proliferation and fibrosis in expanded portal tracts include the extension of proliferated bile ducts into lobules, mononuclear cells and neutrophil infiltration into the widened portal areas as observed in the BDL group. The data indicate that melatonin attenuates BDL-induced cholestatic liver injury, bile duct proliferation and fibrosis. The α-smooth muscle actin (α-SMA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in the BDL were observed to be reduced with the melatonin treatment. These results suggest that administration of melatonin is a potentially beneficial agent to reduce liver damage in BDL by decreasing oxidative stress. © The Author(s) 2012.

  9. Hepatoprotective efficacy of Spirulina platensis against lead-induced oxidative stress and genotoxicity in catfish; Clarias gariepinus.

    PubMed

    Sayed, Alaa El-Din H; El-Sayed, Yasser S; El-Far, Ali H

    2017-09-01

    Lead (Pb) is a toxic environmental pollutant that induces a broad range of biochemical and physiological hazards in living organisms. We investigated the possible hepatoprotective effects of Spirulina platensis (SP) in counteracting the Pb-induced oxidative damage. Ninety-six adult African catfish were allocated into four equal groups. The 1st group (control) fed basal diet while the 2nd group (Pb-treated) fed on basal diet and exposed to 1mg Pb(NO 3 ) 2 /L. The 3rd and 4th groups fed SP-supplemented basal diets at levels of 0.25% and 0.5%, respectively and exposed to Pb. Serum samples were used to analyze hepatic function biomarkers, electrolytes, and oxidant and antioxidant status. Lipid peroxidation and DNA fragmentation were determined in the liver tissues. Pb exposure induced hepatic dysfunction, electrolytes (Na + , K + , Ca +2 , and Cl - ) imbalance, as well a significant decrease in GSH content, and LDH, AChE, SOD, CAT and GST enzymes activity. SP supplementation reverted these biochemical and genetic alterations close to control levels. This amelioration was higher with 0.5% SP and at the 4th week of exposure, showing concentration- and time-dependency. Thus, the current study suggests that SP could protect the catfish liver against lead-induced injury by scavenging ROS, sustaining the antioxidant status and diminishing DNA oxidative damage. The dietary inclusion of SP can be used as a promising protective agent to counteract oxidative stress-mediated diseases and toxicities. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yannam, Govardhana Rao; Han, Bing; Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevatedmore » alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.« less

  11. NMR-based metabonomic and quantitative real-time PCR in the profiling of metabolic changes in carbon tetrachloride-induced rat liver injury.

    PubMed

    Li, Xiaowei; Zhang, Fusheng; Wang, Dongqin; Li, Zhenyu; Qin, Xuemei; Du, Guanhua

    2014-02-01

    Carbon tetrachloride (CCl4) is commonly used as a model toxicant to induce chronic and acute liver injuries. In this study, metabolite profiling and gene expression analysis of liver tissues were performed by nuclear magnetic resonance and quantitative real-time polymerase chain reaction to understand the responses of acute liver injury system in rats to CCl4. Acute liver injury was successfully induced by CCl4 as revealed by histopathological results and significant increase in alanine aminotransferase and serum aspartate aminotransferase. We found that CCl4 caused a significant increase in lactate, succinate, citrate, dimethylgycine, choline and taurine. CCl4 also caused a decrease in some of the amino acids such as leucine/isoleucine, glutamine/glutathione and betaine. Gene function analysis revealed that 10 relevant enzyme genes exhibited changes in expressions in the acute liver injury model. In conclusion, the metabolic pathways, including tricarboxylic acid cycle, antioxidant defense systems, fatty acid β-oxidation, glycolysis and choline and mevalonate metabolisms were impaired in CCl4-treated rat livers. These findings provided an overview of the biochemical consequences of CCl4 exposure and comprehensive insights into the metabolic aspects of CCl4-induced hepatotoxicity in rats. These findings may also provide reference of the mechanisms of acute liver injury that could be used to study the changes in functional genes and metabolites. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Induction of peroxisomal beta-oxidation by a microbial catabolite of cholic acid in rat liver and cultured rat hepatocytes.

    PubMed Central

    Nishimaki-Mogami, T; Takahashi, A; Toyoda, K; Hayashi, Y

    1993-01-01

    The capability of (4R)-4-(2,3,4,6,6a beta,7,8,9,9a alpha,9b beta-decahydro-6a beta-methyl-3-oxo-1H-cyclopental[f]quinolin-7 beta-yl)valeric acid (DCQVA), a catabolite of cholic acid produced by enterobacteria, to induce peroxisome proliferation in vivo and in vitro was studied. Rats given 0.3% DCQVA in the diet for 2 weeks showed marked increases in peroxisomal beta-oxidation, mitochondrial 2,4-dienoyl-CoA reductase and microsomal laurate omega-oxidation activities in the liver compared with control rats given the diet without DCQVA. Cultured rat hepatocytes treated with DCQVA for 72 h also exhibited greatly enhanced beta-oxidation activity. The increased activity was concentration-dependent and the effective concentrations were comparable with those of clofibric acid that produced the same degree of induction in the assay. The results demonstrate that DCQVA is a potent peroxisome proliferator that occurs naturally in rat intestine. PMID:8216219

  13. Choline-Deficient-Diet-Induced Fatty Liver Is a Metastasis-Resistant Microenvironment.

    PubMed

    Nakamura, Miki; Suetsugu, Atsushi; Hasegawa, Kosuke; Matsumoto, Takuro; Aoki, Hitomi; Kunisada, Takahiro; Shimizu, Masahito; Saji, Shigetoyo; Moriwaki, Hisataka; Hoffman, Robert M

    2017-07-01

    Fatty liver disease is increasing in the developed and developing world. Liver metastasis from malignant lymphoma in the fatty liver is poorly understood. In a previous report, we developed color-coded imaging of the tumor microenvironment (TME) of the murine EL4-RFP malignant lymphoma during metastasis, including the lung. In the present report, we investigated the potential and microenvironment of the fatty liver induced by a choline-deficient diet as a metastatic site in this mouse lymphoma model. C57BL/6-GFP transgenic mice were fed with a choline-deficient diet in order to establish a fatty liver model. EL4-RFP cells were injected in the spleen of normal mice and fatty-liver mice. Metastases in mice with fatty liver or normal liver were imaged with the Olympus SZX7 microscope and the Olympus FV1000 confocal microscope. Metastases of EL4-RFP were observed in the liver, ascites and bone marrow. Primary tumors were imaged in the spleen at the injection site. The fewest metastases were observed in the fatty liver. In addition, the fewest cancer-associated fibroblasts (CAFs) were observed in the fatty liver. The relative metastatic resistance of the fatty liver may be due to the reduced number of CAFs in the fatty livers. The mechanism of the effect of the choline-deficient diet is discussed. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  14. Protective potential of Black grapes against lead induced oxidative stress in rats.

    PubMed

    Lakshmi, B V S; Sudhakar, M; Aparna, M

    2013-05-01

    From time immemorial Vitis vinifera (Black grapes) have been used both for medicinal and nourishment purposes. The aim of this study is to investigate the protective effect of Black grapes against lead nitrate induced oxidative stress. Exposure to lead significantly increased malondialdehyde levels with a significant decrease in superoxide dismutase and catalase activities, and the concentration of GSH in the liver and kidneys of rats. Significantly increased levels of AST, ALT, ALP, BUN and serum creatinine and decreased levels of total protein were observed. The administration of lead significantly decreased the body weight and organ weights at the end of the experimental period. Statistically significant decrease in hemoglobin, red blood cell and total leukocyte count was observed. Pretreatment of hydroalcoholic extract of Black grapes to lead exposed rats significantly ameliorated lead-induced oxidative stress in tissues and produced improvement in hematological parameters over lead-exposed rats, indicating the beneficial role of Black grapes to counteract the lead-induced oxidative stress. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhang, Da-Gang

    The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl{sub 4})-induced acute liver injury. Mice were intraperitoneally injected with CCl{sub 4} (0.15 ml/kg). In CCl{sub 4} + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl{sub 4}. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl{sub 4}-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatmentmore » inhibited CCl{sub 4}-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl{sub 4}-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl{sub 4}-induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl{sub 4}-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl{sub 4}-induced acute liver injury. These results suggest that OCA protects against CCl{sub 4}-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl{sub 4}-induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl{sub 4}-induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.« less

  16. Non-invasive evaluation of liver stiffness after splenectomy in rabbits with CCl4-induced liver fibrosis.

    PubMed

    Wang, Ming-Jun; Ling, Wen-Wu; Wang, Hong; Meng, Ling-Wei; Cai, He; Peng, Bing

    2016-12-14

    To investigate the diagnostic performance of liver stiffness measurement (LSM) by elastography point quantification (ElastPQ) in animal models and determine the longitudinal changes in liver stiffness by ElastPQ after splenectomy at different stages of fibrosis. Liver stiffness was measured in sixty-eight rabbits with CCl 4 -induced liver fibrosis at different stages and eight healthy control rabbits by ElastPQ. Liver biopsies and blood samples were obtained at scheduled time points to assess liver function and degree of fibrosis. Thirty-one rabbits with complete data that underwent splenectomy at different stages of liver fibrosis were then included for dynamic monitoring of changes in liver stiffness by ElastPQ and liver function according to blood tests. LSM by ElastPQ was significantly correlated with histologic fibrosis stage ( r = 0.85, P < 0.001). The optimal cutoff values by ElastPQ were 11.27, 14.89, and 18.21 kPa for predicting minimal fibrosis, moderate fibrosis, and cirrhosis, respectively. Longitudinal monitoring of the changes in liver stiffness by ElastPQ showed that early splenectomy (especially F1) may delay liver fibrosis progression. ElastPQ is an available, convenient, objective and non-invasive technique for assessing liver stiffness in rabbits with CCl 4 -induced liver fibrosis. In addition, liver stiffness measurements using ElastPQ can dynamically monitor the changes in liver stiffness in rabbit models, and in patients, after splenectomy.

  17. The chemoprotection of a blueberry anthocyanin extract against the acrylamide-induced oxidative stress in mitochondria: unequivocal evidence in mice liver.

    PubMed

    Zhao, Mengyao; Wang, Pengpu; Zhu, Yuchen; Liu, Xin; Hu, Xiaosong; Chen, Fang

    2015-09-01

    Acrylamide (AA) is one of the most important contaminants occurring in heated food products. Accumulating evidence indicates that AA-induced toxicity is associated with oxidative stress and long-term exposure to AA induced mitochondria collapse and finally leads to apoptosis. Whereas anthocyanins are natural antioxidants and have a strong ability to reduce oxidative damage in vivo. This study investigates the protection of a blueberry anthocyanin extract (BAE) against AA-induced mitochondrial oxidative stress in mice models. The activities of electron transport chain complexes, oxidative status, and the structure and function of mitochondria were measured. Results showed that pretreatment with BAE markedly inhibited reactive oxygen species (ROS) formation, and prevented the successive events associated with the mitochondrial damage and dysfunction, including recovered activities of electron transport chain, ATPase and superoxide dismutase, ameliorated depolarization of mitochondrial membrane potential and membrane lipid peroxidation, reduced release of cytochrome c and protection of mitochondria against swelling. In a word, mitochondria are a key target at the organelle level for the protective effect of BAE against AA toxicity. These results will be helpful to provide new clues for a better understanding of the AA toxicity intervention mechanism and for exploring effective dietary constituents for intervention of AA toxicity.

  18. 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.

  19. Ameliorating reactive oxygen species-induced in vitro lipid peroxidation in brain, liver, mitochondria and DNA damage by Zingiber officinale Roscoe.

    PubMed

    Ajith, T A

    2010-01-01

    Iron is an essential nutrient for a number of cellular activities. However, excess cellular iron can be toxic by producing reactive oxygen species (ROS) such as superoxide anion (O(2) (-)) and hydroxyl radical (HO(·)) that damage proteins, lipids and DNA. Mutagenic and genotoxic end products of lipid peroxidation can induce the decline of mitochondrial respiration and are associated with various human ailments including aging, neurodegenerative disorders, cancer etc. Zingiber officinale Roscoe (ginger) is a widely used spice around the world. The protective effect of aqueous ethanol extract of Z. officinale against ROS-induced in vitro lipid peroxidation and DNA damage was evaluated in this study. The lipid peroxidation was induced by hydroxyl radical generated from Fenton's reaction in rat liver and brain homogenates and mitochondrial fraction (isolated from rat liver). The DNA protection was evaluated using H(2)O(2)-induced changes in pBR-322 plasmid and Fenton reaction-induced DNA fragmentation in rat liver. The results indicated that Z. officinale significantly (P<0.001) protected the lipid peroxidation in all the tissue homogenate/mitochondria. The extract at 2 and 0.5 mg/ml could protect 92 % of the lipid peroxidation in brain homogenate and liver mitochondria respectively. The percent inhibition of lipid peroxidation at 1mg/ml of Z. officinale in the liver homogenate was 94 %. However, the extract could partially alleviate the DNA damage. The protective mechanism can be correlated to the radical scavenging property of Z. officinale. The results of the study suggest the possible nutraceutical role of Z. officinale against the oxidative stress induced human ailments.

  20. Paeoniflorin regulates macrophage activation in dimethylnitrosamine-induced liver fibrosis in rats

    PubMed Central

    2012-01-01

    Background Macrophages in other organs (e.g. kidneys, lungs, and spleen, et. al) have rarely been reported in the development of liver fibrosis. Therefore, it is important to investigate macrophage activation in the main organs in liver fibrosis. We investigated the potential antifibrogenic effects of paeoniflorin (PF) in a dimethylnitrosamine (DMN)-induced rat model with special focus on inhibiting macrophage activation in the main organs. Methods Rat hepatic fibrosis was induced by treatment with DMN three times weekly over a 4-week period. DMN rats were treated with water, PF, or gadolinium chloride (GdCl3) from the beginning of the 3rd week. The expression of CD68, marker of macrophage, was investigated using immunohistochemical, real-time PCR, and western blot analysis. Results Hepatic hydroxyproline content markedly decreased and histopathology improved in the DMN-PF rats. Expression of desmin and collagen 1 decreased notably in DMN-PF liver. CD68 expression in the liver, spleen and kidney increased markedly after 2 weeks but decreased in DMN-water rats. PF and GdCl3 decreased CD68 expression in the liver and spleen and there was no effect on kidney. CD68 expression in the lung increased gradually during the course of DMN-induced liver fibrosis, and PF inhibited CD68 expression in the lung significantly while GdCl3 increased CD68 markedly. Expression of tumor necrosis factor (TNF-α) was decreased significantly by GdCl3 in the liver, as revealed by real-time PCR analysis. However, GdCl3 could not decrease TNF-α level in the serum by enzyme linked immunosorbent assay (ELISA). Conclusions Macrophage activation was disrupted in the liver, spleen, lung and kidney during development of DMN-induced liver fibrosis. PF administration attenuated DMN-induced liver fibrosis at least in part by regulating macrophage disruption in the main organs. PMID:23237422

  1. SNX10 mediates alcohol-induced liver injury and steatosis by regulating the activation of chaperone-mediated autophagy.

    PubMed

    You, Yan; Li, Wan-Zhen; Zhang, Sulin; Hu, Bin; Li, Yue-Xuan; Li, Hai-Dong; Tang, Huan-Huan; Li, Qian-Wen; Guan, Yun-Yun; Liu, Li-Xin; Bao, Wei-Lian; Shen, Xiaoyan

    2018-07-01

    Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. However, the cellular defense mechanisms underlying ALD are not well understood. Recent studies highlighted the involvement of chaperone-mediated autophagy (CMA) in regulating hepatic lipid metabolism. Sorting nexin (SNX)-10 has a regulatory function in endolysosomal trafficking and stabilisation. Here, we investigated the roles of SNX10 in CMA activation and in the pathogenesis of alcohol-induced liver injury and steatosis. Snx10 knockout (Snx10 KO) mice and their wild-type (WT) littermates fed either the Lieber-DeCarli liquid alcohol diet or a control liquid diet, and primary cultured WT and Snx10 KO hepatocytes stimulated with ethanol, were used as in vivo and in vitro ALD models, respectively. Activation of CMA, liver injury parameters, inflammatory cytokines, oxidative stress and lipid metabolism were measured. Compared with WT littermates, Snx10 KO mice exhibited a significant amelioration in ethanol-induced liver injury and hepatic steatosis. Both in vivo and in vitro studies showed that SNX10 deficiency upregulated lysosome-associated membrane protein type 2A (LAMP-2A) expression and CMA activation, which could be reversed by SNX10 overexpression in vitro. LAMP-2A interference confirmed that the upregulation of Nrf2 and AMPK signalling pathways induced by SNX10 deficiency relied on CMA activation. Pull-down assays revealed an interaction between SNX10 and cathepsin A (CTSA), a key enzyme involved in LAMP-2A degradation. Deficiency in SNX10 inhibited CTSA maturation and increased the stability of LAMP-2A, resulting in an increase in CMA activity. SNX10 controls CMA activity by mediating CTSA maturation, and, thus, has an essential role in alcohol-induced liver injury and steatosis. Our results provide evidence for SNX10 as a potential promising therapeutic target for preventing or ameliorating liver injury in ALD. Alcoholic liver disease is a major cause of morbidity and

  2. Interleukin-32γ attenuates ethanol-induced liver injury by the inhibition of cytochrome P450 2E1 expression and inflammatory responses.

    PubMed

    Lee, Dong Hun; Kim, Dae Hwan; Hwang, Chul Ju; Song, Sukgil; Han, Sang Bae; Kim, Youngsoo; Yoo, Hwan Soo; Jung, Young Suk; Kim, Soo Hyun; Yoon, Do Young; Hong, Jin Tae

    2015-05-01

    Alcohol abuse and alcoholism lead to alcoholic liver disease (ALD), which is a major type of chronic liver disease worldwide. Interleukin-32 (IL-32) is a novel cytokine involved in inflammation and cancer development. However, the role of IL-32 in chronic liver disease has not been reported. In the present paper, we tested the effect of IL-32γ on ethanol-induced liver injury in IL-32γ-overexpressing transgenic mice (IL-32γ mice) after chronic ethanol feeding. Male C57BL/6 and IL-32γ mice (10-12 weeks old) were fed on a Lieber-DeCarli diet containing 6.6% ethanol for 6 weeks. IL-32γ-transfected HepG2 and Huh7 cells, as well as primary hepatocytes from IL-32γ mice, were treated with or without ethanol. The hepatic steatosis and damage induced by ethanol administration were attenuated in IL-32γ mice. Ethanol-induced cytochrome P450 2E1 expression and hydrogen peroxide levels were decreased in the livers of IL-32γ mice, primary hepatocytes from IL-32γ mice and IL-32γ-overexpressing human hepatic cells. The ethanol-induced expression levels of cyclo-oxygenase-2 (COX-2) and IL-6 were reduced in the livers of IL-32γ mice. Because nuclear transcription factor κB (NF-κB) is a key redox transcription factor of inflammatory responses, we examined NF-κB activity. Ethanol-induced NF-κB activities were significantly lower in the livers of IL-32γ mice than in wild-type (WT) mice. Furthermore, reduced infiltration of natural killer cells, cytotoxic T-cells and macrophages in the liver after ethanol administration was observed in IL-32γ mice. These data suggest that IL-32γ prevents ethanol-induced hepatic injury via the inhibition of oxidative damage and inflammatory responses.

  3. Ethanol metabolism and oxidative stress are required for unfolded protein response activation and steatosis in zebrafish with alcoholic liver disease

    PubMed Central

    Tsedensodnom, Orkhontuya; Vacaru, Ana M.; Howarth, Deanna L.; Yin, Chunyue; Sadler, Kirsten C.

    2013-01-01

    SUMMARY Secretory pathway dysfunction and lipid accumulation (steatosis) are the two most common responses of hepatocytes to ethanol exposure and are major factors in the pathophysiology of alcoholic liver disease (ALD). However, the mechanisms by which ethanol elicits these cellular responses are not fully understood. Recent data indicates that activation of the unfolded protein response (UPR) in response to secretory pathway dysfunction can cause steatosis. Here, we examined the relationship between alcohol metabolism, oxidative stress, secretory pathway stress and steatosis using zebrafish larvae. We found that ethanol was immediately internalized and metabolized by larvae, such that the internal ethanol concentration in 4-day-old larvae equilibrated to 160 mM after 1 hour of exposure to 350 mM ethanol, with an average ethanol metabolism rate of 56 μmol/larva/hour over 32 hours. Blocking alcohol dehydrogenase 1 (Adh1) and cytochrome P450 2E1 (Cyp2e1), the major enzymes that metabolize ethanol, prevented alcohol-induced steatosis and reduced induction of the UPR in the liver. Thus, we conclude that ethanol metabolism causes ALD in zebrafish. Oxidative stress generated by Cyp2e1-mediated ethanol metabolism is proposed to be a major culprit in ALD pathology. We found that production of reactive oxygen species (ROS) increased in larvae exposed to ethanol, whereas inhibition of the zebrafish CYP2E1 homolog or administration of antioxidants reduced ROS levels. Importantly, these treatments also blocked ethanol-induced steatosis and reduced UPR activation, whereas hydrogen peroxide (H2O2) acted as a pro-oxidant that synergized with low doses of ethanol to induce the UPR. Collectively, these data demonstrate that ethanol metabolism and oxidative stress are conserved mechanisms required for the development of steatosis and hepatic dysfunction in ALD, and that these processes contribute to ethanol-induced UPR activation and secretory pathway stress in hepatocytes. PMID

  4. Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC-induced cholestatic liver injury.

    PubMed

    Addante, Annalisa; Roncero, Cesáreo; Almalé, Laura; Lazcanoiturburu, Nerea; García-Álvaro, María; Fernández, Margarita; Sanz, Julián; Hammad, Seddik; Nwosu, Zeribe C; Lee, Se-Jin; Fabregat, Isabel; Dooley, Steven; Ten Dijke, Peter; Herrera, Blanca; Sánchez, Aránzazu

    2018-05-11

    Bone morphogenetic protein 9 (BMP9) interferes with liver regeneration upon acute injury, while promoting fibrosis upon carbon tetrachloride-induced chronic injury. We have now addressed the role of BMP9 in 3,5 diethoxicarbonyl-1,4 dihydrocollidine (DDC)-induced cholestatic liver injury, a model of liver regeneration mediated by hepatic progenitor cell (known as oval cell), exemplified as ductular reaction and oval cell expansion. WT and BMP9KO mice were submitted to DDC diet. Livers were examined for liver injury, fibrosis, inflammation and oval cell expansion by serum biochemistry, histology, RT-qPCR and western blot. BMP9 signalling and effects in oval cells were studied in vitro using western blot and transcriptional assays, plus functional assays of DNA synthesis, cell viability and apoptosis. Crosslinking assays and short hairpin RNA approaches were used to identify the receptors mediating BMP9 effects. Deletion of BMP9 reduces liver damage and fibrosis, but enhances inflammation upon DDC feeding. Molecularly, absence of BMP9 results in overactivation of PI3K/AKT, ERK-MAPKs and c-Met signalling pathways, which together with an enhanced ductular reaction and oval cell expansion evidence an improved regenerative response and decreased damage in response to DDC feeding. Importantly, BMP9 directly targets oval cells, it activates SMAD1,5,8, decreases cell growth and promotes apoptosis, effects that are mediated by Activin Receptor-Like Kinase 2 (ALK2) type I receptor. We identify BMP9 as a negative regulator of oval cell expansion in cholestatic injury, its deletion enhancing liver regeneration. Likewise, our work further supports BMP9 as an attractive therapeutic target for chronic liver diseases. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Crocin attenuates hemorrhagic shock-induced oxidative stress and organ injuries in rats.

    PubMed

    Yang, Long; Dong, Xiujuan

    2017-06-01

    We aimed to evaluate the effect of natural antioxidant crocin in alleviating hemorrhagic shock (HS)-induced organ damages. HS rats were treated with crocin during resuscitation. Mortality at 12h and 24h post resuscitation was documented. HS and resuscitation induced organ injuries, as characterized by elevated wet/dry ratio, quantitative assessment ratio, blood urea nitrogen, creatinine, aspartate aminotransferase and alanine aminotransferase, whereas rats received crocin treatment demonstrated improvements in all the above characteristics. This protective effect coincided with reduced malondialdehyde and increased glutathione in both serum and lung tissues, indicating attenuated oxidative stress in crocin-treated rats. Myeloperoxide levels in lung, kidney and liver were also reduced. Crocin can potentially be used to protect organs from HS-induced damages during resuscitation due to its anti-oxidative role. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. [Effect of American Ginseng Capsule on the liver oxidative injury and the Nrf2 protein expression in rats exposed by electromagnetic radiation of frequency of cell phone].

    PubMed

    Luo, Ya-ping; Ma, Hui-Rong; Chen, Jing-Wei; Li, Jing-Jing; Li, Chun-xiang

    2014-05-01

    To observe the effect of American Ginseng Capsule (AGC) on the liver oxidative injury and the Nrf2 protein expression in the liver tissue of rats exposed by 900 MHz cell phone electromagnetic radiation. Totally 40 male SD rats were randomly divided into the normal control group, the model group, the Shuifei Jibin Capsule (SJC) group, and the AGC group,10 in each group. Rats in the normal control group were not irradiated. Rats in the rest three groups were exposed by imitated 900 MHz cellular phone for 4 h in 12 consecutive days. Meanwhile, rats in the SJC group and the AGC group were intragastrically administrated with suspension of SJC and AGC (1 mL/200 g body weight) respectively. Normal saline was administered to rats in the normal control group and the model group. The histolomorphological changes of the liver tissue were observed by HE staining. Contents of malonic dialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-PX)were detected by colorimetry. The Nrf2 protein expression of hepatocytes was detected by immunohistochemical assay and Western blot. Compared with the normal control group, hepatocyte nucleus was atrophied or partially disappeared, the contents of liver MDA and Nrf2 protein obviously increased (P <0. 05, P <0. 01); contents of liver SOD and GSH decreased (P <0. 05) in the model group. Compared with the model group, karyopyknosis was obviously attenuated and approached to the normal level in the SJC group and the AGC group. The contents of liver MDA and Nrf2 protein expression decreased (P <0. 05), and the contents of liver SOD, GSH, and GSH-PX obviously increased (P < 0.05) in the SJC group. The contents of liver MDA and the Nrf2 protein expression decreased (P < 0.05), and contents of SOD and GSH obviously increased in the AGC group (P <0.01, P <0.05). The electromagnetic radiation induced by 900 MHz cell phone could affect the expression of Nrf2 protein, induce oxidative injury, and induce abnormal

  7. Effect of antioxidants on vanadate-induced toxicity towards isolated perfused rat livers.

    PubMed

    Younes, M; Kayser, E; Strubelt, O

    1991-01-01

    The effect of trolox C, a water soluble vitamin E analogue, propyl gallate and ascorbate on vanadate hepatotoxicity was investigated in vitro. In isolated perfused livers from fasted rats, sodium orthovanadate (2 mmol/l) led to toxic responses including reduction of oxygen consumption, release of cytosolic (glutamate-pyruvate-transaminase (GPT) and lactate dehydrogenase (LDH)) and mitochondrial (glutamate-dehydrogenase (GLDH)) enzymes, intracellular accumulation of calcium, a marked depletion of glutathione (GSH) and an enhanced formation and release of thiobarbituric acid- (TBA) reactive material. Trolox C and propyl gallate inhibited the release of GPT and LDH partially and that of GLDH totally, but had no influence on vanadate-induced calcium accumulation or on the reduction of oxygen consumption. Both agents suppressed vanadate-induced lipid peroxidation (LPO) and partially prevented GSH depletion. Ascorbate failed to provide any protection probably due to the interference of its pro-oxidant potential with its antioxidant activity. The protection, mainly of mitochondria, afforded by those agents which also inhibited LPO substantiates our previous findings that the pro-oxidant activity of vanadate is mainly responsible for its direct hepatotoxic actions [2]. Besides, reduction of organ perfusion rate due to vasoconstriction also contributes to vanadate toxicity, but oxidative stress is not involved in this indirect toxic activity.

  8. A transcriptomics data-driven gene space accurately predicts liver cytopathology and drug-induced liver injury

    PubMed Central

    Kohonen, Pekka; Parkkinen, Juuso A.; Willighagen, Egon L.; Ceder, Rebecca; Wennerberg, Krister; Kaski, Samuel; Grafström, Roland C.

    2017-01-01

    Predicting unanticipated harmful effects of chemicals and drug molecules is a difficult and costly task. Here we utilize a ‘big data compacting and data fusion’—concept to capture diverse adverse outcomes on cellular and organismal levels. The approach generates from transcriptomics data set a ‘predictive toxicogenomics space’ (PTGS) tool composed of 1,331 genes distributed over 14 overlapping cytotoxicity-related gene space components. Involving ∼2.5 × 108 data points and 1,300 compounds to construct and validate the PTGS, the tool serves to: explain dose-dependent cytotoxicity effects, provide a virtual cytotoxicity probability estimate intrinsic to omics data, predict chemically-induced pathological states in liver resulting from repeated dosing of rats, and furthermore, predict human drug-induced liver injury (DILI) from hepatocyte experiments. Analysing 68 DILI-annotated drugs, the PTGS tool outperforms and complements existing tests, leading to a hereto-unseen level of DILI prediction accuracy. PMID:28671182

  9. Royal Jelly Modulates Oxidative Stress and Apoptosis in Liver and Kidneys of Rats Treated with Cisplatin

    PubMed Central

    Karadeniz, Ali; Simsek, Nejdet; Karakus, Emre; Yildirim, Serap; Kara, Adem; Can, Ismail; Kisa, Fikrullah; Emre, Habib; Turkeli, Mehmet

    2011-01-01

    Cisplatin (CDDP) is one of the most active cytotoxic agents in the treatment of cancer and has adverse side effects such as nephrotoxicity and hepatotoxicity. The present study was designed to determine the effects of royal jelly (RJ) against oxidative stress caused by CDDP injury of the kidneys and liver, by measuring tissue biochemical and antioxidant parameters and investigating apoptosis immunohistochemically. Twenty-four Sprague Dawley rats were divided into four groups, group C: control group received 0.9% saline; group CDDP: injected i.p. with cisplatin (CDDP, 7 mg kg−1 body weight i.p., single dose); group RJ: treated for 15 consecutive days by gavage with RJ (300 mg/kg/day); group RJ + CDDP: treated by gavage with RJ 15 days following a single injection of CDDP. Malondialdehyde (MDA) and glutathione (GSH) levels, glutathione S-transferase (GST), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) activities were determined in liver and kidney homogenates, and the liver and kidney were also histologically examined. RJ elicited a significant protective effect towards liver and kidney by decreasing the level of lipid peroxidation (MDA), elevating the level of GSH, and increasing the activities of GST, GSH-Px, and SOD. In the immunohistochemical examinations were observed significantly enhanced apoptotic cell numbers and degenerative changes by cisplatin, but these histological changes were lower in the liver and kidney tissues of RJ + CDDP group. Besides, treatment with RJ lead to an increase in antiapoptotic activity hepatocytes and tubular epithelium. In conclusion, RJ may be used in combination with cisplatin in chemotherapy to improve cisplatin-induced oxidative stress parameters and apoptotic activity. PMID:21904651

  10. [Acetylcholine activation of alpha-ketoglutarate oxidation in liver mitochondria].

    PubMed

    Shostakovskaia, I V; Doliba, N M; Gordiĭ, S K; Babskiĭ, A M; Kondrashova, M N

    1986-01-01

    Activation of alpha-ketoglutarate oxidation in the rat liver mitochondria takes place 15 and 30 min after intraperitoneal injection of acetyl choline. This mediator in doses of 25, 50 and 100 micrograms per 100 g of body weight causes a pronounced stimulation of phosphorylation respiration rate and calcium capacity of mitochondria with alpha-ketoglutarate oxidation. Acetyl choline is found to have a moderate inhibitory action on oxidation of lower (physiological) concentrations of succinate. Its stimulating action on alpha-ketoglutarate oxidation is associated with activation of M-cholinoreceptors; atropine, a choline-blocker, removes completely this effect. It is supposed that alpha-ketoglutarate and succinate are included into the composition of two reciprocal hormonal-substrate nucleotide systems.

  11. Hepatoprotective effect of Scoparia dulcis on carbon tetrachloride induced acute liver injury in mice.

    PubMed

    Tsai, Jen-Chieh; Peng, Wen-Huang; Chiu, Tai-Hui; Huang, Shun-Chieh; Huang, Tai-Hung; Lai, Shang-Chih; Lai, Zhen-Rung; Lee, Chao-Ying

    2010-01-01

    This study aims to investigate the hepatoprotective activity and active constituents of the ethanol extract of Scoparia dulcis (SDE). The hepatoprotective effect of SDE (0.1, 0.5 and 1 g/kg) was evaluated on the carbon tetrachloride (CCl(4))-induced acute liver injury. The active constituents were detected by high performance liquid chromatography (HPLC). Mice pretreated orally with SDE (0.5 and 1.0 g/kg) and silymarin (200 mg/kg) for five consecutive days before the administering of a single dose of 0.2% CCl(4) (10 ml/kg of bw, ip) showed a significant inhibition of the increase of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Histological analyses also showed that SDE (0.5 and 1.0 g/kg) and silymarin reduced the extent of liver lesions induced by CCl(4), including vacuole formation, neutrophil infiltration and necrosis. Moreover, SDE decreased the malondialdehyde (MDA) level and elevated the content of reduced glutathione (GSH) in the liver as compared to those in the CCl(4) group. Furthermore, SDE (0.5 and 1.0 g/kg) enhanced the activities of anti-oxidative enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GRd) and glutathione-S-transferase (GST). The quantities of active constituents in SDE were about 3.1 mg luteolin/g extract and 1.1 mg apigenin/g extract. The hepatoprotective mechanisms of SDE were likely associated to the decrease in MDA level and increase in GSH level by increasing the activities of antioxidant enzymes such as SOD, GPx, GRd and GST. These results demonstrated that SDE could alleviate CCl(4)-induced acute liver injury in mice.

  12. Drug-Induced Liver Toxicity and Prevention by Herbal Antioxidants: An Overview

    PubMed Central

    Singh, Divya; Cho, William C.; Upadhyay, Ghanshyam

    2016-01-01

    The liver is the center for drug and xenobiotic metabolism, which is influenced most with medication/xenobiotic-mediated toxic activity. Drug-induced hepatotoxicity is common and its actual frequency is hard to determine due to underreporting, difficulties in detection or diagnosis, and incomplete observation of exposure. The death rate is high, up to about 10% for drug-induced liver damage. Endorsed medications represented >50% of instances of intense liver failure in a study from the Acute Liver Failure Study Group of the patients admitted in 17 US healing facilities. Albeit different studies are accessible uncovering the mechanistic aspects of medication prompted hepatotoxicity, we are in the dilemma about the virtual story. The expanding prevalence and effectiveness of Ayurveda and natural products in the treatment of various disorders led the investigators to look into their potential in countering drug-induced liver toxicity. Several natural products have been reported to date to mitigate the drug-induced toxicity. The dietary nature and less adverse reactions of the natural products provide them an extra edge over other candidates of supplementary medication. In this paper, we have discussed the mechanism involved in drug-induced liver toxicity and the potential of herbal antioxidants as supplementary medication. PMID:26858648

  13. Human Mesenchymal Stem Cells Provide Protection against Radiation-Induced Liver Injury by Antioxidative Process, Vasculature Protection, Hepatocyte Differentiation, and Trophic Effects

    PubMed Central

    Francois, Sabine; Mouiseddine, Moubarak; Allenet-Lepage, Bénédicte; Voswinkel, Jan; Douay, Luc; Benderitter, Marc; Chapel, Alain

    2013-01-01

    To evaluate the potential therapeutic effect of the infusion of hMSCs for the correction of liver injuries, we performed total body radiation exposure of NOD/SCID mice. After irradiation, mir-27b level decreases in liver, increasing the directional migration of hMSCs by upregulating SDF1α. A significant increase in plasmatic transaminases levels, apoptosis process in the liver vascular system, and in oxidative stress were observed. hMSC injection induced a decrease in transaminases levels and oxidative stress, a disappearance of apoptotic cells, and an increase in Nrf2, SOD gene expression, which might reduce ROS production in the injured liver. Engrafted hMSCs expressed cytokeratin CK18 and CK19 and AFP genes indicating possible hepatocyte differentiation. The presence of hMSCs expressing VEGF and Ang-1 in the perivascular region, associated with an increased expression of VEGFr1, r2 in the liver, can confer a role of secreting cells to hMSCs in order to maintain the endothelial function. To explain the benefits to the liver of hMSC engraftment, we find that hMSCs secreted NGF, HGF, and anti-inflammatory molecules IL-10, IL1-RA contributing to prevention of apoptosis, increasing cell proliferation in the liver which might correct liver dysfunction. MSCs are potent candidates to repair and protect healthy tissues against radiation damages. PMID:24369528

  14. A non-human primate model of human radiation-induced venocclusive liver disease and hepatocyte injury

    PubMed Central

    Yamamoto, Toshiyuki; Ito, Ryotaro; Brooks, Jenna M.; Guzman-Lepe, Jorge; Galambos, Csaba; Fong, Jason V.; Deutsch, Melvin; Quader, Mubina A.; Yamanouchi, Kosho; Kabarriti, Rafi; Mehta, Keyur; Soto-Gutierrez, Alejandro; Roy-Chowdhury, Jayanta; Locker, Joseph; Abe, Michio; Enke, Charles A.; Baranowska-Kortylewicz, Janina; Solberg, Timothy D.; Guha, Chandan; Fox, Ira J.

    2014-01-01

    Background Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Since the characteristic venocclusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic venocclusive disease. Methods We performed a dose escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results At doses ≥40Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses where radiation-induced liver disease was mild or non-existent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions The cynomolgus monkey, as the first animal model of human venocclusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury. PMID:24315566

  15. Non-invasive evaluation of liver stiffness after splenectomy in rabbits with CCl4-induced liver fibrosis

    PubMed Central

    Wang, Ming-Jun; Ling, Wen-Wu; Wang, Hong; Meng, Ling-Wei; Cai, He; Peng, Bing

    2016-01-01

    AIM To investigate the diagnostic performance of liver stiffness measurement (LSM) by elastography point quantification (ElastPQ) in animal models and determine the longitudinal changes in liver stiffness by ElastPQ after splenectomy at different stages of fibrosis. METHODS Liver stiffness was measured in sixty-eight rabbits with CCl4-induced liver fibrosis at different stages and eight healthy control rabbits by ElastPQ. Liver biopsies and blood samples were obtained at scheduled time points to assess liver function and degree of fibrosis. Thirty-one rabbits with complete data that underwent splenectomy at different stages of liver fibrosis were then included for dynamic monitoring of changes in liver stiffness by ElastPQ and liver function according to blood tests. RESULTS LSM by ElastPQ was significantly correlated with histologic fibrosis stage (r = 0.85, P < 0.001). The optimal cutoff values by ElastPQ were 11.27, 14.89, and 18.21 kPa for predicting minimal fibrosis, moderate fibrosis, and cirrhosis, respectively. Longitudinal monitoring of the changes in liver stiffness by ElastPQ showed that early splenectomy (especially F1) may delay liver fibrosis progression. CONCLUSION ElastPQ is an available, convenient, objective and non-invasive technique for assessing liver stiffness in rabbits with CCl4-induced liver fibrosis. In addition, liver stiffness measurements using ElastPQ can dynamically monitor the changes in liver stiffness in rabbit models, and in patients, after splenectomy. PMID:28028365

  16. KEAP1-NRF2 COMPLEX IN ISCHEMIA-INDUCED HEPATOCELLULAR DAMAGE OF MOUSE LIVER TRANSPLANTS

    PubMed Central

    Ke, Bibo; Shen, Xiu-Da; Zhang, Yu; Ji, Haofeng; Gao, Feng; Yue, Shi; Kamo, Naoko; Zhai, Yuan; Yamamoto, Masayuki; Busuttil, Ronald W.; Kupiec-Weglinski, Jerzy W.

    2015-01-01

    Background The Keap1-Nrf2 signaling pathway regulates host cell defense responses against oxidative stress and maintains the cellular redox balance. Aims&Methods: We investigated the function/molecular mechanisms by which Keap1-Nrf2 complex may influence liver ischemia/reperfusion injury (IRI) in a mouse model of hepatic cold storage (20h at 4 C) followed by orthotopic liver transplantation (OLT). Results The Keap1 hepatocyte-specific knock-out (HKO) in the donor liver ameliorated post-transplant IRI, evidenced by improved hepatocellular function and OLT outcomes (Keap1HKO Keap1HKO; 100% survival), as compared with controls (WT WT; 50% survival; p<0.01). In contrast, donor liver Nrf2 deficiency exacerbated IRI in transplant recipients (Nrf2KO Nrf2KO; 40% survival). Ablation of Keap1 signaling reduced macrophage/neutrophil trafficking, pro-inflammatory cytokine programs, and hepatocellular necrosis/apoptosis, while simultaneously promoting anti-apoptotic functions in OLTs. At the molecular level, Keap1HKO increased Nrf2 levels, stimulated Akt phosphorylation, and enhanced expression of anti-oxidant Trx1, HIF-1 , and HO-1. Pretreatment of liver donors with PI3K inhibitor (LY294002) disrupted Akt/HIF-1 signaling and recreated hepatocellular damage in otherwise IR-resistant Keap1HKO transplants. In parallel in vitro studies, hydrogen peroxide-stressed Keap1-deficient hepatocytes were characterized by enhanced expression of Nrf2, Trx1, and Akt phosphorylation, in association with decreased release of lactate dehydrogenase (LDH) in cell culture supernatants. Conclusions Keap1-Nrf2 complex prevents oxidative injury in IR-stressed OLTs through Keap1 signaling, which negatively regulates Nrf2 pathway. Activation of Nrf2 induces Trx1 and promotes PI3K/Akt, crucial for HIF-1 activity. HIF-1 -mediated overexpression of HO-1/CyclinD1 facilitates cytoprotection by limiting hepatic inflammatory responses, and hepatocellular necrosis/apoptosis in PI3K-dependent manner. PMID

  17. Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease.

    PubMed

    Gariani, Karim; Ryu, Dongryeol; Menzies, Keir J; Yi, Hyon-Seung; Stein, Sokrates; Zhang, Hongbo; Perino, Alessia; Lemos, Vera; Katsyuba, Elena; Jha, Pooja; Vijgen, Sandrine; Rubbia-Brandt, Laura; Kim, Yong Kyung; Kim, Jung Tae; Kim, Koon Soon; Shong, Minho; Schoonjans, Kristina; Auwerx, Johan

    2017-01-01

    To date, no pharmacological therapy has been approved for non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to evaluate the therapeutic potential of poly ADP-ribose polymerase (PARP) inhibitors in mouse models of NAFLD. As poly ADP-ribosylation (PARylation) of proteins by PARPs consumes nicotinamide adenine dinucleotide (NAD + ), we hypothesized that overactivation of PARPs drives NAD + depletion in NAFLD. Therefore, we assessed the effectiveness of PARP inhibition to replenish NAD + and activate NAD + -dependent sirtuins, hence improving hepatic fatty acid oxidation. To do this, we examined the preventive and therapeutic benefits of the PARP inhibitor (PARPi), olaparib, in different models of NAFLD. The induction of NAFLD in C57BL/6J mice using a high-fat high-sucrose (HFHS)-diet increased PARylation of proteins by PARPs. As such, increased PARylation was associated with reduced NAD + levels and mitochondrial function and content, which was concurrent with elevated hepatic lipid content. HFHS diet supplemented with PARPi reversed NAFLD through repletion of NAD + , increasing mitochondrial biogenesis and β-oxidation in liver. Furthermore, PARPi reduced reactive oxygen species, endoplasmic reticulum stress and fibrosis. The benefits of PARPi treatment were confirmed in mice fed with a methionine- and choline-deficient diet and in mice with lipopolysaccharide-induced hepatitis; PARP activation was attenuated and the development of hepatic injury was delayed in both models. Using Sirt1 hep-/- mice, the beneficial effects of a PARPi-supplemented HFHS diet were found to be Sirt1-dependent. Our study provides a novel and practical pharmacological approach for treating NAFLD, fueling optimism for potential clinical studies. Non-alcoholic fatty liver disease (NAFLD) is now considered to be the most common liver disease in the Western world and has no approved pharmacological therapy. PARP inhibitors given as a treatment in two different mouse

  18. Oxidative deamination of alicyclic primary amines by liver microsomes from rats and rabbits.

    PubMed

    Kurebayashi, H; Tanaka, A; Yamaha, T; Tatahashi, A

    1988-09-01

    1. Substrate selectivity and species difference in the oxidative deamination of the alicyclic primary amines, cyclopentylamine, cyclohexylamine, cycloheptylamine, 1- and 2-aminoindane, and 1- and 2-aminotetralin were studied using liver microsomes from rats and rabbits. 2. The deamination rates of the amines were much greater with liver microsomes from rabbits than from rats. Substrate selectivity resulted in much faster deamination of 1-aminoindane and 1-aminotetralin than of the corresponding 2-amino compounds, especially in rats. 3. When 1-aminoindane and 1-aminotetralin were incubated with rat liver microsomes and NADPH under 18O2, oxygen-18 was incorporated into the deaminated products, 1-indanone and 1-tetralone. The carbinolamine is a key intermediate in the oxidative deamination by rat liver microsomes, indicating the contribution of cytochrome P-450-dependent alpha-C-oxidation to the reaction. 4. Alicyclic primary amines gave type II binding spectra with rat and rabbit liver microsomes, but the spectra appeared to contain type I components. 5. The ratios of the alcohols, cyclohexanol, 2-tetralol and 2-indanol in the deaminated products were high in both rats and rabbits. The ketones were precursors of the alcohols, and substrate selectivity in reduction of the alicyclic ketones with NADPH was similar in both species.

  19. Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Xie, Yuchao; Ramachandran, Anup; Breckenridge, David G.

    Metabolic activation and oxidant stress are key events in the pathophysiology of acetaminophen (APAP) hepatotoxicity. The initial mitochondrial oxidative stress triggered by protein adduct formation is amplified by c-jun-N-terminal kinase (JNK), resulting in mitochondrial dysfunction and ultimately cell necrosis. Apoptosis signal-regulating kinase 1 (ASK1) is considered the link between oxidant stress and JNK activation. The objective of the current study was to assess the efficacy and mechanism of action of the small-molecule ASK1 inhibitor GS-459679 in a murine model of APAP hepatotoxicity. APAP (300 mg/kg) caused extensive glutathione depletion, JNK activation and translocation to the mitochondria, oxidant stress and livermore » injury as indicated by plasma ALT activities and area of necrosis over a 24 h observation period. Pretreatment with 30 mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affecting the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5 h after APAP, GS-459679 was still protective, which was paralleled by reduced JNK activation and p-JNK translocation to mitochondria. However, GS-459679 treatment was not more effective than N-acetylcysteine, and the combination of GS-459679 and N-acetylcysteine exhibited similar efficacy as N-acetylcysteine monotherapy, suggesting that GS-459769 and N-acetylcysteine affect the same pathway. Importantly, inhibition of ASK1 did not impair liver regeneration as indicated by PCNA staining. In conclusion, the ASK1 inhibitor GS-459679 protected against APAP toxicity by attenuating JNK activation and oxidant stress in mice and may have therapeutic potential for APAP overdose patients. - Highlights: • Two ASK1 inhibitors protected against acetaminophen-induced liver injury. • The ASK1 inhibitors protect when used as pre- or post-treatment. • Protection by ASK1

  20. Drug-induced liver injury caused by iodine-131

    PubMed Central

    Kim, Chei Won; Park, Ji Sun; Oh, Se Hwan; Park, Jae-Hyung; Shim, Hyun-Ik; Yoon, Jae Woong; Park, Jin Seok; Hong, Seong Bin; Kim, Jun Mi; Le, Trong Binh; Lee, Jin Woo

    2016-01-01

    Iodine-131 is a radioisotope that is routinely used for the treatment of differentiated thyroid cancer after total or near-total thyroidectomy. However, there is some evidence that iodine-131 can induce liver injury . Here we report a rare case of drug-induced liver injury (DILI) caused by iodine-131 in a patient with regional lymph node metastasis after total thyroidectomy. A 47-year-old woman was admitted with elevated liver enzymes and symptoms of general weakness and nausea. Ten weeks earlier she had undergone a total thyroidectomy for papillary thyroid carcinoma and had subsequently been prescribed levothyroxine to reduce the level of thyroid-stimulating hormone. Eight weeks after surgery she underwent iodine-131 ablative therapy at a dose of 100 millicuries, and subsequently presented with acute hepatitis after 10 days. To rule out all possible causative factors, abdominal ultrasonography, endoscopic ultrasonography (on the biliary tree and gall bladder), and a liver biopsy were performed. DILI caused by iodine-131 was suspected. Oral prednisolone was started at 30 mg/day, to which the patient responded well. PMID:27209646