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Sample records for ethanol-induced hepatic damage

  1. Quercetin Attenuates Chronic Ethanol-Induced Hepatic Mitochondrial Damage through Enhanced Mitophagy

    PubMed Central

    Yu, Xiao; Xu, Yanyan; Zhang, Shanshan; Sun, Jian; Liu, Peiyi; Xiao, Lin; Tang, Yuhan; Liu, Liegang; Yao, Ping

    2016-01-01

    Emerging evidence suggested mitophagy activation mitigates ethanol-induced liver injury. However, the effect of ethanol on mitophagy is inconsistent. Importantly, the understanding of mitophagy status after chronic ethanol consumption is limited. This study evaluated the effect of quercetin, a naturally-occurring flavonoid, on chronic ethanol-induced mitochondrial damage focused on mitophagy. An ethanol regime to mice for 15 weeks (accounting for 30% of total calories) led to significant mitochondrial damage as evidenced by changes of the mitochondrial ultrastructure, loss of mitochondrial membrane potential and remodeling of membrane lipid composition, which was greatly attenuated by quercetin (100 mg/kg.bw). Moreover, quercetin blocked chronic ethanol-induced mitophagy suppression as denoted by mitophagosomes-lysosome fusion and mitophagy-related regulator elements, including LC3II, Parkin, p62 and voltage-dependent anion channel 1 (VDAC1), paralleling with increased FoxO3a nuclear translocation. AMP-activated protein kinase (AMPK) and extracellular signal regulated kinase 2 (ERK2), instead of AKT and Sirtuin 1, were involved in quercetin-mediated mitophagy activation. Quercetin alleviated ethanol-elicited mitochondrial damage through enhancing mitophagy, highlighting a promising preventive strategy for alcoholic liver disease. PMID:26742072

  2. Ethanol-induced hepatic autophagy: Friend or foe?

    PubMed

    Eid, Nabil; Ito, Yuko; Otsuki, Yoshinori

    2015-05-28

    Excessive alcohol intake may induce hepatic apoptosis, steatosis, fibrosis, cirrhosis and even cancer. Ethanol-induced activation of general or selective autophagy as mitophagy or lipophagy in hepatocytes is generally considered a prosurvival mechanism. On the other side of the coin, upregulation of autophagy in non-hepatocytes as stellate cells may stimulate fibrogenesis and subsequently induce detrimental effects on the liver. The autophagic response of other non-hepatocytes as macrophages and endothelial cells is unknown yet and needs to be investigated as these cells play important roles in ethanol-induced hepatic steatosis and damage. Selective pharmacological stimulation of autophagy in hepatocytes may be of therapeutic importance in alcoholic liver disease. PMID:26019731

  3. Iron-Mediated Lysosomal Membrane Permeabilization in Ethanol-Induced Hepatic Oxidative Damage and Apoptosis: Protective Effects of Quercetin

    PubMed Central

    Li, Yanyan; Chen, Man; Xu, Yanyan; Yu, Xiao; Xiong, Ting; Du, Min; Sun, Jian; Liu, Liegang; Tang, Yuhan; Yao, Ping

    2016-01-01

    Iron, in its free ferrous states, can catalyze Fenton reaction to produce OH∙, which is recognized as a crucial role in the pathogenesis of alcoholic liver diseases (ALD). As a result of continuous decomposition of iron-containing compounds, lysosomes contain a pool of redox-active iron. To investigate the important role of intralysosomal iron in alcoholic liver injury and the potential protection of quercetin, male C57BL/6J mice fed by Lieber De Carli diets containing ethanol (30% of total calories) were cotreated by quercetin or deferoxamine (DFO) for 15 weeks and ethanol-incubated mice primary hepatocytes were pretreated with FeCl3, DFO, and bafilomycin A1 at their optimal concentrations and exposure times. Chronic ethanol consumption caused an evident increase in lysosomal redox-active iron accompanying sustained oxidative damage. Iron-mediated ROS could trigger lysosomal membrane permeabilization (LMP) and subsequent mitochondria apoptosis. The hepatotoxicity was attenuated by reducing lysosomal iron while being exacerbated by escalating lysosomal iron. Quercetin substantially alleviated the alcoholic liver oxidative damage and apoptosis by decreasing lysosome iron and ameliorating iron-mediated LMP, which provided a new prospective of the use of quercetin against ALD. PMID:27057276

  4. BHT blocks NfkB activation and Ethanol-Induced Brain Damage

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Binge ethanol administration causes corticolimbic brain damage that models alcoholic neurodegeneration. The mechanism of binge ethanol induced degeneration is unknown, but is not glutamate neurotoxicity. To test the hypothesis that oxidative stress and inflammation are mechanisms of binge ethanol ...

  5. Glutathione prevents ethanol induced gastric mucosal damage and depletion of sulfhydryl compounds in humans.

    PubMed Central

    Loguercio, C; Taranto, D; Beneduce, F; del Vecchio Blanco, C; de Vincentiis, A; Nardi, G; Romano, M

    1993-01-01

    Whether parenteral administration of reduced glutathione prevented ethanol induced damage to and depletion of sulfhydryl compounds in the human gastric mucosa was investigated. Ten healthy volunteers underwent endoscopy on three separate occasions. Gastric mucosal damage was induced by spraying 80% ethanol on to the gastric mucosa through the biopsy channel of the endoscope. The gastric mucosal score, total sulfhydryls, glutathione, and cysteine were evaluated in basal conditions and after ethanol administration with and without pretreatment with parenteral glutathione. Glutathione significantly decreased the extent of ethanol induced macroscopic injury to the mucosa of the gastric body and antrum. Glutathione's protective effect is associated with appreciable inhibition of ethanol induced depletion of gastric sulfhydryl compounds. This is the first report of protection against ethanol induced gastric mucosal damage by a sulfhydryl containing agent in humans. PMID:8432465

  6. Diallyl trisulfide attenuates ethanol-induced hepatic steatosis by inhibiting oxidative stress and apoptosis.

    PubMed

    Chen, Lian-Yun; Chen, Qin; Cheng, Yi-Feng; Jin, Huan-Huan; Kong, De-Song; Zhang, Feng; Wu, Li; Shao, Jiang-Juan; Zheng, Shi-Zhong

    2016-04-01

    Inhibiting the major characteristics of alcoholic fatty liver (AFL) such as lipid accumulation, oxidative stress and apoptosis is a promising strategy of treating AFL. Diallyl trisulfide (DATS) is the major constituent isolated from garlic, which shows promise in the treatment of chronic liver disease. However, the effects of DATS on ethanol-induced liver injury and the related mechanisms remain unclear. The aim of this study was to evaluate the potential protective effects of DATS on AFL and the potential mechanisms. A single intragastric dose of ethanol was given to rats in vivo, while ethanol-stimulated LO2 cells were used as an in vitro model. Our results demonstrated that DATS prevented ethanol-induced injury, as indicated by the reduced activities of aspartate transaminase (AST) and alanine aminotransferase (ALT) in the serum and culture medium, and inhibition of cell apoptosis. Furthermore, DATS reduced hepatic steatosis by up-regulating the expression of peroxisome proliferator-activated receptor-alpha (PPAR-α) and down-regulating the expression of sterolregulatory element binding protein 1c(SREBP-1c). In addition, DATS alleviated ethanol-induced oxidative stress by enhancing non-enzymatic antioxidant and enzymatic antioxidants contents and by reducing the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). These data collectively revealed that DATS protected ethanol-induced liver injury by inhibiting lipid accumulation and oxidative stress. PMID:27044810

  7. Ethanol-induced impairment of hepatic glycoprotein secretion in the isolated rat liver perfusion model

    SciTech Connect

    Volentine, G.D.; Ogden, K.A.; Tuma, D.J.; Sorrell, M.F.

    1987-05-01

    The authors have previously shown that acute administration of ethanol inhibits hepatic glycoprotein secretion in vivo. This ethanol-induced effect appears to be mediated by its reactive metabolite, acetaldehyde. Since hormonal influences and vascular changes can not be controlled in vivo during ethanol administration, they investigated the effect of ethanol in the isolated perfused liver model. Rat liver from fed animals was perfused with oxygenated KRB at 3 ml/min/g liver for 4 hrs. Since ethanol inhibits proteins synthesis in vitro, protein acceptor pool size was equalized in both ethanol and control perfused livers with 1 mM cycloheximide. /sup 3/H-glucosamine was used to label hepatic secretory glycoproteins in the perfusate. Colchicine, a known inhibitor of protein secretion, impaired the secretion of labeled glycoproteins with a concomitant retention of these export proteins in the liver; therefore, confirming the authors secretory model. Ethanol (50 mM) inhibited the appearance of glucosamine-labeled glycoproteins by 60% into the perfusate as compared to control livers. Pretreatment of animals with cyanamide (an aldehyde dehydrogenase inhibitor) further potentiated this effect of ethanol in the isolated perfused liver. These data suggest that ethanol inhibits hepatic glycoprotein secretion in the isolated liver perfusion model, and this ethanol-induced impairment appears to be mediated by acetaldehyde.

  8. Protective role of intracellular glutathione against ethanol-induced damage in cultured rat gastric mucosal cells

    SciTech Connect

    Mutoh, H.; Hiraishi, H.; Ota, S.; Yoshida, H.; Ivey, K.J.; Terano, A.; Sugimoto, T. )

    1990-06-01

    This study investigated whether intracellular glutathione is cytoprotective against ethanol-induced injury to cultured rat gastric mucosal cells in vitro. Secondly, it investigated whether reduced glutathione or oxidized glutathione is responsible for this cytoprotection. Cytolysis was quantified by measuring 51Cr release from prelabeled cells. Concentrations of ethanol greater than 12% caused cell damage and increased 51Cr release in a dose-dependent and time-related fashion. When a substrate for glutathione synthesis, N-acetyl-L-cysteine, was provided to cultured cells for 4 h before challenge with ethanol, cytolysis was significantly decreased corresponding with an increase in cellular glutathione content. Pretreatment with diethyl maleate, which depletes reduced glutathione without forming oxidized glutathione, potentiated ethanol-induced cell damage in a dose-dependent manner with the decrease of cellular glutathione content. The administration of tert-butyl hydroperoxide (which is specifically reduced by glutathione peroxidase to generate oxidized glutathione from reduced glutathione) or diamide (which nonenzymatically oxidizes reduced glutathione to oxidized glutathione) enhanced ethanol injury. We conclude that in cultured gastric mucosal cells, (a) intracellular glutathione maintains integrity of gastric mucosal cells against ethanol in vitro; and (b) reduced glutathione rather than oxidized glutathione is responsible for this cytoprotection. We postulate that the presence of reduced glutathione is essential to allow glutathione peroxidase to catalyze the ethanol-generated toxic oxygen radical, hydrogen peroxide.

  9. Hepatoprotective effects of pecan nut shells on ethanol-induced liver damage.

    PubMed

    Müller, Liz Girardi; Pase, Camila Simonetti; Reckziegel, Patrícia; Barcelos, Raquel C S; Boufleur, Nardeli; Prado, Ana Cristina P; Fett, Roseane; Block, Jane Mara; Pavanato, Maria Amália; Bauermann, Liliane F; da Rocha, João Batista Teixeira; Burger, Marilise Escobar

    2013-01-01

    The hepatoprotective activity of the aqueous extract of the shells of pecan nut was investigated against ethanol-induced liver damage. This by-product of the food industry is popularly used to treat toxicological diseases. We evaluated the phytochemical properties of pecan shell aqueous extract (AE) and its in vitro and ex vivo antioxidant activity. The AE was found to have a high content of total polyphenols (192.4±1.9 mg GAE/g), condensed tannins (58.4±2.2 mg CE/g), and antioxidant capacity, and it inhibited Fe(2+)-induced lipid peroxidation (LP) in vitro. Rats chronically treated with ethanol (Et) had increased plasmatic transaminases (ALT, AST) and gamma glutamyl transpeptidase (GGT) levels (96%, 59.13% and 465.9%, respectively), which were effectively prevented (87; 41 and 383%) by the extract (1:40, w/v). In liver, ethanol consumption increased the LP (121%) and decreased such antioxidant defenses as glutathione (GSH) (33%) and superoxide dismutase (SOD) (47%) levels, causing genotoxicity in erythrocytes. Treatment with pecan shell AE prevented the development of LP (43%), GSH and SOD depletion (33% and 109%, respectively) and ethanol-induced erythrocyte genotoxicity. Catalase activity in the liver was unchanged by ethanol but was increased by the extract (47% and 73% in AE and AE+Et, respectively). Therefore, pecan shells may be an economic agent to treat liver diseases related to ethanol consumption. PMID:21924598

  10. Effects of chronic normovolemic anemia on gastric microcirculation and ethanol-induced gastric damage in rats.

    PubMed

    Marroni, N; Casadevall, M; Panés, J; Piera, C; Jou, J M; Pique, J M

    1994-04-01

    The effects of chronic normovolemic anemia on gastric microcirculation and gastric mucosal susceptibility to ethanol-induced gastric damage were investigated in anesthetized rats. Blood exchange by a plasma expander during four consecutive days rendered the animals anemic with a 34% decrease in the baseline hematocrit but without affecting blood volume. Chronic anemia induced a decrease in whole blood viscosity, an increase in gastric mucosal blood flow measured by hydrogen gas clearance, a decrease in gastric vascular resistance, and a decrease in gastric hemoglobin content without changes in the gastric oxygen content, the latter two parameters being measured by reflectance spectrophotometry. Gastric mucosal blood flow was lowered by intragastric administration of 100% ethanol in both anemic and control rats, but the final blood flow was significantly higher in anemic than in control animals. Macroscopic gastric damage induced by ethanol administration was significantly lower in anemic than in control rats. We conclude that chronic normovolemic anemia increases gastric mucosal blood flow and leads a protecting mechanism against gastric mucosal damage induced by absolute ethanol. PMID:8149840

  11. Effects of propranolol and sucralfate on ethanol-induced gastric mucosal damage in chronic portal hypertensive rats.

    PubMed

    Geoffroy, P; Duchateau, A; Thiéfin, G; Zeitoun, P

    1987-10-01

    In a rat model of chronic portal hypertension we studied ethanol-induced gastric mucosal damage and the effects of pretreatment by propranolol and sucralfate. Susceptibility to ethanol was increased in chronic portal hypertensive rats compared with sham-operated rats (55 +/- 8% vs. 25 +/- 4%). Both acute pretreatment (10 min) and chronic pretreatment (3 weeks) with propranolol reduced gastric mucosal injury induced by ethanol in portal hypertensive rats, compared with saline-treated rats. Acute and chronic pretreatment with propranolol had no protective effect in sham-operated rats. In portal hypertensive rats, sucralfate in two different doses (500 and 125 mg/kg) protected the gastric mucosa against ethanol-induced gastric injury compared with animals receiving saline (2 +/- 1% and 3 +/- 2% vs. 25 +/- 3%). Sucralfate at the higher dose did not reduce portal pressure in portal hypertensive rats. We conclude that: (1) chronic portal hypertension increases ethanol-induced gastric damage; (2) acute and chronic propranolol treatment reduces ethanol-induced gastric injury in portal hypertensive rats, probably by decreasing portal hypertension; (3) sucralfate has a cytoprotective effect in portal hypertensive rats without reducing portal pressure. These results suggest a potential application of sucralfate in patients otherwise treated by sclerotherapy. PMID:3693860

  12. miR-217 Regulates Ethanol-Induced Hepatic Inflammation by Disrupting Sirtuin 1–Lipin-1 Signaling

    PubMed Central

    Yin, Huquan; Liang, Xiaomei; Jogasuria, Alvin; Davidson, Nicholas O.; You, Min

    2016-01-01

    Ethanol-mediated injury, combined with gut-derived lipopolysaccharide (LPS), provokes generation of proinflammatory cytokines in Kupffer cells, causing hepatic inflammation. Among the mediators of these effects, miR-217 aggravates ethanol-induced steatosis in hepatocytes. However, the role of miR-217 in ethanol-induced liver inflammation process is unknown. Here, we examined the role of miR-217 in the responses to ethanol, LPS, or a combination of ethanol and LPS in RAW 264.7 macrophages and in primary Kupffer cells. In macrophages, ethanol substantially exacerbated LPS-mediated induction of miR-217 and production of proinflammatory cytokines compared with LPS or ethanol alone. Consistently, ethanol administration to mice led to increases in miR-217 abundance and increased production of inflammatory cytokines in isolated primary Kupffer cells exposed to the combination of ethanol and LPS. miR-217 promoted combined ethanol and LPS-mediated inhibition of sirtuin 1 expression and activity in macrophages. Moreover, miR-217–mediated sirtuin 1 inhibition was accompanied by increased activities of two vital inflammatory regulators, NF-κB and the nuclear factor of activated T cells c4. Finally, adenovirus-mediated overexpression of miR-217 led to steatosis and inflammation in mice. These findings suggest that miR-217 is a pivotal regulator involved in ethanol-induced hepatic inflammation. Strategies to inhibit hepatic miR-217 could be a viable approach in attenuating alcoholic hepatitis. PMID:25797648

  13. Aloe vera gel extract attenuates ethanol-induced hepatic lipid accumulation by suppressing the expression of lipogenic genes in mice.

    PubMed

    Saito, Marie; Tanaka, Miyuki; Misawa, Eriko; Yamada, Muneo; Yamauchi, Kouji; Iwatsuki, Keiji

    2012-01-01

    We have previously reported that Aloe vera gel had hypoglycemic activity and anti-obesity effects, although the effect on alcoholic fatty liver was unclear. We examined in this present study the effect of an Aloe vera gel extract (AVGE) on hepatic lipid metabolism by using an ethanol-induced transient fatty liver mouse model. Ethanol (3 g/kg of mouse weight) was orally administered to induce an accumulation of triglyceride (TG) and increase the mRNA expression of such lipogenic genes as sterol regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FASN) in the liver. Although ethanol ingestion caused a 5.4-fold increase in liver TG, pre-treating with AVGE (1 mg/kg/d) for 1 week significantly suppressed this elevation of the ethanol-induced liver TG level. The expression of lipogenic genes was also lower in the AVGE pre-treatment group than in the control group. This inhibitory effect on the ethanol-induced accumulation of TG was attributed to a reduction in the expression of lipogenic genes that were increased by ethanol. PMID:23132591

  14. Diosmin protects against ethanol-induced hepatic injury via alleviation of inflammation and regulation of TNF-α and NF-κB activation.

    PubMed

    Tahir, Mir; Rehman, Muneeb U; Lateef, Abdul; Khan, Rehan; Khan, Abdul Quaiyoom; Qamar, Wajhul; Ali, Farrah; O'Hamiza, Oday; Sultana, Sarwat

    2013-03-01

    The present investigation was designed to evaluate the efficacy of diosmin against ethanol-induced hepatotoxicity in rats by modulating various mechanisms including ethanol metabolizing enzymes, generation of free radicals, imbalance in oxidant-antioxidant status, oxidative damage to membrane lipids, activation of transcription factors and elevation in inflammatory markers involved in ethanol-induced hepatic damage. Diosmin is a flavone glycoside, having anti-inflammatory and anti-cancer properties. Thirty female Wistar rats segregated in five groups, each with six animals. Group I as control followed by Group II, III and IV were treated with ethanol for 28 days. While groups III and IV were administered with diosmin at 10 mg/kg b wt (D1) and 20 mg/kg b wt (D2) respectively prior to ethanol administration. Group V was given only higher dose of diosmin. In ethanol-treated group, ethanol metabolizing enzymes viz., CYP 450 2E1 and alcohol dehydrogenase (ADH) significantly increased by 77.82% and 32.32% in liver tissues respectively as compared with control group and this enhancement is significantly normalized with diosmin administration. Diosmin administration (D1 & D2) significantly (p < 0.001) attenuates oxidative stress markers i.e., LPO, GSH, GPx, GR and XO by 90.77 & 137.55%, 17.18 & 25%, 37.3 & 49.86%, 21.63 & 44.9% and 56.14 &77.19% respectively. Serum ALT, AST and LDH significantly increased by 102.03, 116.91 and 45.20% in ethanol-treated group as compared with control group. Group III and IV animals showed significant reduction in the serum toxicity markers. Diosmin further alleviated ethanol-induced NF-κB activation, enhanced expression of TNF-α, COX-2 and iNOS. Findings from the present study permit us to conclude that diosmin alleviates alcoholic liver injury via modulating ethanol metabolizing pathway, inhibition of oxidative stress markers and suppression of inflammatory markers. This may represent a novel protective strategy against ethanol-induced

  15. Ethanol-induced mitophagy in liver is associated with activation of the PINK1-Parkin pathway triggered by oxidative DNA damage.

    PubMed

    Eid, Nabil; Ito, Yuko; Horibe, Akio; Otsuki, Yoshinori

    2016-10-01

    Mitophagy is a cytoprotective mechanism against mitochondrial damaging agents. Studies demonstrating morphological evidence for the involvement of the PINK1-Parkin pathway in the hepatocyte mitophagic response to ethanol toxicity, and potential links to apoptosis and mitochondrial alterations such as spheroid formation are still lacking. We addressed these unresolved issues using a rat model of binge alcohol exposure. Adult rats were injected with ethanol (5g/kg) and liver samples were taken at 0, 3, 6, and 24 hours after ethanol administration and processed for light and electron microscopic studies. Ethanol induced a low level of hepatocyte apoptosis, peaking at 3 h and decreasing significantly by 24 h. In contrast, there was enhanced formation of mitophagic vacuoles in the majority of normal hepatocytes of ethanol-treated rats (ETRs), which peaked at 6 h and was maintained up to 24 h based on electron microscopy and TUNEL/LC3 double labelling. Moreover, enhanced mitophagy in ETR hepatocytes was confirmed by increased LC3 puncta formation, and co-localization of Parkin and LC3 with mitochondrial and lysosomal markers. Immunoelectron microscopy demonstrated the localization of PINK1 and Parkin to damaged mitochondria of ETR hepatocytes, which was consistent with co-localization of Parkin with 8-OHdG, a marker of oxidative mitochondrial DNA damage. Furthermore, electron microscopy showed enhanced formation of mitochondrial spheroids in ETR hepatocytes. These data are the first direct morphological evidence linking PINK1-Parkin pathway activation to the enhanced mitophagic response of hepatocytes to ethanol toxicity. Ethanol-induced hepatic mitophagy may be a prosurvival mechanism, which may have therapeutic implications. PMID:26935412

  16. High Intrinsic Aerobic Capacity Protects against Ethanol-Induced Hepatic Injury and Metabolic Dysfunction: Study Using High Capacity Runner Rat Model.

    PubMed

    Szary, Nicholas; Rector, R Scott; Uptergrove, Grace M; Ridenhour, Suzanne E; Shukla, Shivendra D; Thyfault, John P; Koch, Lauren G; Britton, Steven L; Ibdah, Jamal A

    2015-01-01

    Rats artificially selected over several generations for high intrinsic endurance/aerobic capacity resulting in high capacity runners (HCR) has been developed to study the links between high aerobic fitness and protection from metabolic diseases (Wisloff et al., Science, 2005). We have previously shown that the HCR strain have elevated hepatic mitochondrial content and oxidative capacity. In this study, we tested if the elevated hepatic mitochondrial content in the HCR rat would provide "metabolic protection" from chronic ethanol-induced hepatic steatosis and injury. The Leiber-Decarli liquid diet with ethanol (7% v/v; HCR-E) and without (HCR-C) was given to HCR rats (n = 8 per group) from 14 to 20 weeks of age that were weight matched and pair-fed to assure isocaloric intake. Hepatic triglyceride (TG) content and macro- and microvesicular steatosis were significantly greater in HCR-E compared with HCR-C (p < 0.05). In addition, hepatic superoxide dismutase activity and glutathione levels were significantly (p < 0.05) reduced in the HCR-E rats. This hepatic phenotype also was associated with reduced total hepatic fatty acid oxidation (p = 0.03) and β-hydroxyacyl-CoA dehydrogenase activity (p = 0.01), and reductions in microsomal triglyceride transfer protein and apoB-100 protein content (p = 0.01) in HCR-E animals. However, despite these documented hepatic alterations, ethanol ingestion failed to induce significant hepatic liver injury, including no changes in hepatic inflammation, or serum alanine amino transferase (ALTs), free fatty acids (FFAs), triglycerides (TGs), insulin, or glucose. High intrinsic aerobic fitness did not reduce ethanol-induced hepatic steatosis, but protected against ethanol-induced hepatic injury and systemic metabolic dysfunction in a high aerobic capacity rat model. PMID:26610588

  17. High Intrinsic Aerobic Capacity Protects against Ethanol-Induced Hepatic Injury and Metabolic Dysfunction: Study Using High Capacity Runner Rat Model

    PubMed Central

    Szary, Nicholas; Rector, R. Scott; Uptergrove, Grace M.; Ridenhour, Suzanne E.; Shukla, Shivendra D.; Thyfault, John P.; Koch, Lauren G.; Britton, Steven L.; Ibdah, Jamal A.

    2015-01-01

    Rats artificially selected over several generations for high intrinsic endurance/aerobic capacity resulting in high capacity runners (HCR) has been developed to study the links between high aerobic fitness and protection from metabolic diseases (Wisloff et al., Science, 2005). We have previously shown that the HCR strain have elevated hepatic mitochondrial content and oxidative capacity. In this study, we tested if the elevated hepatic mitochondrial content in the HCR rat would provide “metabolic protection” from chronic ethanol-induced hepatic steatosis and injury. The Leiber-Decarli liquid diet with ethanol (7% v/v; HCR-E) and without (HCR-C) was given to HCR rats (n = 8 per group) from 14 to 20 weeks of age that were weight matched and pair-fed to assure isocaloric intake. Hepatic triglyceride (TG) content and macro- and microvesicular steatosis were significantly greater in HCR-E compared with HCR-C (p < 0.05). In addition, hepatic superoxide dismutase activity and glutathione levels were significantly (p < 0.05) reduced in the HCR-E rats. This hepatic phenotype also was associated with reduced total hepatic fatty acid oxidation (p = 0.03) and β-hydroxyacyl-CoA dehydrogenase activity (p = 0.01), and reductions in microsomal triglyceride transfer protein and apoB-100 protein content (p = 0.01) in HCR-E animals. However, despite these documented hepatic alterations, ethanol ingestion failed to induce significant hepatic liver injury, including no changes in hepatic inflammation, or serum alanine amino transferase (ALTs), free fatty acids (FFAs), triglycerides (TGs), insulin, or glucose. High intrinsic aerobic fitness did not reduce ethanol-induced hepatic steatosis, but protected against ethanol-induced hepatic injury and systemic metabolic dysfunction in a high aerobic capacity rat model. PMID:26610588

  18. Carbon Monoxide (CO) Released from Tricarbonyldichlororuthenium (II) Dimer (CORM-2) in Gastroprotection against Experimental Ethanol-Induced Gastric Damage

    PubMed Central

    Magierowska, Katarzyna; Magierowski, Marcin; Hubalewska-Mazgaj, Magdalena; Adamski, Juliusz; Surmiak, Marcin; Sliwowski, Zbigniew; Kwiecien, Slawomir; Brzozowski, Tomasz

    2015-01-01

    The physiological gaseous molecule, carbon monoxide (CO) becomes a subject of extensive investigation due to its vasoactive activity throughout the body but its role in gastroprotection has been little investigated. We determined the mechanism of CO released from its donor tricarbonyldichlororuthenium (II) dimer (CORM-2) in protection of gastric mucosa against 75% ethanol-induced injury. Rats were pretreated with CORM-2 30 min prior to 75% ethanol with or without 1) non-selective (indomethacin) or selective cyclooxygenase (COX)-1 (SC-560) and COX-2 (celecoxib) inhibitors, 2) nitric oxide (NO) synthase inhibitor L-NNA, 3) ODQ, a soluble guanylyl cyclase (sGC) inhibitor, hemin, a heme oxygenase (HO)-1 inductor or zinc protoporphyrin IX (ZnPPIX), an inhibitor of HO-1 activity. The CO content in gastric mucosa and carboxyhemoglobin (COHb) level in blood was analyzed by gas chromatography. The gastric mucosal mRNA expression for HO-1, COX-1, COX-2, iNOS, IL-4, IL-1β was analyzed by real-time PCR while HO-1, HO-2 and Nrf2 protein expression was determined by Western Blot. Pretreatment with CORM-2 (0.5–10 mg/kg) dose-dependently attenuated ethanol-induced lesions and raised gastric blood flow (GBF) but large dose of 100 mg/kg was ineffective. CORM-2 (5 mg/kg and 50 mg/kg i.g.) significantly increased gastric mucosal CO content and whole blood COHb level. CORM-2-induced protection was reversed by indomethacin, SC-560 and significantly attenuated by celecoxib, ODQ and L-NNA. Hemin significantly reduced ethanol damage and raised GBF while ZnPPIX which exacerbated ethanol-induced injury inhibited CORM-2- and hemin-induced gastroprotection and the accompanying rise in GBF. CORM-2 significantly increased gastric mucosal HO-1 mRNA expression and decreased mRNA expression for iNOS, IL-1β, COX-1 and COX-2 but failed to affect HO-1 and Nrf2 protein expression decreased by ethanol. We conclude that CORM-2 released CO exerts gastroprotection against ethanol-induced gastric

  19. [Protective effects of S-adenosylmethionine against CCl4 - and ethanol-induced experimental hepatic fibrosis].

    PubMed

    Zhang, F; Gu, J-X; Zou, X-P; Zhuge, Y-Z

    2016-01-01

    In this study the effects of S-adenosylmethionine (SAM) on experimental hepatic fibrotic rats induced by carbon tetrachloride (CCl(4)) and ethanol and the relevant potential mechanisms were explored. Hepatic fibrotic rat models were established with CCl(4) diluted in olive oil being drunk with 10% ethanol in water. SAM was used both for prevention and treatment. Histological evaluation was carried out by hematoxylin-eosin (HE) and Masson staining of hepatic samples. Serum biochemical assays showed that alanine aminotransferase (ALT) was increased and albumin (ALB) was decreased by CCl(4) and ethanol, and both effects were suppressed by preventing and treating use of SAM. The model control rats got significantly higher scores in fatty degeneration, lobular inflammation, and hepatocyte ballooning. A significant improvement was observed in the SAM-prevented rats and SAM-treated rats, which was consistent with the change of fibrosis scoring in each group. Smad3 was induced by CCl(4) and ethanol in the model control group, which was significantly down regulated by SAM. SAM reduced both total Smad3 and phospho-Smad3 in vitro. SAM had a protective effect on hepatic fibrosis in rats induced by CCl(4) combined with ethanol and the down-regulation of activity and expression of Smad3 were involved in the potential mechanisms. PMID:27239849

  20. Hydrogen sulfide prevents ethanol-induced gastric damage in mice: role of ATP-sensitive potassium channels and capsaicin-sensitive primary afferent neurons.

    PubMed

    Medeiros, Jand Venes R; Bezerra, Víctor H; Gomes, Antoniella S; Barbosa, André Luiz R; Lima-Júnior, Roberto César P; Soares, Pedro Marcos G; Brito, Gerly Anne C; Ribeiro, Ronaldo A; Cunha, Fernando Q; Souza, Marcellus H L P

    2009-09-01

    The aim of this study was to evaluate the protective effect of hydrogen sulfide (H(2)S) on ethanol-induced gastric lesions in mice and the influence of ATP-sensitive potassium (K(ATP)) channels, capsaicin-sensitive sensory afferent neurons, and transient receptor potential vanilloid (TRPV) 1 receptors on such an effect. Saline and L-cysteine alone or with propargylglycine, sodium hydrogen sulfide (NaHS), or Lawesson's reagent were administrated for testing purposes. For other experiments, mice were pretreated with glibenclamide, neurotoxic doses of capsaicin, or capsazepine. Afterward, mice received L-cysteine, NaHS, or Lawesson's reagent. After 30 min, 50% ethanol was administrated by gavage. After 1 h, mice were sacrificed, and gastric damage was evaluated by macroscopic and microscopic analyses. L-cysteine, NaHS, and Lawesson's reagent treatment prevented ethanol-induced macroscopic and microscopic gastric damage in a dose-dependent manner. Administration of propargylglycine, an inhibitor of endogenous H(2)S synthesis, reversed gastric protection induced by L-cysteine. Glibenclamide reversed L-cysteine, NaHS, or Lawesson's reagent gastroprotective effects against ethanol-induced macroscopic damage in a dose-dependent manner. Chemical ablation of sensory afferent neurons by capsaicin reversed gastroprotective effects of L-cysteine or H(2)S donors (NaHS or Lawesson's reagent) in ethanol-induced macroscopic gastric damage. Likewise, in the presence of the TRPV1 antagonist capsazepine, the gastroprotective effects of L-cysteine, NaHS, or Lawesson's reagent were also abolished. Our results suggest that H(2)S prevents ethanol-induced gastric damage. Although there are many mechanisms through which this effect can occur, our data support the hypothesis that the activation of K(ATP) channels and afferent neurons/TRPV1 receptors is of primary importance. PMID:19491326

  1. The influence of acute or chronic nicotine treatment on ethanol-induced gastric mucosal damage in rats.

    PubMed

    Cho, C H; Chen, B W; Hui, W M; Lam, S K

    1990-01-01

    The influences of acute or chronic nicotine pretreatment on ethanol-induced changes on gastric secretion, mucosal blood flow (GMBF), and glandular mucosal damage were studied in anesthetized rats. Ethanol administration decreased gastric acid secretion and GMBF, which were accompanied by a marked increase in gastric mucosal damage. Acute nicotine incubation 2 or 4 mg dose-dependently elevated both the titratable acid in the luminal solution and the gastric secretory volume; it also prevented the depressive action on GMBF and gastric mucosal damage in ethanol-treated animals. Chronic nicotine treatment for 10 days reduced the inhibitory action of ethanol on gastric acid secretion; the higher dose (25 micrograms/ml drinking water) potentiated the decrease of GMBF and the ulcerogenic property of ethanol. However, chronic treatment with the lower dose (5 micrograms/ml drinking water) had the opposite effects; it also markedly increased the gastric secretory volume. It is concluded that acute nicotine pretreatment elevates, whereas chronic nicotine pretreatment differentially affects GMBF. These effects could account for their protective or preventive actions on ethanol ulceration. The increase in nonacid gastric secretory volume by nicotine could partially explain its antiulcer effect. Furthermore, the acid secretory state of the stomach appears unrelated to the ulcerogenic property of ethanol. PMID:2295286

  2. Protective effect of anacardic acids from cashew (Anacardium occidentale) on ethanol-induced gastric damage in mice.

    PubMed

    Morais, Talita C; Pinto, Natália B; Carvalho, Karine Maria M B; Rios, Jeison B; Ricardo, Nagila Maria P S; Trevisan, Maria Teresa S; Rao, Vietla S; Santos, Flávia A

    2010-01-01

    Cashew nut-shell liquid and the contained anacardic acids (AAs) have been shown to possess antioxidant, lipoxygenase inhibitory, anti-Helicobacter pylori and antitumor properties. Despite these known effects, hitherto there were no published reports on their likely gastroprotective effects. The present study was designed to verify whether AAs afford gastroprotection against the ethanol-induced gastric damage and to examine the underlying mechanism(s). Gastric damage was induced by intragastric administration of 0.2mL of ethanol (96%). Mice in groups were pretreated orally with AAs (10, 30 and 100mg/kg), misoprostol (50 microg/kg), or vehicle (2% Tween 80 in saline, 10mL/kg), 45min before ethanol administration. They were sacrificed 30min later, the stomachs excised, and the mucosal lesion area (mm(2)) measured by planimetry. Gastroprotection was assessed in relation to inhibition of gastric lesion area. To study the gastroprotective mechanism(s), its relations to capsaicin-sensitive fibers, endogenous prostaglandins, nitric oxide and ATP-sensitive potassium channels were analysed. Treatments effects on ethanol-associated oxidative stress markers GSH, MDA, catalase, SOD, and total nitrate/nitrite levels as an index of NO were measured in gastric tissue. Besides, the effects of AAs on gastric secretory volume and total acidity were analysed in 4-h pylorus-ligated rat. AAs afforded a dose-related gastroprotection against the ethanol damage and further prevented the ethanol-induced changes in the levels of GSH, MDA, catalase, SOD and nitrate/nitrite. However, they failed to modify the gastric secretion or the total acidity. It was observed that the gastroprotection by AAs was greatly reduced in animals pretreated with capsazepine, indomethacin, l-NAME or glibenclamide. These results suggest that AAs afford gastroprotection principally through an antioxidant mechanism. Other complementary mechanisms include the activation of capsaicin-sensitive gastric afferents

  3. Lipids and Oxidative Stress Associated with Ethanol-Induced Neurological Damage

    PubMed Central

    2016-01-01

    The excessive intake of alcohol is a serious public health problem, especially given the severe damage provoked by chronic or prenatal exposure to alcohol that affects many physiological processes, such as memory, motor function, and cognitive abilities. This damage is related to the ethanol oxidation in the brain. The metabolism of ethanol to acetaldehyde and then to acetate is associated with the production of reactive oxygen species that accentuate the oxidative state of cells. This metabolism of ethanol can induce the oxidation of the fatty acids in phospholipids, and the bioactive aldehydes produced are known to be associated with neurotoxicity and neurodegeneration. As such, here we will review the role of lipids in the neuronal damage induced by ethanol-related oxidative stress and the role that lipids play in the related compensatory or defense mechanisms. PMID:26949445

  4. Effects of chronic nitric oxide synthase inhibition in cold-restraint and ethanol-induced gastric mucosal damage in rats.

    PubMed

    Qiu, B S; Pfeiffer, C J; Cho, C H

    1996-01-01

    Gastric actions of Nw-nitro-1-arginine methyl ester (L-NAME) were investigated in rats, as this agent is a reliable nitric oxide synthase inhibitor L-NAME solutions were placed in subcutaneous osmotic minipumps which continuously released L-NAME at 0.1, 1.0, 10, or 40 mg/kg/day. L-NAME dose and time-dependently enhanced stress-induced gastric ulceration but did not affect mucosal mast cell population. Ulcerogenic actions of L-NAME were reversed by L-arginine but not by D-arginine. Ten L-NAME treatment also enhanced the ethanol-induced gastric mucosal damage, depressed gastric mucosal blood flow but did not alter gastric mucus, secretory volume, or acid output. It is concluded that in the present models, chronic nitric oxide synthase inhibition enhanced ulcerogenesis by decreasing mucosal resistance due to reduced mucosal blood perfusion. This implicates nitric oxide as a mucosal defense factor which acts in part by maintaining mucosal blood flow. PMID:8626050

  5. Failure of the inhibition of rat gastric mucosal 5-lipoxygenase by novel acetohydroxamic acids to prevent ethanol-induced damage.

    PubMed

    Boughton-Smith, N K; Whittle, B J

    1988-09-01

    1. The role of leukotriene B4 (LTB4) and LTC4 as mediators of gastric mucosal damage following ethanol challenge in vivo has been investigated using two selective 5-lipoxygenase inhibitors, BW A4C and BW A137C. 2. Oral administration of ethanol to rats in vivo, induced macroscopic damage to the gastric mucosa and markedly increased the formation of the 5-lipoxygenase products, LTB4 and LTC4, from the mucosa ex vivo. 3. Pretreatment with the acetohydroxamic acids BW A4C and BW A137C (5-50 mg kg-1 p.o.) dose-dependently reduced ethanol-stimulated LTB4 and LTC4 formation by the gastric mucosa, with an ID50 of approximately 5 mg kg-1 p.o. 4. A single oral dose of BW A4C (20 mg kg-1) induced near-maximal inhibition of mucosal LTB4 formation within 30 min, which was well maintained for 5 h, whereas BW A137C (20 mg kg-1 p.o.) induced maximal inhibition between 30 and 60 min after administration, which then diminished over the subsequent 5 h. 5. The mucosal formation of the cyclo-oxygenase product, 6-keto-prostaglandin F1 alpha, which was unaltered following ethanol challenge, was not inhibited by the acetohydroxamic acids. Likewise, the small increase in mucosal thromboxane B2 formation following challenge was not inhibited by BW A4C. 6. Neither BW A4C nor BW A137C, at doses that almost completely inhibited the mucosal synthesis of LTB4 or LTC4, reduced the macroscopic gastric mucosal damage induced by ethanol. 7. Pretreatment with the lipoxygenase inhibitor BW 755C (5-50 mg kg-1 p.o.) did reduce mucosal damage, but there was a dissociation between the degree of protection and the inhibition of leukotriene biosynthesis. 8. Oral administration of high doses of either BW A4C or BW A137C (300mgkg-1) did not induce macroscopic gastric damage over a 3 h period. 9. These findings suggest that the leukotrienes, LTB4 and LTC4 are not the primary mediators of ethanol-induced acute mucosal damage, but do not exclude their role in more chronic gastric damage and inflammation. PMID

  6. Chronic parenterally administered nicotine and stress- or ethanol-induced gastric mucosal damage in rats.

    PubMed

    Wong, D; Ogle, C W

    1995-01-13

    Mini-osmotic pumps containing solutions of either 0.9% NaCl (infused at the rate of 0.5 microliter/h) or nicotine (infused in doses of 0.224, 1.03 or 1.88 mg/kg per day) were implanted s.c. into rats 12 days before experimentation. The alkaloid increased solid food consumption, but fluid intake and average weight gain were similar among the animals given saline or nicotine. Chronic nicotine treatment dose dependently intensified cold (4 degrees C)-restraint stress-induced ulceration and increased mast cell degranulation. Oral administration of 40% ethanol to nicotine-treated animals also produced greater mucosal damage; mast cell degranulation by ethanol was significantly worsened after alkaloid treatment. These findings show that the stress ulcer-intensifying action of the alkaloid is mainly through a systemic mechanism. In the case of ethanol-evoked mucosal damage, in addition to a topical effect, stimulation of the stomach wall ganglia is likely to participate in the exaggerated post-vagal ulcerogenic responses as seen in stress. PMID:7720788

  7. 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

  8. Protective effect of panax notoginseng saponins on acute ethanol-induced liver injury is associated with ameliorating hepatic lipid accumulation and reducing ethanol-mediated oxidative stress.

    PubMed

    Ding, Ren-Bo; Tian, Ke; Cao, Yi-Wei; Bao, Jiao-Lin; Wang, Meng; He, Chengwei; Hu, Yuanjia; Su, Huanxing; Wan, Jian-Bo

    2015-03-11

    The aim of present study was to evaluate the effects of Panax notoginseng saponins (PNS) against acute ethanol-induced liver injury and further to elucidate its probable mechanisms. Mice were treated with PNS (100 or 300 mg/kg) once daily for seven consecutive days priors to ethanol gavage (4.7 g/kg) every 12 h for a total of three doses. Acute alcohol gavage dramatically significantly increased serum activities of alanine aminotransferase (ALT) (23.4 ± 5.0 IU/L vs 11.7 ± 4.1 IU/L) and aspartate aminotransferase (AST) (52.6 ± 14.9 IU/L vs 31.1 ± 12.9 IU/L), and hepatic triglyceride level (4.04 ± 0.64 mg/g vs 1.92 ± 0.34 mg/g), these elevations were significantly diminished by pretreatment with PNS at dose of 100 mg/kg or 300 mg/kg. Alcohol exposure markedly induced the lipolysis of white adipose tissue (WAT), up-regulated protein expression of the phosphorylated hormone-sensitive lipase (p-HSL, p < 0.01), and total HSL (p < 0.01), and enhanced fatty acid uptake capacity in liver as indicated by increasing hepatic CD36 expression (p < 0.01), these effects were attenuated by PNS treatment. Additionally, PNS suppressed the elevation of reactive oxygen species (ROS) production and malondialdehyde (MDA) content, reduced TNF-α and IL-6 levels, restored glutathione (GSH) level, enhanced the superoxide dismutase (SOD) activity in liver, and abrogated cytochrome P450 2E1 (CYP2E1) induction. These data demonstrated that pretreatment with PNS protected against acute ethanol-induced liver injury, possibly through ameliorating hepatic lipid accumulation and reducing CYP2E1-mediated oxidative stress. Our findings also suggested that PNS may be potential to be developed as an effective agent for acute ethanol-induced liver injury. PMID:25665731

  9. Protective effects of green tea polyphenol extracts against ethanol-induced gastric mucosal damages in rats: stress-responsive transcription factors and MAP kinases as potential targets.

    PubMed

    Lee, Jeong-Sang; Oh, Tae-Young; Kim, Young-Kyung; Baik, Joo-Hyun; So, Sung; Hahm, Ki-Baik; Surh, Young-Joon

    2005-11-11

    There are multiple lines of compelling evidence from epidemiologic and laboratory studies supporting that frequent consumption of green tea is inversely associated with the risk of chronic human diseases including cancer. The chemopreventive and chemoprotective effects of green tea have been largely attributed to antioxidative and anti-inflammatory activities of its polyphenolic constituents, such as epigallocatechin gallate. The present study was designed to evaluate the efficacy of green tea polyphenols in protecting against alcohol-induced gastric damage and to elucidate the underlying mechanisms. Intragastric administration of ethanol to male Sprague-Dawley rats caused significant gastric mucosal damage, which was accompanied by elevated expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as well as transient activation of redox-sensitive transcription factors, such as NF-kappaB and AP-1, and mitogen-activated protein kinases (MAPKs). Oral administration of the green tea polyphenolic extract (GTE) significantly ameliorated mucosal damages induced by ethanol and also attenuated the ethanol-induced expression of COX-2 and iNOS. Inactivation of MAPKs, especially p38 and ERKl/2, by GTE might be responsible for inhibition of ethanol-induced expression of COX-2 and iNOS. PMID:16095631

  10. Carbon monoxide alleviates ethanol-induced oxidative damage and inflammatory stress through activating p38 MAPK pathway

    SciTech Connect

    Li, Yanyan; Gao, Chao; Shi, Yanru; Tang, Yuhan; Liu, Liang; Xiong, Ting; Du, Min; Xing, Mingyou; Liu, Liegang; Yao, Ping

    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. 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.

  11. Biochemical and immunological basis of silymarin effect, a milk thistle (Silybum marianum) against ethanol-induced oxidative damage.

    PubMed

    Das, Subir Kumar; Mukherjee, Sukhes

    2012-06-01

    Ethanol metabolism induces generation of excessive amount of reactive oxygen species (ROS) which results in immune dysfunction. We examined the efficacy of silymarin on ethanol-induced oxidative stress, immunomodulatory activity, and vascular function in mice blood. Effectiveness of silymarin was compared with potent antioxidant ascorbic acid. In the present study, 8- to 10-week-old male BALB/c mice (20-30 g) were divided into the four groups of six each. One group were fed with ethanol (1.6 g/kg body weight), while second group were fed with ethanol (1.6 g/kg body weight) and silybin (250 mg/kg body weight), and the third group were exposed to ethanol (250 mg/kg body weight) and ascorbic acid (250 mg/kg body weight) per day for 12 weeks. The control group was fed with isocaloric glucose solution instead of ethanol. Ethanol exposure significantly increased thiobarbituric acid reactive substance (TBARS) and nitrite levels besides glutathione-S-transferase (GST) activity, and significantly decreased reduced glutathione (GSH) content and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) in whole blood hemolyzate, while silymarin treatment significantly normalized these altered parameters. Silymarin significantly prevented ethanol-induced, elevated activities of interleukin (IL)-10, tumor necrosis factor (TNF)-α, γ interferon (IFN-γ), vascular endothelial growth factor (VEGF)-A, and transforming growth factor (TGF)-β1, as well as decreased IL-4 activity in mice blood. These results were comparable with the activity of ascorbic acid. PMID:22409310

  12. Effect of indole-3-carbinol on ethanol-induced liver injury and acetaldehyde-stimulated hepatic stellate cells activation using precision-cut rat liver slices.

    PubMed

    Guo, Yu; Wu, Xiao-Qian; Zhang, Chun; Liao, Zhang-Xiu; Wu, Yong; Xia, Zheng-Yuan; Wang, Hui

    2010-12-01

    1. Indole-3-carbinol (I3C), a major indole compound found in high levels in cruciferous vegetables, shows a broad spectrum of biological activities. However, few studies have reported the effect of I3C on alcoholic liver injury. In the present study, we investigated the protective effect of I3C on acute ethanol-induced hepatotoxicity and acetaldehyde-stimulated hepatic stellate cells (HSC) activation using precision-cut liver slices (PCLS). 2. Rat PCLS were incubated with 50 mmol/L ethanol or 350 μmol/L acetaldehyde, and different concentrations (100-400 μmol/L) of I3C were added into the culture system of these two liver injury models, respectively. Hepatotoxicity was assessed by measuring enzyme leakage and malondialdehyde (MDA) content in tissue. Activities of alcoholic enzymes were also determined. α-Smooth muscle actin (α-SMA), transforming growth factor (TGF-β(1) ) and hydroxyproline (HYP) were used as indices to evaluate the activation of HSC. In addition, matrix metalloproteinase-1 (MMP-1) and the tissue inhibitor of metalloproteinase (TIMP-1) were observed to estimate collagen degradation. 3. I3C significantly reduced the enzyme leakage in ethanol-treated slices. In I3C groups, cytochrome P450 (CYP) 2E1 activities were inhibited by 40.9-51.8%, whereas alcohol dehydrogenase (ADH) activity was enhanced 1.6-fold compared with the ethanol-treated group. I3C also showed an inhibitory effect against HSC activation and collagen production stimulated by acetaldehyde. After being incubated with I3C (400 μmol/L), the expression of MMP-1 was markedly enhanced, whereas TIMP-1 was decreased. 4. These results showed that I3C protected PCLS against alcoholic liver injury, which might be associated with the regulation of ethanol metabolic enzymes, attenuation of oxidative injury and acceleration of collagen degradation. PMID:20880187

  13. Novel role of Zn(II)-curcumin in enhancing cell proliferation and adjusting proinflammatory cytokine-mediated oxidative damage of ethanol-induced acute gastric ulcers.

    PubMed

    Mei, Xueting; Xu, Donghui; Xu, Sika; Zheng, Yanping; Xu, Shibo

    2012-04-15

    Alcohol consumption can induce gastric ulcers and zinc deficiency. Zinc complexes were reported to have anti-ulcer activity as it acts as an anti-inflammatory and antioxidant. Zn(II)-curcumin complex and its solid dispersions (SDs) were synthesized and evaluated for its gastroprotective activity and mechanism against ethanol-induced ulcer. The Swiss murine fibroblast cell line (3T3) was used as an alternative in vitro model to evaluate the effects of Zn(II)-curcumin on cell proliferation. Zn(II)-curcumin were administered orally for seven consecutive days prior to induction of ulcers using ethanol. Gross and microscopic lesions, immunological and biochemical parameters were taken into consideration. The results showed that solid dispersions (SDs) of Zn(II)-curcumin (2.5-20 μM) enhanced the proliferation of 3T3 cells more significantly than curcumin at the same concentrations (P<0.01). Oral administration of Zn(II)-curcumin (12, 24 and 48 mg/kg) SDs dose-dependently prevented formation of ulcer lesions induced by ethanol. The levels of proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and oxidative stress superoxide dismutase (SOD), glutathione peroxidase (GPX-Px), malonaldehyde (MDA) and H(+)-K(+)-ATPase were in the rats exposed to ethanol in ulceration have been altered. Zn(II)-curcumin prevented formation of ulcer lesions, significantly inhibited TNF-α and IL-6 mRNA expression, increased the activity of SOD and GSH-Px, reduced MDA levels and H(+)-K(+)-ATPase in mucosa of rats compared to controls (P<0.05). These findings suggest that the gastroprotective activity of Zn(II)-curcumin complex might contribute in stimulating cell proliferation and adjusting the proinflammatory cytokine-mediated oxidative damage to the gastric mucosa. PMID:22465177

  14. Insulin Protects against Hepatic Damage Postburn

    PubMed Central

    Jeschke, Marc G; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G; Cox, Robert A; Brooks, Natasha C; Finnerty, Celeste C; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

    2011-01-01

    Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes. PMID:21267509

  15. Effects of aqueous extracts from Quercus ilex L. root bark, Punica granatum L. fruit peel and Artemisia herba-alba Asso leaves on ethanol-induced gastric damage in rats.

    PubMed

    Gharzouli, K; Khennouf, S; Amira, S; Gharzouli, A

    1999-02-01

    The gastroprotective effect of tannic acid and the aqueous extract of Quercus ilex L. root bark, Punica granatum L. fruit peel and Artemisia herba-alba Asso leaves was investigated in the rat against ethanol-induced damage. Tannic acid, Q. ilex and P. granatum extracts gave 100% precipitation of ovine haemoglobin in vitro, whereas A. herba-alba extract was devoid of any protein-binding property. Oral administration of these plant extracts or tannic acid induced a significant decrease in gastric lesions (47.7%-76%). The observed protection was more pronounced when the test solution was given at the same time with ethanol, except for Q. ilex extract. The acid content of the stomach was significantly increased by P. granatum (368%) and A. herba-alba (251%) extracts prepared in ethanol. It is suggested that monomeric and polymeric polyphenols can strengthen the gastric mucosal barrier. PMID:10189949

  16. Imipramine blocks ethanol-induced ASMase activation, ceramide generation, and PP2A activation, and ameliorates hepatic steatosis in ethanol-fed mice

    PubMed Central

    Rahmini, Yasmeen; Ross, Ruth A.; Zhao, Zhenwen; Xu, Yan; Crabb, David W.

    2012-01-01

    Our previous data showed the inhibitory effect of ethanol on AMP-activated protein kinase phosphorylation, which appears to be mediated, in part, through increased levels of hepatic ceramide and activation of protein phosphatase 2A (Liangpunsakul S, Sozio MS, Shin E, Zhao Z, Xu Y, Ross RA, Zeng Y, Crabb DW. Am J Physiol Gastrointest Liver Physiol 298: G1004–G1012, 2010). The effect of ethanol on AMP-activated protein kinase phosphorylation was reversed by imipramine, suggesting that the generation of ceramide via acid sphingomyelinase (ASMase) is stimulated by ethanol. In this study, we determined the effects of imipramine on the development of hepatic steatosis, the generation of ceramide, and downstream effects of ceramide on inflammatory, insulin, and apoptotic signaling pathways, in ethanol-fed mice. The effect of ethanol and imipramine (10 μg/g body wt ip) on ceramide levels, as well as inflammatory, insulin, and apoptotic signaling pathways, was studied in C57BL/6J mice fed the Lieber-DeCarli diet. Ethanol-fed mice developed the expected steatosis, and cotreatment with imipramine for the last 2 wk of ethanol feeding resulted in improvement in hepatic steatosis. Ethanol feeding for 4 wk induced impaired glucose tolerance compared with controls, and this was modestly improved with imipramine treatment. There was a significant decrease in total ceramide concentrations in response to imipramine in ethanol-fed mice treated with and without imipramine (287 ± 11 vs. 348 ± 12 pmol/mg tissue). The magnitude and specificity of inhibition on each ceramide species differed. A significant decrease was observed for C16 (28 ± 3 vs. 33 ± 2 pmol/mg tissue) and C24 (164 ± 9 vs. 201 ± 4 pmol/mg tissue) ceramide. Ethanol feeding increased the levels of the phosphorylated forms of ERK slightly and increased phospho-p38 and phospho-JNK substantially. The levels of phospho-p38 and phospho-JNK were reduced by treatment with imipramine. The activation of ASMase and

  17. Noninvasive Monitoring of Hepatic Damage from Hepatitis C Virus Infection

    PubMed Central

    Alavez-Ramírez, J.; Fuentes-Allen, J. L.; López-Estrada, J.

    2011-01-01

    The mathematical model for the dynamics of the hepatitis C proposed in Avendaño et al. (2002), with four populations (healthy and unhealthy hepatocytes, the viral load of the hepatitis C virus, and T killer cells), is revised. Showing that the reduced model obtained by considering only the first three of these populations, known as basic model, has two possible equilibrium states: the uninfected one where viruses are not present in the individual, and the endemic one where viruses and infected cells are present. A threshold parameter (the basic reproductive virus number) is introduced, and in terms of it, the global stability of both two possible equilibrium states is established. Other central result consists in showing, by model numerical simulations, the feasibility of monitoring liver damage caused by HCV, avoiding unnecessary biopsies and the undesirable related inconveniences/imponderables to the patient; another result gives a mathematical modelling basis to recently developed techniques for the disease assessment based essentially on viral load measurements. PMID:21331263

  18. Subcellular location of secretory proteins retained in the liver during the ethanol-induced inhibition of hepatic protein secretion in the rat

    SciTech Connect

    Volentine, G.D.; Tuma, D.J.; Sorrell, M.F.

    1986-01-01

    Ethanol administration inhibits the secretion of proteins by the liver, resulting in their hepatocellular retention. Experiments were designed in this study to determine the subcellular location of the retained secretory proteins. Ethanol was administered acutely to nonfasted rats by gastric intubation, whereas control animals received an isocaloric dose of glucose. Two hours after intubation, when maximum blood ethanol levels (45 mM) were observed, (/sup 3/H)leucine and (/sup 14/C)fucose were injected simultaneously into the dorsal vein of the penis. The labelling of secretory proteins was determined in the liver and plasma at various time periods after label injection. Ethanol treatment decreased the secretion of both leucine- and fucose-labeled proteins into the plasma. This inhibition of secretion was accompanied by a corresponding increase in the hepatic retention of both leucine- and fucose-labeled immunoprecipitable secretory proteins. At the time of maximum inhibition of secretion, leucine labeled secretory proteins located in the Golgi apparatus represented about 50% of the accumulated secretory proteins in the livers of the ethanol-treated rats, whereas the remainder was essentially equally divided among the rough and smooth endoplasmic reticulum and cytosol. Because fucose is incorporated into secretory proteins almost exclusively in the Golgi complex, fucose-labeled proteins accumulated in the livers of the ethanol-treated rats mainly in the Golgi apparatus, with the remainder located in the cytosol. These results show that ethanol administration causes an impaired movement of secretory proteins along the secretory pathway, and that secretory proteins accumulate mainly, but not exclusively, in the Golgi apparatus.

  19. Cdc42-Dependent Activation of NADPH Oxidase Is Involved in Ethanol-Induced Neuronal Oxidative Stress

    PubMed Central

    Wang, Xin; Ke, Zunji; Chen, Gang; Xu, Mei; Bower, Kimberly A.; Frank, Jacqueline A.; Zhang, Zhuo; Shi, Xianglin; Luo, Jia

    2012-01-01

    It has been suggested that excessive reactive oxygen species (ROS) and oxidative stress play an important role in ethanol-induced damage to both the developing and mature central nervous system (CNS). The mechanisms underlying ethanol-induced neuronal ROS, however, remain unclear. In this study, we investigated the role of NADPH oxidase (NOX) in ethanol-induced ROS generation. We demonstrated that ethanol activated NOX and inhibition of NOX reduced ethanol-promoted ROS generation. Ethanol significantly increased the expression of p47phox and p67phox, the essential subunits for NOX activation in cultured neuronal cells and the cerebral cortex of infant mice. Ethanol caused serine phosphorylation and membrane translocation of p47phox and p67phox, which were prerequisites for NOX assembly and activation. Knocking down p47phox with the small interfering RNA was sufficient to attenuate ethanol-induced ROS production and ameliorate ethanol-mediated oxidative damage, which is indicated by a decrease in protein oxidation and lipid peroxidation. Ethanol activated cell division cycle 42 (Cdc42) and overexpression of a dominant negative (DN) Cdc42 abrogate ethanol-induced NOX activation and ROS generation. These results suggest that Cdc42-dependent NOX activation mediates ethanol-induced oxidative damages to neurons. PMID:22662267

  20. Ethanol Induces Endoplasmic Reticulum Stress in the Developing Brain

    PubMed Central

    Ke, Zunji; Wang, Xin; Liu, Ying; Fan, Zhiqin; Chen, Gang; Xu, Mei; Bower, Kimberley A.; Frank, Jacqueline A.; Li, Mingtao; Fang, Shengyun; Shi, Xianglin; Luo, Jia

    2016-01-01

    Background Ethanol exposure during brain development causes profound damages to the central nervous system (CNS). The underlying cellular/molecular mechanisms remain unclear. The endoplasmic reticulum (ER) is involved in posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress, which is characterized by translational attenuation, synthesis of ER chaperone proteins, and activation of transcription factors. Sustained ER stress ultimately leads to cell death. ER stress is implicated in various neurodegenerative processes. Methods Using a third trimester equivalent mouse model of ethanol exposure, we tested the hypothesis that ethanol induces ER stress in the developing brain. Seven-day-old C57BL/6 mice were acutely exposed to ethanol by subcutaneous injection and the expression of ER stress-inducible proteins (ERSIPs) and signaling pathways associated with ER stress were examined. Results Ethanol exposure significantly increased the expression of ERSIPs and activated signaling pathways associated with ER stress; these include ATF6, CHOP/GADD153, GRP78, and mesencephalic astrocyte-derived neurotrophic factor as well as the phosphorylation of IRE1α, eIF2α, PERK, and PKR. The ethanol-induced increase in ERSIPs occurred within 4 hours of ethanol injection, and levels of some ERSIPs remained elevated after 24 hours of ethanol exposure. Ethanol-induced increase in phosphorylated eIF2α, caspase-12, and CHOP was distributed in neurons of specific areas of the cerebral cortex, hippocampus, and thalamus. Conclusions Our finding indicates that ethanol induces ER stress in immature neurons, providing novel insight into ethanol’s detrimental effect on the developing CNS. PMID:21599712

  1. Hepatitis C virus and neurological damage

    PubMed Central

    Mathew, Shilu; Faheem, Muhammed; Ibrahim, Sara M; Iqbal, Waqas; Rauff, Bisma; Fatima, Kaneez; Qadri, Ishtiaq

    2016-01-01

    Chronic hepatitis C virus (HCV) infection exhibits a wide range of extrahepatic complications, affecting various organs in the human body. Numerous HCV patients suffer neurological manifestations, ranging from cognitive impairment to peripheral neuropathy. Overexpression of the host immune response leads to the production of immune complexes, cryoglobulins, as well as autoantibodies, which is a major pathogenic mechanism responsible for nervous system dysfunction. Alternatively circulating inflammatory cytokines and chemokines and HCV replication in neurons is another factor that severely affects the nervous system. Furthermore, HCV infection causes both sensory and motor peripheral neuropathy in the mixed cryoglobulinemia as well as known as an important risk aspect for stroke. These extrahepatic manifestations are the reason behind underlying hepatic encephalopathy and chronic liver disease. The brain is an apt location for HCV replication, where the HCV virus may directly wield neurotoxicity. Other mechanisms that takes place by chronic HCV infection due the pathogenesis of neuropsychiatric disorders includes derangement of metabolic pathways of infected cells, autoimmune disorders, systemic or cerebral inflammation and alterations in neurotransmitter circuits. HCV and its pathogenic role is suggested by enhancement of psychiatric and neurological symptoms in patients attaining a sustained virologic response followed by treatment with interferon; however, further studies are required to fully assess the impact of HCV infection and its specific antiviral targets associated with neuropsychiatric disorders. PMID:27134702

  2. Hepatitis C virus and neurological damage.

    PubMed

    Mathew, Shilu; Faheem, Muhammed; Ibrahim, Sara M; Iqbal, Waqas; Rauff, Bisma; Fatima, Kaneez; Qadri, Ishtiaq

    2016-04-28

    Chronic hepatitis C virus (HCV) infection exhibits a wide range of extrahepatic complications, affecting various organs in the human body. Numerous HCV patients suffer neurological manifestations, ranging from cognitive impairment to peripheral neuropathy. Overexpression of the host immune response leads to the production of immune complexes, cryoglobulins, as well as autoantibodies, which is a major pathogenic mechanism responsible for nervous system dysfunction. Alternatively circulating inflammatory cytokines and chemokines and HCV replication in neurons is another factor that severely affects the nervous system. Furthermore, HCV infection causes both sensory and motor peripheral neuropathy in the mixed cryoglobulinemia as well as known as an important risk aspect for stroke. These extrahepatic manifestations are the reason behind underlying hepatic encephalopathy and chronic liver disease. The brain is an apt location for HCV replication, where the HCV virus may directly wield neurotoxicity. Other mechanisms that takes place by chronic HCV infection due the pathogenesis of neuropsychiatric disorders includes derangement of metabolic pathways of infected cells, autoimmune disorders, systemic or cerebral inflammation and alterations in neurotransmitter circuits. HCV and its pathogenic role is suggested by enhancement of psychiatric and neurological symptoms in patients attaining a sustained virologic response followed by treatment with interferon; however, further studies are required to fully assess the impact of HCV infection and its specific antiviral targets associated with neuropsychiatric disorders. PMID:27134702

  3. How does ethanol induce apoptotic cell death of SK-N-SH neuroblastoma cells.

    PubMed

    Moon, Yong; Kwon, Yongil; Yu, Shun

    2013-07-15

    A body of evidence suggests that ethanol can lead to damage of neuronal cells. However, the mechanism underlying the ethanol-induced damage of neuronal cells remains unclear. The role of mitogen-activated protein kinases in ethanol-induced damage was investigated in SK-N-SH neuroblastoma cells. 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide cell viability assay, DNA fragmentation detection, and flow cytometric analysis showed that ethanol induced apoptotic cell death and cell cycle arrest, characterized by increased caspase-3 activity, DNA fragmentation, nuclear disruption, and G1 arrest of cell cycle of the SK-N-SH neuroblastoma cells. In addition, western blot analysis indicated that ethanol induced a lasting increase in c-Jun N-terminal protein kinase activity and a transient increase in p38 kinase activity of the neuroblastoma cells. c-Jun N-terminal protein kinase or p38 kinase inhibitors significantly reduced the ethanol-induced cell death. Ethanol also increased p53 phosphorylation, followed by an increase in p21 tumor suppressor protein and a decrease in phospho-Rb (retinoblastoma) protein, leading to alterations in the expressions and activity of cyclin dependent protein kinases. Our results suggest that ethanol mediates apoptosis of SK-N-SH neuroblastoma cells by activating p53-related cell cycle arrest possibly through activation of the c-Jun N-terminal protein kinase-related cell death pathway. PMID:25206494

  4. Lithium protects ethanol-induced neuronal apoptosis

    SciTech Connect

    Zhong Jin . E-mail: jizhong@iupui.edu; Yang Xianlin; Yao Weiguo; Lee Weihua

    2006-12-01

    Lithium is widely used for the treatment of bipolar disorder. Recent studies have demonstrated its neuroprotective effect. Ethanol is a potent neurotoxin that is particularly harmful to the developing nervous system. In this study, we evaluated lithium's neuroprotection against ethanol-induced apoptosis. Transient exposure of infant mice to ethanol caused apoptotic cell death in brain, which was prevented significantly by administering a low dose of lithium 15 min later. In cultured cerebellar granule neurons, ethanol-induced apoptosis and activation of caspase-3/9, both of which were prevented by lithium. However, lithium's protection is not mediated by its commonly known inhibition of glycogen synthase3{beta}, because neither ethanol nor lithium has significant effects on the phosphorylation of Akt (ser473) or GSK3{beta} (ser9). In addition, the selective GSK-3{beta} inhibitor SB-415286 was unable to prevent ethanol-induced apoptosis. These data suggest lithium may be used as a potential preventive measure for ethanol-induced neurological deficits.

  5. Neuroprotection by Vitamin C Against Ethanol-Induced Neuroinflammation Associated Neurodegeneration in the Developing Rat Brain.

    PubMed

    Ahmad, Ashfaq; Shah, Shahid A; Badshah, Haroon; Kim, Min J; Ali, Tahir; Yoon, Gwang H; Kim, Tae H; Abid, Nouman B; Rehman, Shafiq Ur; Khan, Sohail; Kim, Myeong O

    2016-01-01

    Ethanol induces oxidative stress and its exposure during early developmental age causes neuronal cell death which leads to several neurological disorders. We previously reported that vitamin C can protect against ethanol-induced apoptotic cell death in the developing rat brain. Here, we extended our study to understand the therapeutic efficacy of vitamin C against ethanol-induced oxidative stress, neuroinflammation mediated neurodegeneration in postnatal day 7 (PND7) rat. A single episode of ethanol (5g/kg) subcutaneous administration to postnatal day 7 rat significantly induced the production of reactive oxygen species (ROS), and activated both microglia and astrocytes followed by the induction of different apoptotic markers. On the other hand, due to its free radical scavenging properties, vitamin C treatment significantly reduced the production of reactive oxygen species, suppressed both activated microglia and astrocytes and reversed other changes including elevated level of Bax/Bcl-2 ratio, cytochrome c and different caspases such as caspase-9 and caspase-3 induced by ethanol in developing rat brain. Moreover, vitamin C treatment also reduced ethanol-induced activation of Poly [ADP-Ribose] Polymerase 1(PARP-1) and neurodegeneration as evident from Flouro-Jade-B and Nissl stainined neuronal cell death in PND7 rat brain. These findings suggest that vitamin C mitigated ethanol-induced oxidative stress, neuroinflammation and apoptotic neuronal loss and may be beneficial against ethanol damaging effects in brain development. PMID:26831257

  6. Quercetin prevents ethanol-induced iron overload by regulating hepcidin through the BMP6/SMAD4 signaling pathway.

    PubMed

    Tang, Yuhan; Li, Yanyan; Yu, Haiyan; Gao, Chao; Liu, Liang; Chen, Shaodan; Xing, Mingyou; Liu, Liegang; Yao, Ping

    2014-06-01

    Emerging evidence has demonstrated that chronic ethanol exposure induces iron overload, enhancing ethanol-mediated liver damage. The purpose of this study was to explore the effects of the naturally occurring compound quercetin on ethanol-induced iron overload and liver damage, focusing on the signaling pathway of the iron regulatory hormone hepcidin. Adult male C57BL/6J mice were pair-fed with isocaloric-Lieber De Carli diets containing ethanol (accounting for 30% of total calories) and/or carbonyl iron (0.2%) and treated with quecertin (100 mg/kg body weight) for 15 weeks. Mouse primary hepatocytes were incubated with ethanol (100 mM) and quercetin (100 μM) for 24 h. Mice exposed to either ethanol or iron presented significant fatty infiltration and iron deposition in the liver; these symptoms were exacerbated in mice cotreated with ethanol and iron. Quercetin attenuated the abnormity induced by ethanol and/or iron. Ethanol suppressed BMP6 and intranuclear SMAD4 as well as decreased hepcidin expression. These effects were partially alleviated by quercetin supplementation in mice and hepatocytes. Importantly, ethanol caused suppression of SMAD4 binding to the HAMP promoter and of hepcidin messenger RNA expression. These effects were exacerbated by anti-BMP6 antibody and partially alleviated by quercetin or human recombinant BMP6 in cultured hepatocytes. In contrast, co-treatment with iron and ethanol, especially exposure of iron alone, activated BMP6/SMAD4 pathway and up-regulated hepcidin expression, which was also normalized by quercetin in vivo. Quercetin prevented ethanol-induced hepatic iron overload different from what carbonyl iron diet elicited in the mechanism, by regulating hepcidin expression via the BMP6/SMAD4 signaling pathway. PMID:24746831

  7. PKCε plays a causal role in acute ethanol-induced steatosis

    PubMed Central

    Kaiser, J. Phillip; Beier, Juliane I.; Zhang, Jun; Hoetker, J. David; von Montfort, Claudia; Guo, Luping; Zheng, Yuting; Monia, Brett P.; Bhatnagar, Aruni; Arteel, Gavin E.

    2009-01-01

    Steatosis is a critical stage in the pathology of alcoholic liver disease (ALD), and preventing steatosis could protect against later stages of ALD. PKCε has been shown to contribute to hepatic steatosis in experimental non-alcoholic fatty liver disease (NAFLD); however, the role of PKCε in ethanol-induced steatosis has not been determined. The purpose of this study was to therefore test the hypothesis that PKCε contributes to ethanol-induced steatosis. Accordingly, the effect of acute ethanol on indices of hepatic steatosis and insulin signaling were determined in PKCε knockout mice and in wild-type mice that received an antisense oligonucleotide (ASO) to knockdown PKCε expression. Acute ethanol (6 g/kg i.g.) caused a robust increase in hepatic non-esterified free fatty acids (NEFA), which peaked 1 h after ethanol exposure. This increase in NEFA was followed by elevated diacylglycerols (DAG), as well as by the concomitant activation of PKCε. Acute ethanol also changed the expression of insulin-responsive genes (i.e. increased G6Pase, downregulated GK), in a pattern indicative of impaired insulin signaling. Acute ethanol exposure subsequently caused a robust increase in hepatic triglycerides. The accumulation of triglycerides caused by ethanol was blunted in ASO-treated or in PKCε−/− mice. Taken together, these data suggest that the increase in NEFA caused by hepatic ethanol metabolism leads to an increase in DAG production via the triacylglycerol pathway. DAG then subsequently activates PKCε, which then exacerbates hepatic lipid accumulation by inducing insulin resistance. These data also suggest that PKCε plays a causal role in at least the early phases of ethanol-induced liver injury. PMID:19022218

  8. Halothane hepatitis in an animal model: time course of hepatic damage.

    PubMed Central

    Knights, K. M.; Gourlay, G. K.; Hall, P. D.; Adams, J. F.; Cousins, M. J.

    1987-01-01

    The present study extends previous reports of hepatic damage 24 h after halothane anaesthesia in the phenobarbitone pretreated hypoxic rat model by fully characterizing the lesion during the time course of its onset and recovery. Phenobarbitone treated animals exposed to halothane (1% for 2 h in 14% inspired oxygen) were killed 1, 2, 4, 6, 12 and 24 h and 2, 3, 5, 10, 15 and 30 days after commencement of the anaesthetic period. Blood was collected 1 day before the administration of halothane and at the time of killing for determination of serum alanine aminotransferase (ALT), a biochemical index of hepatic damage. Liver tissue was obtained immediately at post-mortem for histological examination. Serum ALT was increased at the end of the anaesthetic period, i.e. 2 h, with peak levels occurring at 12-24 h and remaining elevated for 3 days after exposure. Minor changes in liver histology were evident at 2 h in 50% of the animals and by 6 h all animals had mild hepatic injury. The extent of the necrosis was maximal at 24 h and this was sustained until 3 days. By 5 days after exposure minimal evidence of liver damage was observed and animals killed at 30 days had morphologically normal livers. Elevation of serum ALT or changes in liver histology were not observed in other treatment groups. The early onset of damage at 2-6 h is in keeping with direct hepatotoxicity associated with the biotransformation of halothane. Images Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:3689669

  9. Protective effect of tetrahydrocoptisine against ethanol-induced gastric ulcer in mice

    SciTech Connect

    Li, Weifeng Huang, Huimin; Niu, Xiaofeng Fan, Ting; Mu, Qingli; Li, Huani

    2013-10-01

    Excessive alcohol consumption can lead to gastric ulcer and the present work was aimed to examine the protective effect of tetrahydrocoptisine (THC) in the model of ethanol-induced gastric ulcer in mice. Fasted mice treated with ethanol 75% (0.5 ml/100 g) were pre-treated with THC (10 or 20 mg/kg, ip), cimetidine (100 mg/kg, ip) or saline in different experimental sets for a period of 3 days, and animals were euthanized 4 h after ethanol ingestion. Gross and microscopic lesions, immunological and biochemical parameters were taken into consideration. The results showed that ethanol induced gastric damage, improving nitric oxide (NO) level, increased pro-inflammatory cytokine (TNF-α and IL-6) levels and myeloperoxidase (MPO) activity, as well as the expression of nuclear factor-κB (NF-κB) in the ethanol group. Pretreatment of THC at doses of 10 and 20 mg/kg bodyweight significantly attenuated the gastric lesions as compared to the ethanol group. These results suggest that the gastroprotective activity of THC is attributed to reducing NO production and adjusting the pro-inflammatory cytokine, inhibited neutrophil accumulation and NF-κB expression. - Highlights: • THC decreased ethanol-induced pro-inflammatory cytokine release. • THC inhibited the production of NO in serum and gastric tissue. • THC reduced NF-κB expression and MPO accumulation in ethanol-induced gastric tissue.

  10. Evaluation of hepatic damage by reactive metabolites--with consideration of circadian variation of murine hepatic glutathione levels.

    PubMed

    Mori, Koji; Kumano, Atsushi; Kodama, Toshihisa; Takiguchi, Shigeyuki; Takano, Naomi; Kumada, Kohei; Hatao, Kana; Kimura, Takashi

    2014-08-01

    Generally, reactive metabolites are detoxified by conjugation with glutathione (GSH). A GSH-depleted model was prepared by administering L-buthionine-(S,R)-sulfoximine (BSO), which can be used to detect hepatic damage by reactive metabolites. However, BSO may cause adverse effects on other organs, such as renal damage by reactive metabolites because it depletes GSH in the whole body. The present study was designed to examine whether it was possible to specifically detect hepatic damage by reactive metabolites without reducing renal GSH levels by administering BSO in a time course when hepatic GSH levels are naturally reduced. Male BALB/c mice were administered reverse osmosis (RO) water or 20 mmol/l BSO in drinking water for 4 days. Subsequently, animals in the RO water group were orally administered 500 mg/kg acetaminophen (APAP) at 9:00 or 15:00 and in the BSO group at 9:00 for 4 days. As a result, severe hepatic damage and necrosis of the renal proximal tubules were observed in the BSO/APAP administration at 9:00 group, and all animals died on 1 or 2 days after APAP administration. Hepatic damage was clearly increased in the RO water/APAP administration at 15:00 group compared with the RO water/APAP administration at 9:00 group. However, renal damage and deaths were not observed. This BSO administration model may detect renal damage induced by reactive metabolites. Using an administration time course, whereby hepatic GSH levels were naturally reduced, hepatic damage by reactive metabolites can be detected without secondary renal effects. PMID:25056778

  11. Diosmin Protects against Ethanol-Induced Gastric Injury in Rats: Novel Anti-Ulcer Actions

    PubMed Central

    Arab, Hany H.; Salama, Samir A.; Omar, Hany A.; Arafa, El-Shaimaa A.; Maghrabi, Ibrahim A.

    2015-01-01

    Alcohol consumption has been commonly associated with gastric mucosal lesions including gastric ulcer. Diosmin (DIO) is a natural citrus flavone with remarkable antioxidant and anti-inflammatory features that underlay its protection against cardiac, hepatic and renal injuries. However, its impact on gastric ulcer has not yet been elucidated. Thus, the current study aimed to investigate the potential protective effects of DIO against ethanol-induced gastric injury in rats. Pretreatment with DIO (100 mg/kg p.o.) attenuated the severity of ethanol gastric mucosal damage as evidenced by lowering of ulcer index (UI) scores, area of gastric lesions, histopathologic aberrations and leukocyte invasion. These actions were analogous to those exerted by the reference antiulcer sucralfate. DIO suppressed gastric inflammation by curbing of myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) levels along with nuclear factor kappa B (NF-κB) p65 expression. It also augmented the anti-inflammatory interleukin-10 (IL-10) levels. Meanwhile, DIO halted gastric oxidative stress via inhibition of lipid peroxides with concomitant enhancement of glutathione (GSH), glutathione peroxidase (GPx) and the total antioxidant capacity (TAC). With respect to gastric mucosal apoptosis, DIO suppressed caspase-3 activity and cytochrome C (Cyt C) with enhancement of the anti-apoptotic B cell lymphoma-2 (Bcl-2) in favor of cell survival. These favorable actions were associated with upregulation of the gastric cytoprotective prostaglandin E2 (PGE2) and nitric oxide (NO). Together, these findings accentuate the gastroprotective actions of DIO in ethanol gastric injury which were mediated via concerted multi-pronged actions, including suppression of gastric inflammation, oxidative stress and apoptosis besides boosting of the antioxidant and the cytoprotective defenses. PMID:25821971

  12. Diosmin protects against ethanol-induced gastric injury in rats: novel anti-ulcer actions.

    PubMed

    Arab, Hany H; Salama, Samir A; Omar, Hany A; Arafa, El-Shaimaa A; Maghrabi, Ibrahim A

    2015-01-01

    Alcohol consumption has been commonly associated with gastric mucosal lesions including gastric ulcer. Diosmin (DIO) is a natural citrus flavone with remarkable antioxidant and anti-inflammatory features that underlay its protection against cardiac, hepatic and renal injuries. However, its impact on gastric ulcer has not yet been elucidated. Thus, the current study aimed to investigate the potential protective effects of DIO against ethanol-induced gastric injury in rats. Pretreatment with DIO (100 mg/kg p.o.) attenuated the severity of ethanol gastric mucosal damage as evidenced by lowering of ulcer index (UI) scores, area of gastric lesions, histopathologic aberrations and leukocyte invasion. These actions were analogous to those exerted by the reference antiulcer sucralfate. DIO suppressed gastric inflammation by curbing of myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) levels along with nuclear factor kappa B (NF-κB) p65 expression. It also augmented the anti-inflammatory interleukin-10 (IL-10) levels. Meanwhile, DIO halted gastric oxidative stress via inhibition of lipid peroxides with concomitant enhancement of glutathione (GSH), glutathione peroxidase (GPx) and the total antioxidant capacity (TAC). With respect to gastric mucosal apoptosis, DIO suppressed caspase-3 activity and cytochrome C (Cyt C) with enhancement of the anti-apoptotic B cell lymphoma-2 (Bcl-2) in favor of cell survival. These favorable actions were associated with upregulation of the gastric cytoprotective prostaglandin E2 (PGE2) and nitric oxide (NO). Together, these findings accentuate the gastroprotective actions of DIO in ethanol gastric injury which were mediated via concerted multi-pronged actions, including suppression of gastric inflammation, oxidative stress and apoptosis besides boosting of the antioxidant and the cytoprotective defenses. PMID:25821971

  13. Hepatic Primary and Secondary Cholesterol Deposition and Damage in Niemann-Pick Disease.

    PubMed

    Bosch, Marta; Fajardo, Alba; Alcalá-Vida, Rafael; Fernández-Vidal, Andrea; Tebar, Francesc; Enrich, Carlos; Cardellach, Francesc; Pérez-Navarro, Esther; Pol, Albert

    2016-03-01

    Niemann-Pick C disease is a neurovisceral disorder caused by mutations in the NPC gene that result in systemic accumulation of intracellular cholesterol. Although neurodegeneration defines the disease's severity, in most patients it is preceded by hepatic complications such as cholestatic jaundice or hepatomegaly. To analyze the contribution of the hepatic disease in Niemann-Pick C disease progression and to evaluate the degree of primary and secondary hepatic damage, we generated a transgenic mouse with liver-selective expression of NPC1 from embryonic stages. Hepatic NPC1 re-expression did not ameliorate the onset and progression of neurodegeneration of the NPC1-null animal. However, the mice showed reduced hepatomegalia and dramatic, although not complete, reduction of hepatic cholesterol and serum bile salts, bilirubin, and transaminase levels. Therefore, hepatic primary and secondary cholesterol deposition and damage occur simultaneously during Niemann-Pick C disease progression. PMID:26784526

  14. Mechanism of the beneficial effects of dantrolene sodium on ethanol-induced acute gastric mucosal injury in rats.

    PubMed

    Büyükokuroğlu, Mehmet Emin; Taysi, Seyithan; Polat, Fevzi; Göçer, Fatma

    2002-05-01

    In our study, we examined anti-ulcerogen and antioxidant effects of dantrolene sodium on ethanol-induced gastric lesions in rats. Dantrolene sodium was administered intraperitoneally (i.p.) in several doses, and famotidine was used at a dose of 20 mg kg (-1). It was found that pretreatment with dantrolene sodium at doses of 1, 5 and 10 mg kg(-1) significantly reduced ethanol-induced gastric damage and malondialdehyde levels, and significantly increased antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. We conclude that dantrolene sodium clearly has antioxidant properties and that the protective effect of dantrolene sodium against ethanol-induced gastric mucosal lesion, at least in part, depends upon the reduction in the lipid peroxidation and an increase in the activity of antioxidant enzymes SOD and GSH-Px. PMID:12123631

  15. p53-Mediated Cellular Response to DNA Damage in Cells with Replicative Hepatitis B Virus

    NASA Astrophysics Data System (ADS)

    Puisieux, Alain; Ji, Jingwei; Guillot, Celine; Legros, Yann; Soussi, Thierry; Isselbacher, Kurt; Ozturk, Mehmet

    1995-02-01

    Wild-type p53 acts as a tumor suppressor gene by protecting cells from deleterious effects of genotoxic agents through the induction of a G_1/S arrest or apoptosis as a response to DNA damage. Transforming proteins of several oncogenic DNA viruses inactivate tumor suppressor activity of p53 by blocking this cellular response. To test whether hepatitis B virus displays a similar effect, we studied the p53-mediated cellular response to DNA damage in 2215 hepatoma cells with replicative hepatitis B virus. We demonstrate that hepatitis B virus replication does not interfere with known cellular functions of p53 protein.

  16. The role of cellular oxidases and catalytic iron in the pathogenesis of ethanol-induced liver injury

    SciTech Connect

    Shaw, S.; Jayatilleke, E. Mount Sinai School of Medicine, New York, NY )

    1992-01-01

    Free radical generation and catalytic iron have been implicated in the pathogenesis of alcohol-induced liver injury but the source of free radicals is a subject of controversy. The mechanism of ethanol-induced liver injury was investigated in isolated hepatocytes from a rodent model of iron loading in which free radical generation was measured by the determination of alkane production. Iron loading increased hepatic non-heme iron 3-fold, increased the prooxidant activity of cytosolic ultrafiltrates 2-fold and doubled ethanol-induced alkane production. The role of cellular oxidases as a source of ethanol induced free radicals was studied through the use of selective inhibitors. In both the presence and absence of iron loading, selective inhibition of xanthine oxidase with oxipurinol diminished ethanol-induced alkane production 0-40%, inhibition of aldehyde oxidase with menadione diminished alkane production 36-75%, while the inhibition of aldehyde and xanthine oxidase by feeding tungstate virtually abolished alkane production. Addition of acetaldehyde to hepatocytes generated alkanes at rates comparable to those achieved with ethanol indicating the importance of acetaldehyde metabolism in free radical generation.

  17. Beneficial effects of Foeniculum vulgare on ethanol-induced acute gastric mucosal injury in rats

    PubMed Central

    Birdane, Fatih Mehmet; Cemek, Mustafa; Birdane, Yavuz Osman; Gülçin, İlhami; Büyükokuroğlu, Mehmet Emin

    2007-01-01

    AIM: To examine the anti-ulcerogenic and antioxidant effects of aqueous extracts of Foeniculum vulgare (FVE) on ethanol-induced gastric lesions in rats. METHODS: FVE was administered by gavage at doses of 75, 150 and 300 mg/kg, and famotidine was used at the dose of 20 mg/kg. Following a 60 min period, all the rats were given 1 mL of ethanol (80%) by gavage. One hour after the administration of ethanol, all groups were sacrificed, and the gastric ulcer index was calculated; whole blood malondialdehyde (MDA) and reduced glutathione (GSH), serum nitrate, nitrite, ascorbic acid, retinol and β-carotene levels were measured in all the groups. RESULTS: It was found that pretreatment with FVE significantly reduced ethanol-induced gastric damage. This effect of FVE was highest and statistically significant in 300 mg/kg group compared with the control (4.18 ± 2.81 vs 13.15 ± 4.08, P < 0.001). Also, pretreatment with FVE significantly reduced the MDA levels, while significantly increased GSH, nitrite, nitrate, ascorbic acid, retinol and β-carotene levels. CONCLUSION: FVE has clearly a protective effect against ethanol-induced gastric mucosal lesion, and this effect, at least in part, depends upon the reduction in lipid peroxidation and augmentation in the antioxidant activity. PMID:17278229

  18. The Involvement of Acetaldehyde in Ethanol-Induced Cell Cycle Impairment

    PubMed Central

    Scheer, Marc A.; Schneider, Katrina J.; Finnigan, Rochelle L.; Maloney, Eamon P.; Wells, Mark A.; Clemens, Dahn L.

    2016-01-01

    Background: Hepatocytes metabolize the vast majority of ingested ethanol. This metabolic activity results in hepatic toxicity and impairs the ability of hepatocytes to replicate. Previous work by our group has shown that ethanol metabolism results in a G2/M cell cycle arrest. The intent of these studies was to discern the roles of acetaldehyde and reactive oxygen, two of the major by-products of ethanol metabolism, in the G2/M cell cycle arrest. Methods: To investigate the role of ethanol metabolites in the cell cycle arrest, VA-13 and VL-17A cells were used. These are recombinant Hep G2 cells that express alcohol dehydrogenase or alcohol dehydrogenase and cytochrome P450 2E1, respectively. Cells were cultured with or without ethanol, lacking or containing the antioxidants N-acetylcysteine (NAC) or trolox, for three days. Cellular accumulation was monitored by the DNA content of the cultures. The accumulation of the cyclin-dependent kinase, Cdc2 in the inactive phosphorylated form (p-Cdc2) and the cyclin-dependent kinase inhibitor p21 were determined by immunoblot analysis. Results: Cultures maintained in the presence of ethanol demonstrated a G2/M cell cycle arrest that was associated with a reduction in DNA content and increased levels of p-Cdc2 and p21, compared with cells cultured in its absence. Inclusion of antioxidants in the ethanol containing media was unable to rescue the cells from the cell cycle arrest or these ethanol metabolism-mediated effects. Additionally, culturing the cells in the presence of acetaldehyde alone resulted in increased levels of p-Cdc2 and p21. Conclusions: Acetaldehyde produced during ethanol oxidation has a major role in the ethanol metabolism-mediated G2/M cell cycle arrest, and the concurrent accumulation of p21 and p-Cdc2. Although reactive oxygen species are thought to have a significant role in ethanol-induced hepatocellular damage, they may have a less important role in the inability of hepatocytes to replace dead or damaged

  19. Role of hypothermia in ethanol-induced conditioned taste aversion.

    PubMed

    Cunningham, C L; Hawks, D M; Niehus, D R

    1988-01-01

    Two experiments examined the effect of ambient temperature during ethanol exposure on development of conditioned taste aversion to saccharin. In both studies, male albino rats receiving saccharin-ethanol (1.5 g/kg, IP) pairings followed by 6-h exposure to a 32 degrees C environment developed a weaker saccharin aversion than did rats experiencing ethanol at room temperature. Exposure to the warm environment reduced ethanol-induced hypothermia, but enhanced ethanol's motor-impairing effect. The influence of ambient temperature on ethanol-induced taste aversion may be due to changes in body temperature, neural sensitivity, or elimination rate. Although alternative accounts cannot be entirely dismissed, this outcome suggests that ethanol-induced hypothermia plays a role in determining strength of conditioned taste aversion and thus may be involved in the regulation of oral ethanol intake in rats. PMID:3137617

  20. Protective Effects of the Traditional Herbal Formula Oryeongsan Water Extract on Ethanol-Induced Acute Gastric Mucosal Injury in Rats

    PubMed Central

    Jeon, Woo-Young; Lee, Mee-Young; Shin, In-Sik; Lim, Hye-Sun; Shin, Hyeun-Kyoo

    2012-01-01

    This study was performed to evaluate the protective effect and safety of Oryeongsan water extract (OSWE) on ethanol-induced acute gastric mucosal injury and an acute toxicity study in rats. Acute gastric lesions were induced via intragastric oral administration of absolute ethanol at a dose of 5 mL/kg. OSWE (100 and 200 mg/kg) was administered to rats 2 h prior to the oral administration of absolute ethanol. The stomach of animal models was opened and gastric mucosal lesions were examined. Gastric mucosal injuries were evaluated by measuring the levels of malondialdehyde (MDA), glutathione (GSH), and the activity of antioxidant enzymes. In the acute toxicity study, no adverse effects of OSWE were observed at doses up to 2000 mg/kg/day. Administration of OSWE reduced the damage by conditioning the gastric mucosa against ethanol-induced acute gastric injury, which included hemorrhage, hyperemia, and loss of epithelial cells. The level of MDA was reduced in OSWE-treated groups compared with the ethanol-induced group. Moreover, the level of GSH and the activity of antioxidant enzymes were significantly increased in the OSWE-treated groups. Our findings suggest that OSWE has a protective effect on the gastric mucosa against ethanol-induced acute gastric injury via the upregulation of antioxidant enzymes. PMID:23118790

  1. Autophagy Protects against CYP2E1/Chronic Ethanol-Induced Hepatotoxicity

    PubMed Central

    Lu, Yongke; Cederbaum, Arthur I.

    2015-01-01

    Autophagy is an intracellular pathway by which lysosomes degrade and recycle long-lived proteins and cellular organelles. The effects of ethanol on autophagy are complex but recent studies have shown that autophagy serves a protective function against ethanol-induced liver injury. Autophagy was found to also be protective against CYP2E1-dependent toxicity in vitro in HepG2 cells which express CYP2E1 and in vivo in an acute alcohol/CYPE1-dependent liver injury model. The goal of the current report was to extend the previous in vitro and acute in vivo experiments to a chronic ethanol model to evaluate whether autophagy is also protective against CYP2E1-dependent liver injury in a chronic ethanol-fed mouse model. Wild type (WT), CYP2E1 knockout (KO) or CYP2E1 humanized transgenic knockin (KI), mice were fed an ethanol liquid diet or control dextrose diet for four weeks. In the last week, some mice received either saline or 3-methyladenine (3-MA), an inhibitor of autophagy, or rapamycin, which stimulates autophagy. Inhibition of autophagy by 3-MA potentiated the ethanol-induced increases in serum transaminase and triglyceride levels in the WT and KI mice but not KO mice, while rapamycin prevented the ethanol liver injury. Treatment with 3-MA enhanced the ethanol-induced fat accumulation in WT mice and caused necrosis in the KI mice; little or no effect was found in the ethanol-fed KO mice or any of the dextrose-fed mice. 3-MA treatment further lowered the ethanol-decrease in hepatic GSH levels and further increased formation of TBARS in WT and KI mice, whereas rapamycin blunted these effects of ethanol. Neither 3-MA nor rapamycin treatment affected CYP2E1 catalytic activity or content or the induction CYP2E1 by ethanol. The 3-MA treatment decreased levels of Beclin-1 and Atg 7 but increased levels of p62 in the ethanol-fed WT and KI mice whereas rapamycin had the opposite effects, validating inhibition and stimulation of autophagy, respectively. These results suggest

  2. Ameliorative effects of pycnogenol on carbon tetrachloride-induced hepatic oxidative damage in rats.

    PubMed

    Ahn, Tai-Hwan; Yang, Young-Su; Lee, Jong-Chan; Moon, Chang-Jong; Kim, Sung-Ho; Jun, Woojin; Park, Seung-Chun; Kim, Jong-Choon

    2007-11-01

    This study evaluated the putative antioxidant activity of Pycnogenol (PYC) against CCl4-induced hepatic oxidative damage in Sprague-Dawley rats. A single oral dose of CCl4 (1.25 mL/kg) produced significantly increased levels of serum aminotransferase (AST) and alanine aminotransferase (ALT) activities. In addition, increased malondialdehyde (MDA) concentration, reduced glutathione (GSH) content, and decreased catalase, superoxide dismutase (SOD) and glutathione-S-transferase (GST) activities were observed in the hepatic tissues. However, concomitant administration with PYC (10 or 20 mg/kg) significantly improved CCl4-induced hepatic injury, as evidenced by the decline of serum AST and ALT activities in a dose dependent manner. Moreover, PYC reduced MDA concentration and increased GSH levels and catalase, SOD and GST activities in hepatic tissues, indicating that concomitant administration with PYC efficiently prevent the CCl4-induced oxidative damage in rats. The free radical scavenging assay showed that PYC has a dose-dependent scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals. These results indicate that PYC has an antioxidant effect against CCl4-induced hepatic oxidative damage and is useful as a hepatoprotective agent against various liver diseases induced by oxidative stress. PMID:17886222

  3. Hepatoprotective effect of resveratrol against ethanol-induced oxidative stress through induction of superoxide dismutase in vivo and in vitro

    PubMed Central

    CHEN, WEI-MING; SHAW, LEE-HSIN; CHANG, PEY-JIUM; TUNG, SHUI-YI; CHANG, TE-SHENG; SHEN, CHEIN-HENG; HSIEH, YUNG-YU; WEI, KUO-LIANG

    2016-01-01

    The present study aimed to investigate the hepatoprotective effect of resveratrol (RSV) against ethanol-induced oxidative stress in vivo, and investigate the underlying mechanisms by which RSV exerts its anti-oxidative effects on hepatic cells. C57BL/6J mice were divided into four groups: Untreated control, ethanol-treated, RSV-treated, and ethanol + RSV-treated. The plasma lipid profile, hepatic lipid accumulation and antioxidative enzyme activities were analyzed. HepG2 cells were used as a cellular model to analyze the effects of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and peroxisome proliferator-activated receptors (PPARs) in the RSV-mediated protection of ethanol-induced oxidative stress. In C57BL/6J mice, ethanol caused a significant increase in plasma triglyceride levels and hepatic lipid accumulation (P<0.05), whereas RSV notably increased SOD activity. In HepG2 cells, SOD activity was enhanced in the RSV-treated HepG2 cells, whereas the activity of CAT and GPx was not affected. Western blot and quantitative polymerase chain reaction analyses demonstrated that RSV significantly increased SOD protein and mRNA expression levels (P<0.05). Using a transient transfection assay, PPARγ was observed to participate in the regulation of SOD gene expression in RSV-administered HepG2 cells. To conclude, the results from the present study suggest that RSV may contribute towards the protection of hepatic cells from ethanol-induced oxidative stress via the induction of SOD activity and gene expression. PMID:27073428

  4. Camellia sinensis (L.) Kuntze Extract Ameliorates Chronic Ethanol-Induced Hepatotoxicity in Albino Rats

    PubMed Central

    Lodhi, Poonam; Tandan, Neeraj; Singh, Neera; Kumar, Divyansh; Kumar, Monu

    2014-01-01

    The goal of this study was to investigate the hepatoprotective effects of aqueous extract of Camellia sinensis or green tea extract (AQGTE) in chronic ethanol-induced albino rats. All animals were divided into 4 groups in the study for a 5-week duration. 50% ethanol was given orally to the rats with two doses (5 mg/kg bw and 10 mg/kg bw) of AQGTE. Ethanol administration caused a significant increase in the levels of plasma and serum enzymatic markers, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), and nonenzymatic markers (cholesterol and triglycerides), lipid peroxidation contents, malondialdehyde (MDA), and glutathione-S-transferase (GST), and decreased the activities of total proteins, albumin, and cellular antioxidant defense enzymes such as superoxide dismutase (SOD). The elevation and reduction in these biochemical enzymes caused the damage in hepatocytes histologically due to the high production of ROS, which retards the antioxidant defense capacity of cell. AQGTE was capable of recovering the level of these markers and the damaged hepatocytes to their normal structures. These results support the suggestion that AQGTE was able to enhance hepatoprotective and antioxidant effects in vivo against ethanol-induced toxicity. PMID:25254057

  5. Gynura procumbens Reverses Acute and Chronic Ethanol-Induced Liver Steatosis through MAPK/SREBP-1c-Dependent and -Independent Pathways.

    PubMed

    Li, Xiao-Jun; Mu, Yun-Mei; Li, Ting-Ting; Yang, Yan-Ling; Zhang, Mei-Tuo; Li, Yu-Sang; Zhang, Wei Kevin; Tang, He-Bin; Shang, Hong-Cai

    2015-09-30

    The present study aimed to evaluate the hepatoprotective effect and mechanism of action of Gynura procumbens on acute and chronic ethanol-induced liver injuries. Ethanol extract from G. procumbens stems (EEGS) attenuated acute ethanol-induced serum alanine aminotransferase levels and hepatic lipid accumulation. Therefore, EEGS was successively extracted by petroleum, ethyl acetate, and n-butyl alcohol. The results showed that the n-butyl alcohol extract was the active fraction of EEGS, and hence it was further fractionated on a polyamide glass column. The 60% ethanol-eluted fraction that contained 13.6% chlorogenic acid was the most active fraction, and its effect was further evaluated using a chronic model. Both the n-butyl alcohol extract and the 60% ethanol-eluted fraction inhibited chronic ethanol-induced hepatic lipid accumulation by modulating lipid metabolism-related regulators through MAPK/SREBP-1c-dependent and -independent signaling pathways and ameliorated liver steatosis. Our findings suggest that EEGS and one of its active ingredients, chlorogenic acid, may be developed as potential effective agents for ethanol-induced liver injury. PMID:26345299

  6. Ethanol induced impairment of glucose metabolism involves alterations of GABAergic signaling in pancreatic β-cells.

    PubMed

    Wang, Shuanglian; Luo, Yan; Feng, Allen; Li, Tao; Yang, Xupeng; Nofech-Mozes, Roy; Yu, Meng; Wang, Changhui; Li, Ziwei; Yi, Fan; Liu, Chuanyong; Lu, Wei-Yang

    2014-12-01

    Alcohol overindulgence is a risk factor of type 2 diabetes mellitus. However, the mechanisms by which alcohol overindulgence damages glucose metabolism remain unclear. Pancreatic islet β-cells are endowed with type-A γ-aminobutyric acid receptor (GABAAR) mediated autocrine signaling mechanism, which regulates insulin secretion and fine-tunes glucose metabolism. In neurons GABAAR is one of the major targets for alcohol. This study investigated whether ethanol alters glucose metabolism by affecting GABAAR signaling in pancreatic β-cells. Blood glucose level of test mice was measured using a blood glucose meter. Insulin secretion by the pancreatic β-cell line INS-1 cells was examined using a specific insulin ELISA kit. Whole-cell patch-clamp recording was used to evaluate GABA-elicited current in INS-1 cells. Western blot and immunostaining were used to measure the expression of GABAAR subunits in mouse pancreatic tissues or in INS-1 cells. Intraperitoneal (i.p.) administration of ethanol (3.0g/kg body weight) to mice altered glucose metabolism, which was associated with decreased expression of GABAAR α1- and δ- subunits on the surface of pancreatic β-cells. Acute treatment of cultured INS-1cells with ethanol (60mM) decreased the GABA-induced current and reduced insulin secretion. In contrast, treating INS-1 cells with GABA (100μM) largely prevented the ethanol-induced reduction of insulin release. Importantly, pre-treating mice with GABA (i.p., 1.5mg/kg body weight) partially reversed ethanol-induced impairment of glucose homeostasis in mice. Our data suggest a novel role of pancreatic GABA signaling in protecting pancreatic islet β-cells from ethanol-induced dysfunction. PMID:25456265

  7. Preventive effects of geranylgeranylacetone on rat ethanol-induced gastritis

    PubMed Central

    Ning, Jian-Wen; Lin, Guan-Bin; Ji, Feng; Xu, Jia; Sharify, Najeeb

    2012-01-01

    AIM: To establish a rat ethanol gastritis model, we evaluated the effects of ethanol on gastric mucosa and studied the preventive effects of geranylgeranylacetone on ethanol-induced chronic gastritis. METHODS: One hundred male Sprague-Dawley rats were randomly divided into 4 equal groups: normal control group, undergoing gastric perfusion of normal saline (NS) by gastrogavage; model control group and 2 model therapy groups that underwent gastric perfusion with ethanol (distillate spirits with 56% ethanol content) by gastrogavage for 4 wk. Low or high doses of geranylgeranylacetone were added 1 h before ethanol perfusion in the 2 model therapy groups, while the same amount of NS, instead of geranylgeranylacetone was used in that model control group. The rats were then sacrificed and stomachs were removed. The injury level of the gastric mucosa was observed by light and electron microscopy, and the levels of prostaglandin 2 (PGE2), endothelin-1 (ET-1) and nitric oxide (NO) were measured by radioimmunoassay and the Griess method. RESULTS: The gastric mucosal epidermal damage score (EDS; 4.5) and ulcer index (UI; 12.0) of the model control group were significantly higher than that of the normal control group (0 and 0 respectively, all P = 0.000). The gastric mucosal EDS and UI of the 2 model therapy groups (EDS: 2.5 and 2.0; UI: 3.5 and 3.0) were significantly lower than that of the model control group (all P < 0.01). There was no statistically significant difference between the low-dose and high-dose model therapy groups. The expression value of plasma ET-1 of the model control group was higher than that of the normal control group (P < 0.01) and the 2 model therapy groups (all P < 0.01). The expression values of gastric mucosal PGE2 and serum NO of the model control group were lower than those of the normal control group (all P < 0.05) and the 2 model therapy groups (all P < 0.05). The thickness of the gastric mucous layerand the hexosamine content in the model

  8. Vitamin E ameliorates high dose trans-dehydrocrotonin-associated hepatic damage in mice.

    PubMed

    Rabelo, Alana Fontales Lima; Guedes, Marjorie Moreira; Tomé, Adriana da Rocha; Lima, Patricia Rodrigues; Maciel, Maria Aparecida; Lira, Silveria Regina de Sousa; Carvalho, Ana Carla da Silva; Santos, Flávia Almeida; Rao, Vietla Satyanarayana

    2010-04-01

    trans-Dehydrocrotonin (t-DCTN), the diterpenoid from Croton cajucara Bentham, exhibits hypoglycemic and hypolipidemic activities, but in high doses is associated with a discrete hepatotoxicity. In the search for measures to mitigate this, pretreatment with the antioxidants N-acetylcysteine and vitamin E has been examined. Mice that received a high dose t-DCTN (100 mg/kg) manifested hepatic damage, as evidenced by significant elevations in serum ALT and AST, and hepatic GSH, and histological alterations, which could be obliterated by pretreatment with vitamin E, but not with N-acetylcysteine, possibly by creating an effective antioxidant balance. PMID:20433064

  9. Ethanol-Induced Cerebellar Ataxia: Cellular and Molecular Mechanisms.

    PubMed

    Dar, M Saeed

    2015-08-01

    The cerebellum is an important target of ethanol toxicity given that cerebellar ataxia is the most consistent physical manifestation of acute ethanol consumption. Despite the significance of the cerebellum in ethanol-induced cerebellar ataxia (EICA), the cellular and molecular mechanisms underlying EICA are incompletely understood. However, two important findings have shed greater light on this phenomenon. First, ethanol-induced blockade of cerebellar adenosine uptake in rodent models points to a role for adenosinergic A1 modulation of EICA. Second, the consistent observation that intracerebellar administration of nicotine in mice leads to antagonism of EICA provides evidence for a critical role of cerebellar nitric oxide (NO) in EICA reversal. Based on these two important findings, this review discusses the potential molecular events at two key synaptic sites (mossy fiber-granule cell-Golgi cell (MGG synaptic site) and granule cell parallel fiber-Purkinje cell (GPP synaptic site) that lead to EICA. Specifically, ethanol-induced neuronal NOS inhibition at the MGG synaptic site acts as a critical trigger for Golgi cell activation which leads to granule cell deafferentation. Concurrently, ethanol-induced inhibition of adenosine uptake at the GPP synaptic site produces adenosine accumulation which decreases glutamate release and leads to the profound activation of Purkinje cells (PCs). These molecular events at the MGG and GPP synaptic sites are mutually reinforcing and lead to cerebellar dysfunction, decreased excitatory output of deep cerebellar nuclei, and EICA. The critical importance of PCs as the sole output of the cerebellar cortex suggests normalization of PC function could have important therapeutic implications. PMID:25578036

  10. Focal cortical damage parallels cognitive impairment in minimal hepatic encephalopathy.

    PubMed

    Montoliu, Carmina; Gonzalez-Escamilla, Gabriel; Atienza, Mercedes; Urios, Amparo; Gonzalez, Olga; Wassel, Abdallah; Aliaga, Roberto; Giner-Duran, Remedios; Serra, Miguel A; Rodrigo, Jose M; Belloch, Vicente; Felipo, Vicente; Cantero, Jose L

    2012-07-16

    Little attention has been paid to cortical integrity in patients with minimal hepatic encephalopathy (MHE), although cognitive functions affected in early stages of liver disease are mainly allocated in different neocortical structures. Here we used cortical surface-based analysis techniques to investigate if patterns of cortical thinning accompany the mildest form of HE. To aim this goal, cortical thickness obtained from high-resolution 3T magnetic resonance imaging (MRI) was measured in patients with no MHE (NMHE), MHE, and healthy controls. Further correlation analyses were performed to examine whether scores in the critical flicker frequency (CFF) test, and blood ammonia levels accounted for the loss of cortical integrity in different stages of liver disease. Finally, we assessed group differences in volume of different subcortical regions and their potential relationships with CFF scores/blood ammonia levels. Results showed a focal thinning of the superior temporal cortex and precuneus in MHE patients when compared with NMHE and controls. Relationships between blood ammonia levels and cortical thickness of the calcarine sulcus accounted for impaired visual judgment in patients with MHE when compared to NMHE. Regression analyses between cortical thickness and CFF predicted differences between controls and the two groups of HE patients, but failed to discriminate between patients with NMHE and MHE. Taking together, these findings provide the first report of cortical thinning in MHE patients, and they yield novel insights into the neurobiological basis of cognitive impairment associated with early stages of liver diseases. PMID:22465844

  11. Protective effects of pogostone from Pogostemonis Herba against ethanol-induced gastric ulcer in rats.

    PubMed

    Chen, Haiming; Liao, Huijun; Liu, Yuhong; Zheng, Yifeng; Wu, Xiaoli; Su, Zuqing; Zhang, Xie; Lai, Zhengquan; Lai, Xiaoping; Lin, Zhi-Xiu; Su, Ziren

    2015-01-01

    We examined the protective effect of pogostone (PO), a chemical constituent isolated from Pogostemonis Herba, on the ethanol-induced gastric ulcer in rats. Administration of PO at doses of 10, 20 and 40 mg/kg body weight prior to ethanol ingestion effectively protected the stomach from ulceration. The gastric lesions were significantly ameliorated by all doses of PO as compared to the vehicle group. Pre-treatment with PO prevented the oxidative damage and the decrease of prostaglandin E2 (PGE2) content. In addition, PO pretreatment markedly increased the mucosa levels of glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT), and decreased gastric malonaldehyde (MDA), relative to the vehicle group. In the mechanistic study, significant elevation of non-protein-sulfhydryl (NP-SH) was observed in the gastric mucosa pretreated by PO. Analysis of serum cytokines indicated that PO pretreatment obviously elevated the decrease of interleukin-10 (IL-10) level, while markedly mitigated the increment of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) secretions in ethanol-induced rats. Taken together, these results strongly indicate that PO could exert a gastro-protective effect against gastric ulceration, and the underlying mechanism might be associated with the stimulation of PGE2, improvement of antioxidant and anti-inflammatory status, as well as preservation of NP-SH. PMID:25481373

  12. Polymer fraction of Aloe vera exhibits a protective activity on ethanol-induced gastric lesions.

    PubMed

    Park, Chul-Hong; Nam, Dong-Yoon; Son, Hyeong-U; Lee, Si-Rim; Lee, Hyun-Jin; Heo, Jin-Chul; Cha, Tae-Yang; Baek, Jin-Hong; Lee, Sang-Han

    2011-04-01

    For centuries, Aloe has been used as a herbal plant remedy against skin disorders, diabetes, and for its cardiac stimulatory activity. Here, we examined the gastroprotective effects of an Aloe vera polymer fraction (Avpf; molecular weight cut-off ≥50 kDa; 150 mg/kg body weight, p.o.) on an ethanol-induced gastric lesion mouse model. Mice pre-treated with Avpf had significantly fewer gastric lesions than their respective controls. To further examine the potential mechanism underlying this effect, we used reverse transcription-polymerase chain reaction to examine nitric oxide synthase and matrix metalloproteinase (MMP)mRNA expression on tissues from gastric lesions. Our results revealed that the mRNA expressions of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) were each reduced by ~50% in Avpf-treated mice vs. the controls, whereas, the mRNA expression levels of endothelial nitric oxide synthase remained unchanged. MMP-9, an index for gastric lesions, also alleviated the ethanol-treated gastric ulceration during Avpf treatment. These findings collectively suggest that Avpf significantly protects the gastric mucosa against ethanol-induced gastric damage, at least in part, by decreasing mRNA expression levels of not only iNOS and nNOS, but also MMP-9. PMID:21286662

  13. Protective effect of tetrahydrocoptisine against ethanol-induced gastric ulcer in mice.

    PubMed

    Li, Weifeng; Huang, Huimin; Niu, Xiaofeng; Fan, Ting; Mu, Qingli; Li, Huani

    2013-10-01

    Excessive alcohol consumption can lead to gastric ulcer and the present work was aimed to examine the protective effect of tetrahydrocoptisine (THC) in the model of ethanol-induced gastric ulcer in mice. Fasted mice treated with ethanol 75% (0.5ml/100g) were pre-treated with THC (10 or 20mg/kg, ip), cimetidine (100mg/kg, ip) or saline in different experimental sets for a period of 3days, and animals were euthanized 4h after ethanol ingestion. Gross and microscopic lesions, immunological and biochemical parameters were taken into consideration. The results showed that ethanol induced gastric damage, improving nitric oxide (NO) level, increased pro-inflammatory cytokine (TNF-α and IL-6) levels and myeloperoxidase (MPO) activity, as well as the expression of nuclear factor-κB (NF-κB) in the ethanol group. Pretreatment of THC at doses of 10 and 20mg/kg bodyweight significantly attenuated the gastric lesions as compared to the ethanol group. These results suggest that the gastroprotective activity of THC is attributed to reducing NO production and adjusting the pro-inflammatory cytokine, inhibited neutrophil accumulation and NF-κB expression. PMID:23769714

  14. Therapeutic efficacy of silymarin and naringenin in reducing arsenic-induced hepatic damage in young rats.

    PubMed

    Jain, Anshu; Yadav, Abhishek; Bozhkov, A I; Padalko, V I; Flora, S J S

    2011-05-01

    We investigated the effects of silymarin and naringenin in counteracting arsenic-induced hepatic oxidative stress post exposure. Male wistar rats were chronically exposed to sodium arsenite for eight months followed by oral treatment with silymarin and naringenin (50 mg/kg each) for 15 consecutive days to evaluate hepatic damage and antioxidant potential. Our results demonstrate a significant decrease in hepatic GSH levels, SOD and catalase activities and an increase in GST and TBARS levels after arsenic administration. Silymarin or naringenin administration increased GSH levels and was beneficial in the recovery of altered SOD and catalase activity besides significantly reducing blood and tissue arsenic concentration. Our results point to the antioxidant potential of these flavonoids, which might be of benefit in the clinical recovery of subject exposed to arsenic. These flavonoids can be incorporated into the diet or co-supplemented during chelation treatment, and thus may afford a protective effect against arsenite-induced cytotoxicity. PMID:20719385

  15. A polymethoxy flavonoids-rich Citrus aurantium extract ameliorates ethanol-induced liver injury through modulation of AMPK and Nrf2-related signals in a binge drinking mouse model.

    PubMed

    Choi, Bong-Keun; Kim, Tae-Won; Lee, Dong-Ryung; Jung, Woon-Ha; Lim, Jong-Hwan; Jung, Ju-Young; Yang, Seung Hwan; Suh, Joo-Won

    2015-10-01

    Nobiletin and tangeretin are polymethoxy flavonoids (PMFs), found in rich quantities in the peel of citrus fruits. In the present study, we assessed the biological effect of the PMFs on liver damage using a mouse model of binge drinking. First, we extracted PMFs from the peels of Citrus aurantium to make Citrus aurantium extract (CAE). Male C57BL/6 mice were orally treated with silymarin and CAE (50, 100, and 200 mg/kg) for 3 days prior to ethanol (5 g/kg, total of 3 doses) oral gavage. Liver injury was observed in the ethanol alone group, as evidenced by increases in serum hepatic enzymes and histopathologic alteration, as well as by hepatic oxidative status disruption. CAE improved serum marker and hepatic structure and restored oxidative status by enhancing antioxidant enzyme levels and by reducing lipid peroxidation levels. In addition, CAE evidently suppressed inflammation and apoptosis in the livers of mice administered with ethanol, by 85% (tumor necrosis factor-α) and 44% compared to the control group, respectively. Furthermore, CAE activated lipid metabolism related signals and enhanced phosphorylation of AMP-activated protein kinase (AMPK) and nuclear factor E2-related factor 2 (Nrf2) with several cytoprotective proteins including heme oxygenase-1, NAD(P)H quinone oxidoreductase 1, and γ-glutamylcysteine synthetase. Taken together, the present study demonstrated that, CAE possesses antioxidant, anti-inflammatory, and antiapoptotic activity against ethanol-induced liver injury. PMID:26178909

  16. Hepatitis

    MedlinePlus

    ... Got Homework? Here's Help White House Lunch Recipes Hepatitis KidsHealth > For Kids > Hepatitis Print A A A ... an important digestive liquid called bile . What Is Hepatitis? Hepatitis is an inflammation (say: in-fluh-MAY- ...

  17. [Interferon-alpha and liver fibrosis in patients with chronic damage due to hepatitis C virus].

    PubMed

    Gonzalez-Huezo, María Sarai; Gallegos-Orozco, Juan Fernando

    2003-01-01

    The present review focuses on the published information published regarding the effects of interferon alpha therapy on liver fibrosis in patients with chronic liver damage secondary to hepatitis C infection. Data reviewed included results of the in vitro effects of interferon on hepatic cell line cultures with regards to indirect markers of fibrosis, activation of hepatic stellate cells and oxidative stress response. In the clinical arena, there is current clear evidence of a favorable histological outcome in patients with sustained viral response to interferon therapy. For this reason, the current review focuses more on the histological outcomes regarding liver fibrosis in patients who have not attained viral response to therapy (non-responders) or who already have biopsy defined cirrhosis. Data in these patients were analyzed according to the results of objective testing of fibrosis through the assessment of liver biopsy and its change during time, specially because the morbidity and mortality of this disease is directly related to the complications of liver cirrhosis and not necessarily to the persistence of the hepatitis C virus. Lastly, it is concluded that the process of liver fibrosis/cirrhosis is a dynamic one and that there is some evidence to support the usefulness of interferon alpha therapy as a means to halt or retard the progression of hepatic fibrosis. The result of current clinical trials in which interferon therapy is being used to modify the progression of fibrosis in non-responders or cirrhotic patients is eagerly awaited. PMID:14702938

  18. Prostacyclin inhibition by indomethacin aggravates hepatic damage and encephalopathy in rats with thioacetamide-induced fulminant hepatic failure

    PubMed Central

    Chu, Chi-Jen; Hsiao, Ching-Chin; Wang, Teh-Fang; Chan, Cho-Yu; Lee, Fa-Yauh; Chang, Full-Young; Chen, Yi-Chou; Huang, Hui-Chun; Wang, Sun-Sang; Lee, Shou-Dong

    2005-01-01

    AIM: Vasodilatation and increased capillary permeability have been proposed to be involved in the pathogenesis of acute and chronic form of hepatic encephalopathy. Prostacyclin (PGI2) and nitric oxide (NO) are important contributors to hyperdynamic circulation in portal hypertensive states. Our previous study showed that chronic inhibition of NO had detrimental effects on the severity of encephalopathy in thioacetamide (TAA)-treated rats due to aggravation of liver damage. To date, there are no detailed data concerning the effects of PGI2 inhibition on the severity of hepatic encephalopathy during fulminant hepatic failure. METHODS: Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of TAA (350 mg/(kg.d) for 3 d. Rats were divided into two groups to receive intraperitoneal injection of indomethacin (5 mg/(kg.d), n = 20) or normal saline (N/S, n = 20) for 5 d, starting 2 d before TAA administration. Severity of encephalopathy was assessed by the counts of motor activity measured with Opto-Varimex animal activity meter. Plasma tumor necrosis factor-α (TNF-α, an index of liver injury) and 6-keto-PGF1α (a metabolite of PGI2) levels were measured by enzyme-linked immunosorbent assay. RESULTS: As compared with N/S-treated rats, the mortality rate was significantly higher in rats receiving indomethacin (20% vs 5%, P<0.01). Inhibition of PGI2 created detrimental effects on total movement counts (indomethacin vs N/S: 438±102 vs 841±145 counts/30 min, P<0.05). Rats treated with indomethacin had significant higher plasma levels of TNF-α (indomethacin vs N/S: 22±5 vs 10±1 pg/mL, P<0.05) and lower plasma levels of 6-keto-PGF1α (P<0.001), but not total bilirubin or creatinine (P>0.05), as compared with rats treated with N/S. CONCLUSION: Chronic indomethacin administration has detrimental effects on the severity of encephalopathy in TAA-treated rats and this phenomenon may be attributed to the

  19. Sulforaphane protects against ethanol-induced oxidative stress and apoptosis in neural crest cells by the induction of Nrf2-mediated antioxidant response

    PubMed Central

    Chen, X; Liu, J; Chen, S-Y

    2013-01-01

    Background and Purpose Nuclear factor erythroid 2-related factor (Nrf2) is a transcription factor that up-regulates a diverse array of antioxidant genes and protects cells from oxidative damage. This study is designed to determine whether D-L-sulforaphane (SFN) can protect neural crest cells (NCCs), an ethanol-sensitive cell population implicated in fetal alcohol spectrum disorders, against ethanol-induced apoptosis and whether protective effects of SFN are mediated by the induction of Nrf2-mediated antioxidant response. Experimental Approach Control, SFN-treated or Nrf2-siRNA transfected NCCs were exposed to ethanol. Nrf2 activation, the expression and activities of Nrf2 downstream antioxidant proteins, reactive oxygen species generation and apoptosis were determined in control and ethanol-exposed NCCs. Key Results Exposure of NCCs to SFN alone significantly increased Nrf2 activation and the expression of Nrf2 downstream antioxidants as well as the activities of the antioxidant enzymes. Treatment of NCCs with SFN along with ethanol significantly decreased ethanol-induced oxidative stress and apoptosis. In contrast, knockdown of Nrf2 by siRNA significantly increased the sensitivity of NCCs to ethanol-induced oxidative stress and apoptosis. Suppression of Nrf2 signalling in NCCs also significantly diminished SFN-mediated antioxidant response and abolished the protective effects of SFN on ethanol-induced oxidative stress and apoptosis. Conclusions and Implications These results demonstrated that Nrf2-mediated antioxidant response plays an important role in the susceptibility of NCCs to ethanol-induced oxidative stress and apoptosis and that the protection of SFN against ethanol-induced oxidative stress and apoptosis in NCCs is mediated by the induction of Nrf2 signalling. PMID:23425096

  20. Glutamine supplementation attenuates ethanol-induced disruption of apical junctional complexes in colonic epithelium and ameliorates gut barrier dysfunction and fatty liver in mice.

    PubMed

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

    2016-01-01

    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 Gln 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 with Gln-free diet and absent in mice fed with 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

  1. Ethanol induces rotational behavior in 6-hydroxydopamine lesioned mice

    SciTech Connect

    Silverman, P.B.

    1987-03-09

    Mice with unilateal striatal lesions created by 6-hydroxydopamine (6HDA) injection were screened for rotational (circling) behavior in response to injection of amphetamine and apomorphine. Those that rotated ipsilaterally in response to amphetamine and contralaterally in response to apomorphine were subsequently challenged with 1 to 3 g/kg (i.p.) ethanol. Surprisingly, ethanol induced dose related contralateral (apomorphine-like) rotation which, despite gross intoxication, was quite marked in most animals. No significant correlation was found between the number of turns made following ethanol and made after apomorphine or amphetamine. 14 references, 2 figures, 1 table.

  2. Central histaminergic transmission modulates the ethanol induced anxiolysis in mice.

    PubMed

    Verma, Lokesh; Jain, Nishant S

    2016-10-15

    Intrigued by the report demonstrating an increase in brain histamine levels by ethanol administration and central histamine transmission to affect the anxiety related behaviors, the present study examined the permissive role of central histaminergic transmission in the acute anxiolytic-like effect of the ethanol on elevated plus maze (EPM) in mice. Results demonstrated that prior administration of the agents that are known to enhance the brain histamine transmission, i.e. low dose of histamine (0.1μg/mouse, i.c.v.) or histamine precursor, l-histidine (500, 1000mg/kg, i.p.) or low dose of histamine releasing agent (H3 receptor inverse agonist), thioperamide (2μg/mouse) attenuated the acute anitanxiety-like effect of ethanol (2g/kg, i.p, 8% w/v) in mice on EPM. However, pre-treatment with the H1 receptor antagonist, cetirizine (0.1μg/mouse, i.c.v.) or H2 receptor antagonist, ranitidine (50μg/mouse, i.c.v.) failed to affect the attenuating effect of low dose of histamine on ethanol induced anxiolysis. On the other hand, only H1 receptor antagonist, cetirizine (0.1μg/mouse, i.c.v.) was able to partially reverse the attenuation of ethanol induced anxiolysis by l-histidine (1000mg/kg, i.p.). Surprisingly, in mice pre-treated with the higher dose of histamine (50μg/mouse, i.c.v.) or thioperamide (10μg/mouse, i.c.v.), the ethanol (2g/kg, i.p.) induced antianxiety-like effect was further enhanced on EPM. Furthermore, this potentiating effect of high dose of histamine on the ethanol (2g/kg, i.p.) was exacerbated on pre-treatment with the H1 receptor antagonist, cetirizine, while H2 receptor antagonist, ranitidine completely reversed this action of high dose of histamine on ethanol. Supportive to these results, i.c.v. pre-treatment with H1 receptor agonist, FMPH (2, 6.5μg/mouse, i.c.v.) attenuated while H2 receptor agonist, amthamine (0.1, 0.5μg/mouse, i.c.v.) enhanced the ethanol induced anxiolysis in mice. Thus, it is reasonable to contemplate that central

  3. S6 Kinase Reflects and Regulates Ethanol-Induced Sedation

    PubMed Central

    Acevedo, Summer F.; Peru y Colón de Portugal, Raniero L.; Gonzalez, Dante A.; Rodan, Aylin R.

    2015-01-01

    Alcohol use disorders (AUDs) affect people at great individual and societal cost. Individuals at risk for AUDs are sensitive to alcohol's rewarding effects and/or resistant to its aversive and sedating effects. The molecular basis for these traits is poorly understood. Here, we show that p70 S6 kinase (S6k), acting downstream of the insulin receptor (InR) and the small GTPase Arf6, is a key mediator of ethanol-induced sedation in Drosophila. S6k signaling in the adult nervous system determines flies' sensitivity to sedation. Furthermore, S6k activity, measured via levels of phosphorylation (P-S6k), is a molecular marker for sedation and overall neuronal activity: P-S6k levels are decreased when neurons are silenced, as well as after acute ethanol sedation. Conversely, P-S6k levels rebound upon recovery from sedation and are increased when neuronal activity is enhanced. Reducing neural activity increases sensitivity to ethanol-induced sedation, whereas neuronal activation decreases ethanol sensitivity. These data suggest that ethanol has acute silencing effects on adult neuronal activity, which suppresses InR/Arf6/S6k signaling and results in behavioral sedation. In addition, we show that activity of InR/Arf6/S6k signaling determines flies' behavioral sensitivity to ethanol-induced sedation, highlighting this pathway in acute responses to ethanol. SIGNIFICANCE STATEMENT Genetic factors play a major role in the development of addiction. Identifying these genes and understanding their molecular mechanisms is a necessary first step in the development of targeted therapeutic intervention. Here, we show that signaling from the insulin receptor in Drosophila neurons determines flies' sensitivity to ethanol-induced sedation. We show that this signaling cascade includes the small GTPase Arf6 and S6 kinase (S6k). In addition, activity of S6k is regulated by acute ethanol exposure and by neuronal activity. S6k activity is therefore both an acute target of ethanol exposure and

  4. Hepatoprotective effect of Caesalpinia gilliesii and Cajanus cajan proteins against acetoaminophen overdose-induced hepatic damage.

    PubMed

    Rizk, Maha Z; Aly, Hanan F; Abo-Elmatty, Dina M; Desoky, M M; Ibrahim, N; Younis, Eman A

    2016-05-01

    This study aims to evaluate two proteins derived from the seeds of the plants Cajanus cajan (Leguminosae) and Caesalpinia gilliesii (Leguminosae) for their abilities to ameliorate the toxic effects of chronic doses of acetoaminphen (APAP) through the determination of certain biochemical parameters including liver marker enzymes: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin. Also, total protein content and hepatic marker enzyme, lactate dehydrogenase were studied. Moreover, liver antioxidants, glutathione (GSH), nitric oxide, and lipid peroxides were determined in this study. Hepatic adenosine triphosphatase (ATPase), adenylate energy charge (ATP, adenosine diphosphate, adenosine monophosphate, and inorganic phosphate), and phosphate potential, serum interleukin-6, tumor necrosis factor-α, and myeloperoxidase were also examined in the present study. On the other hand, histopathological examination of intoxicated and liver treated with both proteins was taken into consideration. The present results show disturbances in all biochemical parameters and hepatic toxicity signs including mild vascular congestion, moderate inflammatory changes with moderate congested sinusoids, moderate nuclear changes (pyknosis), moderate centrilobular necrosis, fatty changes, nuclear pyknosis vascular congestion, and change in fatty centrilobular necrosis liver. Improvement in all biochemical parameters studied was noticed as a result of treatment intoxicated liver with C. gilliesii and C. cajan proteins either paracetamol with or post paracetamol treatment. These results were documented by the amelioration signs in rat's hepatic architecture. Thus, both plant protein extracts can upregulate and counteract the inflammatory process, minimize damage of the liver, delay disease progression, and reduce its complications. PMID:24414985

  5. Fructose surges damage hepatic adenosyl-monophosphate-dependent kinase and lead to increased lipogenesis and hepatic insulin resistance.

    PubMed

    Gugliucci, Alejandro

    2016-08-01

    Fructose may be a key contributor to the biochemical alterations which promote the metabolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM): (a) its consumption in all forms but especially in liquid form has much increased alongside with incidence of MetS conditions; (b) it is metabolized almost exclusively in the liver, where it stimulates de novo lipogenesis to drive hepatic triglyceride (TG) synthesis which (c) contributes to hepatic insulin resistance and NAFLD (Lustig et al., 2015; Weiss et al., 2013; Lim et al., 2010; Schwarzet al., 2015; Stanhope et al., 2009, 2013) [1-6]. The specifics of fructose metabolism and its main location in the liver serve to explain many of the possible mechanisms involved. It also opens questions, as the consequences of large increases in fructose flux to the liver may wreak havoc with the regulation of metabolism and would produce two opposite effects (inhibition and activation of AMP dependent kinase-AMPK) that would tend to cancel each other. We posit that (1) surges of fructose in the portal vein lead to increased unregulated flux to trioses accompanied by unavoidable methylglyoxal (MG) production, (2) the new, sudden flux exerts carbonyl stress on the three arginines on the γ subunits AMP binding site of AMPK, irreversible blocking some of the enzyme molecules to allosteric modulation, (3) this explains why, even when fructose quick phosphorylation increases AMP and should therefore activate AMPK, the effects of fructose are compatible with inactivation of AMPK, which then solves the apparent metabolic paradox. We put forward the hypothesis that fructose loads, via the increase in MG flux worsens the fructose-driven metabolic disturbances that lead to unrestricted de novo lipogenesis, fatty liver and hepatic insulin resistance. It does so via the silencing of AMPK. Our hypothesis is testable and if proven correct will shed some further light on fructose metabolism in the liver. It will

  6. Herbal SGR Formula Prevents Acute Ethanol-Induced Liver Steatosis via Inhibition of Lipogenesis and Enhancement Fatty Acid Oxidation in Mice

    PubMed Central

    Qiu, Ping; Li, Xiang; Kong, De-song; Li, Huan-zhou; Niu, Cong-cong; Pan, Su-hua

    2015-01-01

    Our previous study indicated that herbal SGR formula partially attenuates ethanol-induced fatty liver, but the underlying mechanisms remain unclear. In the present study, mice were pretreated with SGR (100 and 200 mg/kg/d bw) for 30 d before being exposed to ethanol (4.8 g/kg bw). The biochemical indices and histopathological changes were examined to evaluate the protective effects and to explore potential mechanisms by investigating the adiponectin, tumor necrosis factor-α (TNF-α), peroxisome proliferators-activated receptor-α (PPAR-α), sterol regulatory element binding protein-1c (SREBP-1c), adenosine monophosphate-activated protein kinase (AMPK), and so forth. Results showed that SGR pretreatment markedly inhibited acute ethanol-induced liver steatosis, significantly reduced serum and hepatic triglyceride (TG) level, and improved classic histopathological changes. SGR suppressed the protein expression of hepatic SREBP-1c and TNF-α and increased adiponectin, PPAR-α, and AMPK phosphorylation in the liver. Meanwhile, acute toxicity tests showed that no death or toxic side effects within 14 days were observed upon oral administration of the extracts at a dose of 16 g/kg body wt. These results demonstrate that SGR could protect against acute alcohol-induced liver steatosis without any toxic side effects. Therefore, our studies provide novel molecular insights into the hepatoprotective effect of SGR formula, which may be exploited as a therapeutic agent for ethanol-induced hepatosteatosis. PMID:26101535

  7. Herbal SGR Formula Prevents Acute Ethanol-Induced Liver Steatosis via Inhibition of Lipogenesis and Enhancement Fatty Acid Oxidation in Mice.

    PubMed

    Qiu, Ping; Li, Xiang; Kong, De-Song; Li, Huan-Zhou; Niu, Cong-Cong; Pan, Su-Hua

    2015-01-01

    Our previous study indicated that herbal SGR formula partially attenuates ethanol-induced fatty liver, but the underlying mechanisms remain unclear. In the present study, mice were pretreated with SGR (100 and 200 mg/kg/d bw) for 30 d before being exposed to ethanol (4.8 g/kg bw). The biochemical indices and histopathological changes were examined to evaluate the protective effects and to explore potential mechanisms by investigating the adiponectin, tumor necrosis factor-α (TNF-α), peroxisome proliferators-activated receptor-α (PPAR-α), sterol regulatory element binding protein-1c (SREBP-1c), adenosine monophosphate-activated protein kinase (AMPK), and so forth. Results showed that SGR pretreatment markedly inhibited acute ethanol-induced liver steatosis, significantly reduced serum and hepatic triglyceride (TG) level, and improved classic histopathological changes. SGR suppressed the protein expression of hepatic SREBP-1c and TNF-α and increased adiponectin, PPAR-α, and AMPK phosphorylation in the liver. Meanwhile, acute toxicity tests showed that no death or toxic side effects within 14 days were observed upon oral administration of the extracts at a dose of 16 g/kg body wt. These results demonstrate that SGR could protect against acute alcohol-induced liver steatosis without any toxic side effects. Therefore, our studies provide novel molecular insights into the hepatoprotective effect of SGR formula, which may be exploited as a therapeutic agent for ethanol-induced hepatosteatosis. PMID:26101535

  8. Antioxidative Activity of Platinum Nanocolloid and Its Protective Effect Against Chemical-Induced Hepatic Cellular Damage.

    PubMed

    Choi, Mi-Ran; Do, Le Thanh; Chung, Yong-Hoon; Yoo, Hoon; Yu, Rina

    2015-08-01

    Oxidative stress, a major cause of cellular injuries, is closely associated with a variety of chronic diseases such as cancer, liver diseases, degenerative brain disease and aging. In this study, we investigated antioxidant properties of platinum nanocolloid (PNC) against various oxidative stress conditions in vitro/in vivo by treating PNC on liver cell or tissue. Antioxidant activities of the PNC were determined by measuring quenching capacity on reactive oxygen species and its protective action against hydrogen peroxide or CCl4-induced oxidative cellular damage in HepG2 cell or liver tissue of mice. In vitro study, PNC markedly suppressed the production H2O2, ·OH, α,α-diphenyl-β-picrylhydrazyl radical and nitric oxide in a dose-dependent manner. PNC also inhibited hydrogen peroxide-induced oxidative cellular damage in HepG2 hepatocytes. In vivo study with mice, PNC reduced hepatic lipid peroxidation and CCl4 induced toxicity. Our results support that platinum nanocolloid has antioxidant activities and protects hepatic cellular oxidative damage. Thus platinum nanocolloid may have a potential to be used as an antioxidant supplement. PMID:26369119

  9. Role of Nrf2 in preventing ethanol-induced oxidative stress and lipid accumulation

    SciTech Connect

    Wu, Kai Connie; Liu, Jie; Klaassen, Curtis D.

    2012-08-01

    Oxidative stress and lipid accumulation play important roles in alcohol-induced liver injury. Previous reports showed that, in livers of nuclear factor erythroid 2-related factor 2 (Nrf2)-activated mice, genes involved in antioxidant defense are induced, whereas genes involved in lipid biosynthesis are suppressed. To investigate the role of Nrf2 in ethanol-induced hepatic alterations, 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 ethanol (5 g/kg, po). Blood and liver samples were collected 6 h thereafter. Ethanol increased alanine aminotransferase and lactate dehydrogenase activities as well as thiobarbituric acid reactive substances in serum of Nrf2-null and wild-type mice, but not in Nrf2-enhanced mice. After ethanol administration, mitochondrial glutathione concentrations decreased markedly in Nrf2-null mice but not in Nrf2-enhanced mice. H{sub 2}DCFDA staining of primary hepatocytes isolated from the four genotypes of mice indicates that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. Ethanol increased serum triglycerides and hepatic free fatty acids in Nrf2-null mice, and these increases were blunted in Nrf2-enhanced mice. In addition, the basal mRNA and nuclear protein levels of sterol regulatory element-binding protein 1(Srebp-1) were decreased with graded Nrf2 activation. Ethanol further induced Srebp-1 mRNA in Nrf2-null mice but not in Nrf2-enhanced mice. In conclusion, Nrf2 activation prevented alcohol-induced oxidative stress and accumulation of free fatty acids in liver by increasing genes involved in antioxidant defense and decreasing genes involved in lipogenesis. -- Highlights: ► Ethanol depleted mitochondrial GSH in Nrf2-null mice but not in Keap1-KD mice. ► Ethanol increased ROS in hepatocytes isolated from Nrf2-null and wild

  10. Ameliorative effect of Opuntia ficus indica juice on ethanol-induced oxidative stress in rat erythrocytes.

    PubMed

    Alimi, Hichem; Hfaeidh, Najla; Bouoni, Zouhour; Sakly, Mohsen; Rhouma, Khémais Ben

    2013-05-01

    The aim of the present study was to investigate the efficacy of Opuntia ficus indica f. inermis fruit juice (OFIj) on reversing oxidative damages induced by chronic ethanol intake in rat erythrocytes. OFIj was firstly analyzed with HPLC for phenolic and flavonoids content. Secondly, 40 adult male Wistar rats were equally divided into five groups and treated for 90 days as follows: control (C), ethanol-only 3 g/kg body weight (b.w) (E), low dose of OFIj 2 ml/100 g b.w+ethanol (Ldj+E), high dose of OFIj 4 ml/100 g b.w+ethanol (Hdj+E), and only a high dose of OFIj 4 ml/100g b.w (Hdj). HPLC analysis indicated high concentrations of phenolic acids and flavonoids in OFIj. Ethanol treatment markedly decreased the activities of erythrocyte superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and the level of reduced glutathione (GSH). Changes in the erythrocyte's antioxidant ability were accompanied by enhanced oxidative modification of lipids (increase of malondialdeyde level) and proteins (increase in carbonyl groups). Interestingly, pre-administration of either 2 ml/100 g b.w or 4 ml/100 g b.w of OFIj to ethanol-intoxicated rats significantly reversed decreases in enzymatic as well as non enzymatic antioxidants parameters in erythrocytes. Also, the administration of OFIj significantly protected lipids and proteins against ethanol-induced oxidative modifications in rat erythrocytes. The beneficial effect of OFIj can result from the inhibition of ethanol-induced free radicals chain reactions in rat erythrocytes or from the enhancement of the endogenous antioxidants activities. PMID:22285760

  11. Melatonin's role in preventing toxin-related and sepsis-mediated hepatic damage: A review.

    PubMed

    Esteban-Zubero, Eduardo; Alatorre-Jiménez, Moisés Alejandro; López-Pingarrón, Laura; Reyes-Gonzales, Marcos César; Almeida-Souza, Priscilla; Cantín-Golet, Amparo; Ruiz-Ruiz, Francisco José; Tan, Dun-Xian; García, José Joaquín; Reiter, Russel J

    2016-03-01

    The liver is a central organ in detoxifying molecules and would otherwise cause molecular damage throughout the organism. Numerous toxic agents including aflatoxin, heavy metals, nicotine, carbon tetrachloride, thioacetamide, and toxins derived during septic processes, generate reactive oxygen species followed by molecular damage to lipids, proteins and DNA, which culminates in hepatic cell death. As a result, the identification of protective agents capable of ameliorating the damage at the cellular level is an urgent need. Melatonin is a powerful endogenous antioxidant produced by the pineal gland and a variety of other organs and many studies confirm its benefits against oxidative stress including lipid peroxidation, protein mutilation and molecular degeneration in various organs, including the liver. Recent studies confirm the benefits of melatonin in reducing the cellular damage generated as a result of the metabolism of toxic agents. These protective effects are apparent when melatonin is given as a sole therapy or in conjunction with other potentially protective agents. This review summarizes the published reports that document melatonin's ability to protect hepatocytes from molecular damage due to a wide variety of substances (aflatoxin, heavy metals, nicotine, carbon tetrachloride, chemotherapeutics, and endotoxins involved in the septic process), and explains the potential mechanisms by which melatonin provides these benefits. Melatonin is an endogenously-produced molecule which has a very high safety profile that should find utility as a protective molecule against a host of agents that are known to cause molecular mutilation at the level of the liver. PMID:26808084

  12. Ginkgo biloba leaf extract induces DNA damage by inhibiting topoisomerase II activity in human hepatic cells

    PubMed Central

    Zhang, Zhuhong; Chen, Si; Mei, Hu; Xuan, Jiekun; Guo, Xiaoqing; Couch, Letha; Dobrovolsky, Vasily N.; Guo, Lei; Mei, Nan

    2015-01-01

    Ginkgo biloba leaf extract has been shown to increase the incidence in liver tumors in mice in a 2-year bioassay conducted by the National Toxicology Program. In this study, the DNA damaging effects of Ginkgo biloba leaf extract and many of its constituents were evaluated in human hepatic HepG2 cells and the underlying mechanism was determined. A molecular docking study revealed that quercetin, a flavonoid constituent of Ginkgo biloba, showed a higher potential to interact with topoisomerase II (Topo II) than did the other Ginkgo biloba constituents; this in silico prediction was confirmed by using a biochemical assay to study Topo II enzyme inhibition. Moreover, as measured by the Comet assay and the induction of γ-H2A.X, quercetin, followed by keampferol and isorhamnetin, appeared to be the most potent DNA damage inducer in HepG2 cells. In Topo II knockdown cells, DNA damage triggered by Ginkgo biloba leaf extract or quercetin was dramatically decreased, indicating that DNA damage is directly associated with Topo II. DNA damage was also observed when cells were treated with commercially available Ginkgo biloba extract product. Our findings suggest that Ginkgo biloba leaf extract- and quercetin-induced in vitro genotoxicity may be the result of Topo II inhibition. PMID:26419945

  13. Ginkgo biloba leaf extract induces DNA damage by inhibiting topoisomerase II activity in human hepatic cells.

    PubMed

    Zhang, Zhuhong; Chen, Si; Mei, Hu; Xuan, Jiekun; Guo, Xiaoqing; Couch, Letha; Dobrovolsky, Vasily N; Guo, Lei; Mei, Nan

    2015-01-01

    Ginkgo biloba leaf extract has been shown to increase the incidence in liver tumors in mice in a 2-year bioassay conducted by the National Toxicology Program. In this study, the DNA damaging effects of Ginkgo biloba leaf extract and many of its constituents were evaluated in human hepatic HepG2 cells and the underlying mechanism was determined. A molecular docking study revealed that quercetin, a flavonoid constituent of Ginkgo biloba, showed a higher potential to interact with topoisomerase II (Topo II) than did the other Ginkgo biloba constituents; this in silico prediction was confirmed by using a biochemical assay to study Topo II enzyme inhibition. Moreover, as measured by the Comet assay and the induction of γ-H2A.X, quercetin, followed by keampferol and isorhamnetin, appeared to be the most potent DNA damage inducer in HepG2 cells. In Topo II knockdown cells, DNA damage triggered by Ginkgo biloba leaf extract or quercetin was dramatically decreased, indicating that DNA damage is directly associated with Topo II. DNA damage was also observed when cells were treated with commercially available Ginkgo biloba extract product. Our findings suggest that Ginkgo biloba leaf extract- and quercetin-induced in vitro genotoxicity may be the result of Topo II inhibition. PMID:26419945

  14. Ethanol-induced dysfunction of hepatocytes and leukocytes in patients without liver failure.

    PubMed

    Gheorghiu, Mihaela; Bâră, C; Păsărică, Daniela; Braşoveanu, Lorelei; Bleotu, Coralia; Topârceanu, Florica; Trandafir, T; Diaconu, Carmen C

    2004-01-01

    The repeated intake of a great amount of ethanol is followed by functional and organic changes in the body. The intestinal absorption of alcohol is accompanied by an increased absorption of Gram negative bacteria endotoxins in the portal blood. In the liver, endotoxins stimulate CD14 receptors on the membrane of Kupffer cells, with a secondary inflammatory liver response, consisting in the secretion of proinflammatory cytokines and acute phase proteins. Simultaneously, alcohol metabolism in the hepatocytes by alcohol dehydrogenase, microsomal enzymes and catalase pathways determines a large production of ROS (reactive oxygen species), with secondary oxidative aggression on all liver cells: hepatocytes, Kupffer cells, endothelial sinusoidal cells, hepatic stellate cells and liver s lymphocytes. The oxidative aggression, as well as the intermediary products of the alcohol metabolism, cause a structural change of the antigenic structures of the liver and of the released proteins, that induces an immune response on the both pathways (humoral and cellular). The pathophysiological mechanisms and the paraclinical characteristics of the ethanol-induced liver failure are well known, so we were interested to study the patients with chronic alcoholism, but no clinical or paraclinical sign of liver failure, in order to describe the liver's protective mechanisms. For this reason, 153 patients with chronic alcoholism were divided into four test lots, in order to determine: the activity and the serum level of ceruloplasmin, plasma level of MDA (malondialdehyde), lactic and pyruvic acids, serum level of transferrin, alpha1-antitrypsin, CRP (C reactive protein), C3 fraction of the complement, IgA, IgG, IgM, IL-1beta, IL-6 and IL-8, cytosolic level of the cytochrome c in the circulating leukocytes. An immunophenotype study (as normal markers) on the peripheral blood lymphocytes was performed, too. The results demonstrate an important oxidative aggression induced by three sources

  15. Isoliquiritigenin attenuates oxidative hepatic damage induced by carbon tetrachloride with or without buthionine sulfoximine.

    PubMed

    Zhao, ZhengLin; Park, Sang Mi; Guan, LiXin; Wu, YiYan; Lee, Jong Rok; Kim, Sang Chan; Kim, Young Woo; Zhao, RongJie

    2015-01-01

    Glycyrrhizae radix (G. radix) has been demonstrated to have hepatoprotective properties. This study determined the therapeutic effects of isoliquiritigenin (isoLQ) in G. radix, against liver injury induced by CCl4 in rats. CCl4 (0.5 ml/kg/d, twice) or CCl4 plus buthionine sulfoximine exerted severe liver damage assessed by increased plasma levels of alanine aminotransferase and aspartate aminotransferase, in addition to hepatic degeneration and necrosis. These pathological changes were markedly protected by pretreatment with isoLQ (5, 20 mg/kg/d, p.o.) for 3 consecutive days. In addition, pretreatment with isoLQ inhibited CCl4-induced reduction of cytochrome P450 2E1 protein and mRNA expression as well as activity in the liver. Moreover, isoLQ pretreatment reversed the decrease in hepatic antioxidant capacity induced by CCl4 as well as suppressed expression of tumor necrosis factor-alpha and cyclooxigenase-2 in the liver. These results suggest that isoLQ has a protective effect against CCl4-induced liver damage through induction of antioxidant and anti-inflammatory activities. PMID:25450236

  16. Hepatoprotective activity of Symplocos racemosa bark on carbon tetrachloride-induced hepatic damage in rats

    PubMed Central

    Wakchaure, Dhananjay; Jain, Dilpesh; Singhai, Abhay Kumar; Somani, Rahul

    2011-01-01

    The present study aims to evaluate the hepatoprotective activity of ethanol extract of Symplocos racemosa (EESR) bark on carbon tetrachloride (CCl4)-induced hepatic damage in rats. CCl4 with olive oil (1 : 1) (0.2 ml/kg, i.p.) was administered for ten days to induce hepatotoxicity. EESR (200 and 400 mg/kg, p.o.) and silymarin (100 mg/kg p.o.) were administered concomitantly for fourteen days. The degree of hepatoprotection was measured using serum transaminases (AST and ALT), alkaline phosphatase, bilirubin, albumin, and total protein levels. Metabolic function of the liver was evaluated by thiopentone-induced sleeping time. Antioxidant activity was assessed by measuring liver malondialdehyde, glutathione, catalase, and superoxide dismutase levels. Histopathological changes of liver sample were also observed. Significant hepatotoxicity was induced by CCl4 in experimental animals. EESR treatment showed significant dose-dependent restoration of serum enzymes, bilirubin, albumin, total proteins, and antioxidant levels. Improvements in hepatoprotection and morphological and histopathological changes were also observed in the EESR treated rats. It was therefore concluded that EESR bark is an effective hepatoprotective agent in CCl4-induced hepatic damage, and has potential clinical applications for treatment of liver diseases. PMID:22022156

  17. Differential timing of oxidative DNA damage and telomere shortening in hepatitis C and B virus-related liver carcinogenesis.

    PubMed

    Piciocchi, Marika; Cardin, Romilda; Cillo, Umberto; Vitale, Alessandro; Cappon, Andrea; Mescoli, Claudia; Guido, Maria; Rugge, Massimo; Burra, Patrizia; Floreani, Annarosa; Farinati, Fabio

    2016-02-01

    In viral hepatitis, inflammation is correlated with chronic oxidative stress, one of the biological events leading to DNA damage and hepatocellular carcinoma (HCC) development. Aim of this study was to investigate the complex molecular network linking oxidative damage to telomere length and telomerase activity and regulation in hepatitis C and B virus-related liver carcinogenesis. We investigated 142 patients: 21 with HCC (in both tumor and peritumor tissues) and 121 with chronic viral hepatitis in different stages. We evaluated 8-hydroxydeoxyguanosine (8-OHdG), marker of oxidative DNA damage, OGG1 gene polymorphism, telomere length, telomerase activity, TERT promoter methylation, and mitochondrial TERT localization. In hepatitis C-related damage, 8-OHdG levels increased since the early disease stages, whereas hepatitis B-related liver disease was characterized by a later and sharper 8-OHdG accumulation (P = 0.005). In C virus-infected patients, telomeres were shorter (P = 0.03), whereas telomerase activity was higher in tumors than that in the less advanced stages of disease in both groups (P = 0.0001, P = 0.05), with an earlier increase in hepatitis C. Similarly, TERT promoter methylation was higher in tumor and peritumor tissues in both groups (P = 0.02, P = 0.0001). Finally, TERT was localized in mitochondria in tumor and peritumor samples, with 8-OHdG levels significantly lower in mitochondrial than those in genomic DNA (P = 0.0003). These data describe a pathway in which oxidative DNA damage accumulates in correspondence with telomere shortening, telomerase activation, and TERT promoter methylation with a different time course in hepatitis B and C virus-related liver carcinogenesis. Finally, TERT localizes in mitochondria in HCC, where it lacks a canonical function. PMID:26408804

  18. Severe Burn–Induced Endoplasmic Reticulum Stress and Hepatic Damage in Mice

    PubMed Central

    Song, Juquan; Finnerty, Celeste C; Herndon, David N; Boehning, Darren; Jeschke, Marc G

    2009-01-01

    Severe burn injury results in liver dysfunction and damage, with subsequent metabolic derangements contributing to patient morbidity and mortality. On a cellular level, significant postburn hepatocyte apoptosis occurs and likely contributes to liver dysfunction. However, the underlying mechanisms of hepatocyte apoptosis are poorly understood. The endoplasmic reticulum (ER) stress response/unfolded protein response (UPR) pathway can lead to hepatocyte apoptosis under conditions of liver dysfunction. Thus, we hypothesized that ER stress/UPR may mediate hepatic dysfunction in response to burn injury. We investigated the temporal activation of hepatic ER stress in mice after a severe burn injury. Mice received a scald burn over 35% of their body surface and were killed at 1, 7, 14, and 21 d postburn. We found that severe burn induces hepatocyte apoptosis as indicated by increased caspase-3 activity (P < 0.05). Serum albumin levels decreased postburn and remained lowered for up to 21 d, indicating that constitutive secretory protein synthesis was reduced. Significantly, upregulation of the ER stress markers glucose-related protein 78 (GRP78)/BIP, protein disulfide isomerase (PDI), p–protein kinase R–like endoplasmic reticulum kinase (p-PERK), and inositol-requiring enzyme 1α (IRE-1α) were found beginning 1 d postburn (P < 0.05) and persisted up to 21 d postburn (P < 0.05). Hepatic ER stress induced by burn injury was associated with compensatory upregulation of the calcium chaperone/storage proteins calnexin and calreticulin (P < 0.05), suggesting that ER calcium store depletion was the primary trigger for induction of the ER stress response. In summary, thermal injury in mice causes long-term adaptive and deleterious hepatic function alterations characterized by significant upregulation of the ER stress response. PMID:19603103

  19. Severe burn-induced endoplasmic reticulum stress and hepatic damage in mice.

    PubMed

    Song, Juquan; Finnerty, Celeste C; Herndon, David N; Boehning, Darren; Jeschke, Marc G

    2009-01-01

    Severe burn injury results in liver dysfunction and damage, with subsequent metabolic derangements contributing to patient morbidity and mortality. On a cellular level, significant postburn hepatocyte apoptosis occurs and likely contributes to liver dysfunction. However, the underlying mechanisms of hepatocyte apoptosis are poorly understood. The endoplasmic reticulum (ER) stress response/unfolded protein response (UPR) pathway can lead to hepatocyte apoptosis under conditions of liver dysfunction. Thus, we hypothesized that ER stress/UPR may mediate hepatic dysfunction in response to burn injury. We investigated the temporal activation of hepatic ER stress in mice after a severe burn injury. Mice received a scald burn over 35% of their body surface and were killed at 1, 7, 14, and 21 d postburn. We found that severe burn induces hepatocyte apoptosis as indicated by increased caspase-3 activity (P < 0.05). Serum albumin levels decreased postburn and remained lowered for up to 21 d, indicating that constitutive secretory protein synthesis was reduced. Significantly, upregulation of the ER stress markers glucose-related protein 78 (GRP78)/BIP, protein disulfide isomerase (PDI), p-protein kinase R-like endoplasmic reticulum kinase (p-PERK), and inositol-requiring enzyme 1alpha (IRE-1alpha) were found beginning 1 d postburn (P < 0.05) and persisted up to 21 d postburn (P < 0.05). Hepatic ER stress induced by burn injury was associated with compensatory upregulation of the calcium chaperone/storage proteins calnexin and calreticulin (P < 0.05), suggesting that ER calcium store depletion was the primary trigger for induction of the ER stress response. In summary, thermal injury in mice causes long-term adaptive and deleterious hepatic function alterations characterized by significant upregulation of the ER stress response. PMID:19603103

  20. DNA damage produced by cadmium in a human fetal hepatic cell line.

    PubMed

    López-Ortal, P; Souza, V; Bucio, L; González, E; Gutiérrez-Ruiz, M C

    1999-02-19

    Cadmium (Cd) is one of the most important heavy metal environmental toxicants. It alters a wide variety of cellular and biochemical processes. The objective of this work was to study DNA damage and recovery after acute and chronic CdCl2 treatment in a human fetal hepatic cell line (WRL-68 cells). Using the alkaline microgel electrophoresis assay that detects DNA single-strand breaks and/or alkali-labile sites in individual cells, we evaluated for levels of DNA damage. The mean migration length in control cells was 35.37+/-1. 43 microm (8% damaged cells), whereas the mean migration in cells treated with 0.005 microM CdCl2 for 3 h (acute low dose) was 65. 87+/-2.07 microm (88% damaged cells). Treatment with 0.01 microM CdCl2 for the same time (acute high dose) increased the mean migration length to 125.79+/-2.91 microm (92% damaged cells). However, a 0.005 microM CdCl2 treatment for 7 days (chronic treatment) only increased 65% DNA migration to 58.38+/-2.59 microm (88% damaged nucleus). Lipoperoxidative damage expressed as malondialdehyde (MDA) production per milligram of protein was 15. 7+/-2.6 for control cells, whereas in Cd-treated cells the values were 20.2+/-2.4 (acute low dose), 22.9+/-2.2 (acute high dose), and 22.6+/-2.1 (chronic treatment). To study the repair of DNA damage, cells were washed with 0.01 microM meso-2,3-dimercaptosuccinic acid (DMSA), and fresh Dulbecco's modified essential medium (DMEM) added. The percentage of damaged cells diminished after 90 min, with DNA migration returning to control values by 120 min. Cd treatment produced DNA single-strand breaks and the damage was greater in acute high dose treated cells. Lipid peroxidation values did not correlate with DNA single-strand breaks. PMID:10023089

  1. The effects of daily supplementation of Dendrobium huoshanense polysaccharide on ethanol-induced subacute liver injury in mice by proteomic analysis.

    PubMed

    Wang, Xiao-Yu; Luo, Jian-Ping; Chen, Rui; Zha, Xue-Qiang; Wang, He

    2014-09-01

    Polysaccharides isolated from edible Dendrobium huoshanense have been shown to possess a hepatoprotection function for selenium- and carbon tetrachloride-induced liver injury. In this study, we investigated the preventive effects of daily supplementation with an homogeneous polysaccharide (DHP) purified from D. huoshanense on ethanol-induced subacute liver injury in mice and its potential mechanisms in liver protection by a proteomic approach. DHP was found to effectively depress the increased ratio of liver weight to body weight, reduce the elevated levels of serum aspartate aminotransferase, total cholesterol, total bilirubin and low density lipoprotein, and alleviate hepatic steatosis in mice with ethanol-induced subacute liver injury. Hepatic proteomics analysis performed by two-dimensional difference gel electrophoresis (2D-DIGE) coupled with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF/TOF-MS) revealed that cystathionine beta-synthase (Cbs) and D-lactate dehydrogenase (Ldhd) were two key proteins regulated by daily DHP intervention, which may assist in correcting the abnormal hepatic methionine metabolism pathway and decreasing the level of hepatic methylglyoxal generated from disordered metabolic pathways caused by ethanol. Our data suggest that DHP can protect liver function from alcoholic injury with complicated molecular mechanisms involving regulation of Cbs and Ldhd. PMID:24933018

  2. Sodium selenite/selenium nanoparticles (SeNPs) protect cardiomyoblasts and zebrafish embryos against ethanol induced oxidative stress.

    PubMed

    Kalishwaralal, Kalimuthu; Jeyabharathi, Subhaschandrabose; Sundar, Krishnan; Muthukumaran, Azhaguchamy

    2015-10-01

    Alcoholic cardiomyopathy is the damage caused to the heart muscles due to high level of alcohol consumption resulting in enlargement and inflammation of the heart. Selenium is an important trace element that is beneficial to human health. Selenium protects the cells by preventing the formation of free radicals in the body. In the present study, protein mediated synthesis of SeNPs was investigated. Two different sizes of SeNPs were synthesized using BSA and keratin. The synthesized SeNPs were characterized by scanning electron microscopy (SEM) with elemental composition analysis Energy Dispersive X-ray spectroscopy(EDX) and X-ray diffraction (XRD). This study demonstrates the in vitro and in vivo antioxidative effects of sodium selenite and SeNPs. Further selenium and SeNPs were evaluated for their ability to protect against 1% ethanol induced oxidative stress in H9C2 cell line. The selenium and SeNPs were found to reduce the 1% ethanol-induced oxidative damage through scavenging intracellular reactive oxygen species. The selenium and SeNPs could also prevent pericardial edema induced ethanol treatment and reduced apoptosis and cell death in zebrafish embryos. The results indicate that selenium and SeNPs could potentially be used as an additive in alcoholic beverage industry to control the cardiomyopathy. PMID:26302921

  3. The inhibitory effect of ethanol on Sestrin3 in the pathogenesis of ethanol-induced liver injury

    PubMed Central

    Kang, Xinqin; Petyaykina, Kateryna; Tao, Rongya; Xiong, Xiwen; Dong, X. Charlie

    2014-01-01

    Sestrins (Sesns) are a family of stress-sensitive genes that have been suggested to regulate lipid metabolism. Chronic ethanol feeding is known to cause lipid accumulation in hepatocytes. This study was designed to investigate the role of Sesn3 in the pathogenesis of alcohol-induced hepatic steatosis. We demonstrated that ethanol inhibited the expression of Sesn3 in VL-17A cells. Overexpression of Sesn3 ameliorated triglyceride accumulation; downregulation using short hairpin RNA significantly deteriorated triglyceride accumulation in these cells. The expression of Sesn3 was also reduced in mice fed with ethanol for 4 wk. Overexpression of Sesn3 prevented hepatic steatosis, whereas knockdown of Sesn3 worsened hepatic steatosis in ethanol-fed mice. Overexpression of Sesn3 significantly reduced the expression of genes encoding for lipid synthesis through AMPK pathway. Overexpression of Sesn3 augmented the effect of ethanol on phospho-p70 S6 kinase. The levels of hepatic light chain 3, a marker for autophagy, expression were significantly decreased in ethanol-fed mice after Sesn3 gene was knocked down. Our findings suggest that inhibitory effect of ethanol on Sesn3 may play an important role in the development of ethanol-induced fatty liver. PMID:24833709

  4. Hepatitis

    MedlinePlus

    ... has been associated with drinking contaminated water. Hepatitis Viruses Type Transmission Prognosis A Fecal-oral (stool to ... risk for severe disease. Others A variety of viruses can affect the liver Signs and Symptoms Hepatitis ...

  5. Lycopene Pretreatment Ameliorates Acute Ethanol Induced NAD+ Depletion in Human Astroglial Cells

    PubMed Central

    Guest, Jade; Heng, Benjamin; Grant, Ross

    2015-01-01

    Excessive alcohol consumption is associated with reduced brain volume and cognition. While the mechanisms by which ethanol induces these deleterious effects in vivo are varied most are associated with increased inflammatory and oxidative processes. In order to further characterise the effect of acute ethanol exposure on oxidative damage and NAD+ levels in the brain, human U251 astroglioma cells were exposed to physiologically relevant doses of ethanol (11 mM, 22 mM, 65 mM, and 100 mM) for ≤ 30 minutes. Ethanol exposure resulted in a dose dependent increase in both ROS and poly(ADP-ribose) polymer production. Significant decreases in total NAD(H) and sirtuin 1 activity were also observed at concentrations ≥ 22 mM. Similar to U251 cells, exposure to ethanol (≥22 mM) decreased levels of NAD(H) in primary human astrocytes. NAD(H) depletion in primary astrocytes was prevented by pretreatment with 1 μM of lycopene for 3.5 hours. Unexpectedly, in U251 cells lycopene treatment at concentrations ≥ 5 μM resulted in significant reductions in [NAD(H)]. This study suggests that exposure of the brain to alcohol at commonly observed blood concentrations may cause transitory oxidative damage which may be at least partly ameliorated by lycopene. PMID:26075038

  6. Involvement of seven in absentia homolog-1 in ethanol-induced apoptosis in neural crest cells

    PubMed Central

    Sun, Haijing; Chen, Xiaopan; Yuan, Fuqiang; Liu, Jie; Zhao, Yingming; Chen, Shao-yu

    2014-01-01

    Ethanol-induced apoptosis in selected cell populations is a major component of pathogenesis underlying ethanol-induced teratogenesis. However, there is a fundamental gap in understanding how ethanol leads to apoptosis in embryos. In this study, we investigate the role of seven in absentia homolog-1 (Siah1) protein, an E3 ubiquitin ligase, in ethanol-induced apoptosis. Using an in vitro model of neural crest cell (NCC), JoMa1.3 cells, we found that exposure to 100 mM ethanol resulted in a significant increase in Siah1 mRNA expression in NCCs, an ethanol-sensitive cell population implicated in Fetal Alcohol Spectrum Disorders (FASD). Treatment with 100 mM ethanol for 24 hours also significantly increased the protein expression of Siah1 in JoMa1.3 cells. The nuclear translocation and accumulation of Siah1 was evidenced in the cells exposed to ethanol. In addition, we have found that the inhibition of Siah1 function with siRNA prevents ethanol-induced increase in Siah1 protein expression and nuclear translocation in NCCs. Down-regulation of Siah1 by siRNA also greatly diminished ethanol-induced cell death and caspase-3 activation, indicating that inhibition of Siah1 can attenuate ethanol-induced apoptosis. These results strongly suggest that Siah1 plays an important role in ethanol-induced apoptosis in NCCs. PMID:25193017

  7. Hepatic stellate cell-expressed endosialin balances fibrogenesis and hepatocyte proliferation during liver damage.

    PubMed

    Mogler, Carolin; Wieland, Matthias; König, Courtney; Hu, Junhao; Runge, Anja; Korn, Claudia; Besemfelder, Eva; Breitkopf-Heinlein, Katja; Komljenovic, Dorde; Dooley, Steven; Schirmacher, Peter; Longerich, Thomas; Augustin, Hellmut G

    2015-03-01

    Liver fibrosis is a reversible wound-healing response to injury reflecting the critical balance between liver repair and scar formation. Chronic damage leads to progressive substitution of liver parenchyma by scar tissue and ultimately results in liver cirrhosis. Stromal cells (hepatic stellate cells [HSC] and endothelial cells) have been proposed to control the balance between liver fibrosis and regeneration. Here, we show that endosialin, a C-type lectin, expressed in the liver exclusively by HSC and portal fibroblasts, is upregulated in liver fibrosis in mouse and man. Chronic chemically induced liver damage resulted in reduced fibrosis and enhanced hepatocyte proliferation in endosialin-deficient (EN(KO)) mice. Correspondingly, acute-liver-damage-induced hepatocyte proliferation (partial hepatectomy) was increased in EN(KO) mice. A candidate-based screen of known regulators of hepatocyte proliferation identified insulin-like growth factor 2 (IGF2) as selectively endosialin-dependent hepatocyte mitogen. Collectively, the study establishes a critical role of HSC in the reciprocal regulation of fibrogenesis vs. hepatocyte proliferation and identifies endosialin as a therapeutic target in non-neoplastic settings. PMID:25680861

  8. Hepatic stellate cell-expressed endosialin balances fibrogenesis and hepatocyte proliferation during liver damage

    PubMed Central

    Mogler, Carolin; Wieland, Matthias; König, Courtney; Hu, Junhao; Runge, Anja; Korn, Claudia; Besemfelder, Eva; Breitkopf-Heinlein, Katja; Komljenovic, Dorde; Dooley, Steven; Schirmacher, Peter; Longerich, Thomas; Augustin, Hellmut G

    2015-01-01

    Liver fibrosis is a reversible wound-healing response to injury reflecting the critical balance between liver repair and scar formation. Chronic damage leads to progressive substitution of liver parenchyma by scar tissue and ultimately results in liver cirrhosis. Stromal cells (hepatic stellate cells [HSC] and endothelial cells) have been proposed to control the balance between liver fibrosis and regeneration. Here, we show that endosialin, a C-type lectin, expressed in the liver exclusively by HSC and portal fibroblasts, is upregulated in liver fibrosis in mouse and man. Chronic chemically induced liver damage resulted in reduced fibrosis and enhanced hepatocyte proliferation in endosialin-deficient (ENKO) mice. Correspondingly, acute-liver-damage-induced hepatocyte proliferation (partial hepatectomy) was increased in ENKO mice. A candidate-based screen of known regulators of hepatocyte proliferation identified insulin-like growth factor 2 (IGF2) as selectively endosialin-dependent hepatocyte mitogen. Collectively, the study establishes a critical role of HSC in the reciprocal regulation of fibrogenesis vs. hepatocyte proliferation and identifies endosialin as a therapeutic target in non-neoplastic settings. PMID:25680861

  9. Preventive Effect of the Korean Traditional Health Drink (Taemyeongcheong) on Acetaminophen-Induced Hepatic Damage in ICR Mice

    PubMed Central

    Yi, Ruo-Kun; Song, Jia-Le; Lim, Yaung-Iee; Kim, Yong-Kyu; Park, Kun-Young

    2015-01-01

    This study was to investigate the preventive effect of taemyeongcheong (TMC, a Korean traditional health drink) on acetaminophen (APAP, 800 mg/kg BW)-induced hepatic damage in ICR mice. TMC is prepared from Saururus chinensis, Taraxacum officinale, Zingiber officinale, Cirsium setidens, Salicornia herbacea, and Glycyrrhizae. A high dose of TMC (500 mg/kg BW) was found to decrease APAP-induced increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase. TMC pretreatment also increased the hepatic levels of hepatic catalase, superoxide dismutase, glutathione peroxidase, and glutathione, and reduced serum levels of the inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 in mice administered APAP (P<0.05). TMC (500 mg/kg BW) reduced hepatic mRNA levels of TNF-α, IL-1β, IL-6, COX-2, and iNOS by 87%, 84%, 89%, 85%, and 88%, respectively, in mice treated with APAP (P<0.05). Furthermore, histological observations suggested TMC pretreatment dose-dependently prevented APAP-induced hepatocyte damage. These results suggest that TMC could be used as a functional health drink to prevent hepatic damage. PMID:25866750

  10. Preventive Effect of the Korean Traditional Health Drink (Taemyeongcheong) on Acetaminophen-Induced Hepatic Damage in ICR Mice.

    PubMed

    Yi, Ruo-Kun; Song, Jia-Le; Lim, Yaung-Iee; Kim, Yong-Kyu; Park, Kun-Young

    2015-03-01

    This study was to investigate the preventive effect of taemyeongcheong (TMC, a Korean traditional health drink) on acetaminophen (APAP, 800 mg/kg BW)-induced hepatic damage in ICR mice. TMC is prepared from Saururus chinensis, Taraxacum officinale, Zingiber officinale, Cirsium setidens, Salicornia herbacea, and Glycyrrhizae. A high dose of TMC (500 mg/kg BW) was found to decrease APAP-induced increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase. TMC pretreatment also increased the hepatic levels of hepatic catalase, superoxide dismutase, glutathione peroxidase, and glutathione, and reduced serum levels of the inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 in mice administered APAP (P<0.05). TMC (500 mg/kg BW) reduced hepatic mRNA levels of TNF-α, IL-1β, IL-6, COX-2, and iNOS by 87%, 84%, 89%, 85%, and 88%, respectively, in mice treated with APAP (P<0.05). Furthermore, histological observations suggested TMC pretreatment dose-dependently prevented APAP-induced hepatocyte damage. These results suggest that TMC could be used as a functional health drink to prevent hepatic damage. PMID:25866750

  11. Binge ethanol exposure increases the Krüppel-like factor 11-monoamine oxidase (MAO) pathway in rats: Examining the use of MAO inhibitors to prevent ethanol-induced brain injury.

    PubMed

    Duncan, Jeremy W; Zhang, Xiao; Wang, Niping; Johnson, Shakevia; Harris, Sharonda; Udemgba, Chinelo; Ou, Xiao-Ming; Youdim, Moussa B; Stockmeier, Craig A; Wang, Jun Ming

    2016-06-01

    Binge drinking induces several neurotoxic consequences including oxidative stress and neurodegeneration. Because of these effects, drugs which prevent ethanol-induced damage to the brain may be clinically beneficial. In this study, we investigated the ethanol-mediated KLF11-MAO cell death cascade in the frontal cortex of Sprague-Dawley rats exposed to a modified Majchowicz 4-day binge ethanol model and control rats. Moreover, MAO inhibitors (MAOIs) were investigated for neuroprotective activity against binge ethanol. Binge ethanol-treated rats demonstrated a significant increase in KLF11, both MAO isoforms, protein oxidation and caspase-3, as well as a reduction in BDNF expression in the frontal cortex compared to control rats. MAOIs prevented these binge ethanol-induced changes, suggesting a neuroprotective benefit. Neither binge ethanol nor MAOI treatment significantly affected protein expression levels of the oxidative stress enzymes, SOD2 or catalase. Furthermore, ethanol-induced antinociception was enhanced following exposure to the 4-day ethanol binge. These results demonstrate that the KLF11-MAO pathway is activated by binge ethanol exposure and MAOIs are neuroprotective by preventing the binge ethanol-induced changes associated with this cell death cascade. This study supports KLF11-MAO as a mechanism of ethanol-induced neurotoxicity and cell death that could be targeted with MAOI drug therapy to alleviate alcohol-related brain injury. Further examination of MAOIs to reduce alcohol use disorder-related brain injury could provide pivotal insight to future pharmacotherapeutic opportunities. PMID:26805422

  12. Chronic hepatitis C virus infection: Serum biomarkers in predicting liver damage

    PubMed Central

    Valva, Pamela; Ríos, Daniela A; De Matteo, Elena; Preciado, Maria V

    2016-01-01

    Currently, a major clinical challenge in the management of the increasing number of hepatitis C virus (HCV) infected patients is determining the best means for evaluating liver impairment. Prognosis and treatment of chronic hepatitis C (CHC) are partly dependent on the assessment of histological activity, namely cell necrosis and inflammation, and the degree of liver fibrosis. These parameters can be provided by liver biopsy; however, in addition to the risks related to an invasive procedure, liver biopsy has been associated with sampling error mostly due to suboptimal biopsy size. To avoid these pitfalls, several markers have been proposed as non-invasive alternatives for the diagnosis of liver damage. Distinct approaches among the currently available non-invasive methods are (1) the physical ones based on imaging techniques; and (2) the biological ones based on serum biomarkers. In this review, we discuss these approaches with special focus on currently available non-invasive serum markers. We will discuss: (1) class I serum biomarkers individually and as combined panels, particularly those that mirror the metabolism of liver extracellular matrix turnover and/or fibrogenic cell changes; (2) class II biomarkers that are indirect serum markers and are based on the evaluation of common functional alterations in the liver; and (3) biomarkers of liver cell death, since hepatocyte apoptosis plays a significant role in the pathogenesis of HCV infection. We highlight in this review the evidence behind the use of these markers and assess the diagnostic accuracy as well as advantages, limitations, and application in clinical practice of each test for predicting liver damage in CHC. PMID:26819506

  13. Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation and cell death in astroglial cells

    PubMed Central

    Alfonso-Loeches, Silvia; Ureña-Peralta, Juan R.; Morillo-Bargues, Maria José; Oliver-De La Cruz, Jorge; Guerri, Consuelo

    2014-01-01

    Toll-like receptors (TLRs) and NOD-like receptors (NLRs) are innate immunity sensors that provide an early/effective response to pathogenic or injury conditions. We have reported that ethanol-induced TLR4 activation triggers signaling inflammatory responses in glial cells, causing neuroinflammation and brain damage. However, it is uncertain if ethanol is able to activate NLRs/inflammasome in astroglial cells, which is the mechanism of activation, and whether there is crosstalk between both immune sensors in glial cells. Here we show that chronic ethanol treatment increases the co-localization of caspase-1 with GFAP+ cells, and up-regulates IL-1β and IL-18 in the frontal medial cortex in WT, but not in TLR4 knockout mice. We further show that cultured cortical astrocytes expressed several inflammasomes (NLRP3, AIM2, NLRP1, and IPAF), although NLRP3 mRNA is the predominant form. Ethanol, as ATP and LPS treatments, up-regulates NLRP3 expression, and causes caspase-1 cleavage and the release of IL-1β and IL-18 in astrocytes supernatant. Ethanol-induced NLRP3/caspase-1 activation is mediated by mitochondrial (m) reactive oxygen species (ROS) generation because when using a specific mitochondria ROS scavenger, the mito-TEMPO (500 μM) or NLRP3 blocking peptide (4 μg/ml) or a specific caspase-1 inhibitor, Z-YVAD-FMK (10 μM), abrogates mROS release and reduces the up-regulation of IL-1β and IL-18 induced by ethanol or LPS or ATP. Confocal microscopy studies further confirm that ethanol, ATP or LPS promotes NLRP3/caspase-1 complex recruitment within the mitochondria to promote cell death by caspase-1-mediated pyroptosis, which accounts for ≈73% of total cell death (≈22%) and the remaining (≈25%) die by caspase-3-dependent apoptosis. Suppression of the TLR4 function abrogates most ethanol effects on NLRP3 activation and reduces cell death. These findings suggest that NLRP3 participates, in ethanol-induced neuroinflammation and highlight the NLRP3/TLR4 crosstalk in

  14. Strawberry Polyphenols Attenuate Ethanol-Induced Gastric Lesions in Rats by Activation of Antioxidant Enzymes and Attenuation of MDA Increase

    PubMed Central

    Alvarez-Suarez, José M.; Dekanski, Dragana; Ristić, Slavica; Radonjić, Nevena V.; Petronijević, Nataša D.; Giampieri, Francesca; Astolfi, Paola; González-Paramás, Ana M.; Santos-Buelga, Celestino; Tulipani, Sara; Quiles, José L.; Mezzetti, Bruno; Battino, Maurizio

    2011-01-01

    Background and Aim Free radicals are implicated in the aetiology of gastrointestinal disorders such as gastric ulcer, colorectal cancer and inflammatory bowel disease. Strawberries are common and important fruit due to their high content of essential nutrient and beneficial phytochemicals which seem to have relevant biological activity on human health. In the present study we investigated the antioxidant and protective effects of three strawberry extracts against ethanol-induced gastric mucosa damage in an experimental in vivo model and to test whether strawberry extracts affect antioxidant enzyme activities in gastric mucosa. Methods/Principal Findings Strawberry extracts were obtained from Adria, Sveva and Alba cultivars. Total antioxidant capacity and radical scavenging capacity were performed by TEAC, ORAC and electron paramagnetic resonance assays. Identification and quantification of anthocyanins was carried out by HPLC-DAD-MS analyses. Different groups of animals received 40 mg/day/kg body weight of strawberry crude extracts for 10 days. Gastric damage was induced by ethanol. The ulcer index was calculated together with the determination of catalase and SOD activities and MDA contents. Strawberry extracts are rich in anthocyanins and present important antioxidant capacity. Ethanol caused severe gastric damage and strawberry consumption protected against its deleterious role. Antioxidant enzyme activities increased significantly after strawberry extract intake and a concomitantly decrease in gastric lipid peroxidation was found. A significant correlation between total anthocyanin content and percent of inhibition of ulcer index was also found. Conclusions Strawberry extracts prevented exogenous ethanol-induced damage to rats' gastric mucosa. These effects seem to be associated with the antioxidant activity and phenolic content in the extract as well as with the capacity of promoting the action of antioxidant enzymes. A diet rich in strawberries might exert a

  15. Evaluation of hepatic damage and local immune response in goats immunized with native glutathione S-transferase of Fasciola hepatica.

    PubMed

    Zafra, R; Pérez-Ecija, R A; Buffoni, L; Mendes, R E; Martínez-Moreno, A; Martínez-Moreno, F J; Galisteo, M E Martínez; Pérez, J

    2010-01-01

    Worm burden, hepatic damage and local cellular and humoral immune responses were assessed in goats immunized with glutathione-S-transferase and challenged with Fasciola hepatica. Infected but unimmunized and uninfected control groups were also studied. Hepatic damage was evaluated grossly and microscopically. Local immune response was evaluated by (1) microscopical examination of hepatic lymph nodes (HLNs); (2) analysis of the distribution of CD2(+), CD4(+), CD8(+), T-cell receptor gammadelta(+) lymphocytes and immunoglobulin (Ig) G(+) plasma cells; and (3) investigation of the distribution of cells expressing interleukin (IL)-4 and interferon (IFN)-gamma in the hepatic inflammatory infiltrates and HLNs. Immunized animals did not have significant reduction in fluke number, but there was significant (P<0.05) reduction of fluke size relative to the control groups. The lesions in the two infected groups were similar and consisted of fibrous perihepatitis and white tortuous tracts, mainly involving the left hepatic lobe. Microscopical lesions were similar in both infected groups and were typical of chronic fascioliosis. These included portal fibrosis, inflammatory infiltration with plasma cells, formation of lymphoid follicles, accumulation of haemosiderin-laden macrophages and granulomatous foci. Both infected groups had a marked local immune response characterized by infiltration of CD2(+), CD4(+) and CD8(+) T lymphocytes, and IgG(+) plasma cells in hepatic lesions and in HLNs. There was no expression of IL-4 or INF-gamma by cells in the hepatic inflammatory infiltrate, but expression of INF-gamma in HLNs was much lower than that of IL-4, suggesting an immune response dominated by T helper 2 cells. PMID:20185148

  16. Hepatitis

    MedlinePlus

    ... be serious. Some can lead to scarring, called cirrhosis, or to liver cancer. Sometimes hepatitis goes away by itself. If it does not, it can be treated with drugs. Sometimes hepatitis lasts a lifetime. Vaccines can help prevent some viral forms.

  17. Evaluation of protective effects of costunolide and dehydrocostuslactone on ethanol-induced gastric ulcer in mice based on multi-pathway regulation.

    PubMed

    Zheng, Hong; Chen, Yuling; Zhang, Jingze; Wang, Lei; Jin, Zhaoxiang; Huang, Hanhan; Man, Shuli; Gao, Wenyuan

    2016-04-25

    The aim of the present study was to evaluate the anti-ulcerogenic activity of costunolide (Co) and dehydrocostuslactone (De) on ethanol-induced gastric ulcer in mice and to elucidate the potential mechanisms of the action involved. Mice were pretreated orally with Co (5 or 20 mg/kg), De (5 or 20 mg/kg) and omeprazole (OME, 20 mg/kg) for 7 consecutive days, followed by ulcer induction using absolute ethanol (0.2 mL/20 g body weight). Treatment with Co had a remarkable gastroprotection compared to the ethanol-ulcerated mice that significantly reduced the ulcerative lesion index (ULI) and histopathological damage. Daily intragastric administration of Co exerted a powerful anti-inflammatory activity as evidenced by the suppression of nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α, nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, as well as increased interleukin (IL)-10. Also, pretreatment with Co effectively inhibited ethanol-induced malondialdehyde (MDA) overproduction, increased the depleted superoxide dismutase (SOD) and promoted gastric mucosa epithelial cell proliferation by up-regulating proliferating cell nuclear antigen (PCNA) expression. Similarly, De had a protective effect on ethanol-induced ulcer, which was dependent on the inhibition of inflammatory cytokines and MDA generation, but independent of IL-10, SOD and PCNA improvement. Conclusively, the results have clearly demonstrated the anti-ulcerogenic potential of Co and De on ethanol-induced gastric ulcer; nevertheless, the gastroprotective activity of Co was superior to De due to more multi-pathway regulation than De. These findings suggested that Co or De could be a new useful natural gastroprotective tool against gastric ulcer, which provided a scientific basis for the gastroprotection of sesquiterpene lactones. PMID:26970604

  18. Protective activity of andrographolide and arabinogalactan proteins from Andrographis paniculata Nees. against ethanol-induced toxicity in mice.

    PubMed

    Singha, Prajjal K; Roy, Somenath; Dey, Satyahari

    2007-04-20

    To find out the active principles against ethanol-induced toxicity in mice, Andrographis paniculata Nees. (Ap) was chosen and isolated andrographolide (ANDRO) and arabinogalactan proteins (AGPs). ANDRO was detected by HPTLC, FTIR and quantified by HPLC (10mg/g of Ap powder). AGPs was detected by beta-glucosyl Yariv staining of SDS-PAGE gel, FTIR and quantified by single radial gel diffusion assay with beta-glucosyl Yariv reagent (0.5mg/g Ap powder). The mice are pretreated intra-peritoneally (i.p.) with different doses (62.5, 125, 250, and 500mg/kg) of body weight of mice] of ANDRO and AGPs for 7 days and then ethanol (7.5g/kg of body weight) was injected, i.p. Besides, silymarin was used as standard hepatoprotective agent for comparative study with ANDRO and AGPs. The ameliorative activity of ANDRO and AGP against hepatic renal alcohol toxicity was measured by assessing GOT, GPT, ACP, ALP and LP levels in liver and kidney. It has been observed that pretreatment of mice with ANDRO and AGPs at 500mg/kg of body weight and 125mg/kg of body weight respectively could able to minimize the toxicity in compare to ethanol treated group as revealed by the different enzymatic assay in liver and kidney tissues and the results were comparable with silymarin. Hence, out of several ill-defined compounds present in Ap, ANDRO and AGPs are the potential bioactive compounds responsible for protection against ethanol-induced toxicity. PMID:17127022

  19. Hepatoprotective Effect of Houttuynia cordata Thunb Extract against Carbon Tetrachloride-induced Hepatic Damage in Mice

    PubMed Central

    Kang, H.; Koppula, S.

    2014-01-01

    Houttuynia cordata Thunb (Saururaceae) is a traditional medicinal herb used to treat several disease symptoms. The present study was focused on the hepatoprotective effects of H. cordata ethyl acetate extract in experimental mice. Further the antioxidant potential of the extract was also evaluated to substantiate its hepatoprotective properties. Carbon tetrachloride-induced hepatic damage in mice was used to measure the serum biochemical parameters. Morphological changes in hepatocyte architecture were studied by haematoxylin and eosin staining. In vitro alkyl and hydroxyl free radical scavenging assays were performed to evaluate the antioxidant effect. Administration of H. cordata extract significantly reduced the elevated serum levels and regulated the altered levels of serum cholesterol in carbon tetrachloride-treated mice (P<0.05). The morphological changes in hepatocyte architecture were also reversed by H. cordata treatment. Further, the extract showed significant antioxidant actions by scavenging the alkyl and hydroxyl free radicals. The concentration of the extract necessary for 50% scavenging of alkyl and hydroxyl radicals was 15.5 and 410 μg/ml, respectively. H. cordata extract exhibited significant hepatoprotective property in carbon tetrachloride-induced hepatotoxicity in mice. The strong antioxidant activities possessed by the extract might be responsible for such actions. PMID:25284923

  20. Hepatoprotective Effect of Houttuynia cordata Thunb Extract against Carbon Tetrachloride-induced Hepatic Damage in Mice.

    PubMed

    Kang, H; Koppula, S

    2014-07-01

    Houttuynia cordata Thunb (Saururaceae) is a traditional medicinal herb used to treat several disease symptoms. The present study was focused on the hepatoprotective effects of H. cordata ethyl acetate extract in experimental mice. Further the antioxidant potential of the extract was also evaluated to substantiate its hepatoprotective properties. Carbon tetrachloride-induced hepatic damage in mice was used to measure the serum biochemical parameters. Morphological changes in hepatocyte architecture were studied by haematoxylin and eosin staining. In vitro alkyl and hydroxyl free radical scavenging assays were performed to evaluate the antioxidant effect. Administration of H. cordata extract significantly reduced the elevated serum levels and regulated the altered levels of serum cholesterol in carbon tetrachloride-treated mice (P<0.05). The morphological changes in hepatocyte architecture were also reversed by H. cordata treatment. Further, the extract showed significant antioxidant actions by scavenging the alkyl and hydroxyl free radicals. The concentration of the extract necessary for 50% scavenging of alkyl and hydroxyl radicals was 15.5 and 410 μg/ml, respectively. H. cordata extract exhibited significant hepatoprotective property in carbon tetrachloride-induced hepatotoxicity in mice. The strong antioxidant activities possessed by the extract might be responsible for such actions. PMID:25284923

  1. Hepatic enzyme changes in bovine hepatogenous photosensitivity caused by water-damaged alfalfa hay.

    PubMed

    Putnam, M R; Qualls, C W; Rice, L E; Dawson, L J; Edwards, W C

    1986-07-01

    In the winter of 1983, practitioners reported extensive photosensitization in 7 herds of cattle. All herds had a history of having been fed water-damaged alfalfa hay. A cow from one herd was referred to the veterinary teaching hospital at Oklahoma State University. In this herd of approximately 40 adult Polled Herefords, all cattle had had some degree of clinical involvement over the past 4 to 6 weeks. Clinical signs included scaling and erythema of sparsely haired skin, muzzle, and teats, as well as icterus, anorexia, and weight loss. One cow died, and the remaining cattle recovered over an 8- to 10-week period after removal of the hay from the ration. In the referred cow, values for total and conjugated bilirubin, BUN, creatinine, sorbitol dehydrogenase, serum alkaline phosphatase, serum aspartate transaminase, and serum gamma-glutamyl transferase were higher than normal. In the herd of origin, extremely high serum gamma-glutamyl transferase values (180 to 1,400 IU/L) persisted (normal, 2 to 35 IU/L). Feeding the same alfalfa hay to 2 clinically normal cows reproduced the syndrome. The characteristic hepatic lesion was bile duct necrosis, with secondary bile duct hyperplasia. PMID:2874123

  2. Fas Regulates Macrophage Polarization and Fibrogenic Phenotype in a Model of Chronic Ethanol-Induced Hepatocellular Injury.

    PubMed

    Isayama, Fuyumi; Moore, Sherri; Hines, Ian N; Wheeler, Michael D

    2016-06-01

    The role of Fas-mediated apoptosis and its effect on proinflammatory cytokine production in early alcoholic liver disease has not been addressed. Wild-type mice (C57Bl/6) or mice with a functional mutation in the Fas ligand (B6.gld) were given either high-fat control diet or ethanol diet by intragastric cannulation for 2 or 4 weeks. Liver injury, hepatic lipid accumulation, and proinflammatory cytokine production associated with chronic ethanol consumption were largely prevented in B6.gld mice compared with wild-type mice. Conversely, B6.gld mice given ethanol exhibited increases in collagen deposition, hepatic collagen gene expression, and profibrogenic cytokines (eg, transforming growth factor-β and IL-13) and alterations in matrix remodeling proteins (eg, matrix metalloproteinases and tissue inhibitor of metalloproteinases) compared with wild-type mice. Hepatic F4/80(+) macrophage populations were increased significantly in B6.gld mice compared with wild-type mice; hepatic CD3(+) cell populations were not significantly different. Importantly, a shift toward the expression of M2/Th2 cytokines (eg, IL-4 and IL-13) after ethanol exposure was observed in B6.gld mice compared with classical M1 cytokine expression in wild-type mice under similar conditions. In isolated macrophages, stimulation of Fas receptor minimally enhances lipopolysaccharide-induced M1 cytokine production and significantly limits M2 cytokine production. These data support the hypothesis that Fas-mediated signaling is important for an early ethanol-induced proinflammatory response but limits the profibrogenic response, regulating collagen production in response to chronic ethanol. PMID:27102767

  3. Neuroprotective effect of osmotin against ethanol-induced apoptotic neurodegeneration in the developing rat brain.

    PubMed

    Naseer, M I; Ullah, I; Narasimhan, M L; Lee, H Y; Bressan, R A; Yoon, G H; Yun, D J; Kim, M O

    2014-01-01

    Fetal alcohol syndrome is a neurological and developmental disorder caused by exposure of developing brain to ethanol. Administration of osmotin to rat pups reduced ethanol-induced apoptosis in cortical and hippocampal neurons. Osmotin, a plant protein, mitigated the ethanol-induced increases in cytochrome c, cleaved caspase-3, and PARP-1. Osmotin and ethanol reduced ethanol neurotoxicity both in vivo and in vitro by reducing the protein levels of cleaved caspase-3, intracellular [Ca(2+)]cyt, and mitochondrial transmembrane potential collapse, and also upregulated antiapoptotic Bcl-2 protein. Osmotin is a homolog of adiponectin, and it controls energy metabolism via phosphorylation. Adiponectin can protect hippocampal neurons against ethanol-induced apoptosis. Abrogation of signaling via receptors AdipoR1 or AdipoR2, by transfection with siRNAs, reduced the ability of osmotin and adiponectin to protect neurons against ethanol-induced neurodegeneration. Metformin, an activator of AMPK (adenosine monophosphate-activated protein kinase), increased whereas Compound C, an inhibitor of AMPK pathway, reduced the ability of osmotin and adiponectin to protect against ethanol-induced apoptosis. Osmotin exerted its neuroprotection via Bcl-2 family proteins and activation of AMPK signaling pathway. Modulation of AMPK pathways by osmotin, adiponectin, and metformin hold promise as a preventive therapy for fetal alcohol syndrome. PMID:24675468

  4. Opposite effects of GABAA and NMDA receptor antagonists on ethanol-induced behavioral sleep in rats.

    PubMed

    Beleslin, D B; Djokanović, N; Jovanović Mićić, D; Samardzić, R

    1997-01-01

    The effects of the GABAA receptor antagonists, pentylenetetrazol, bicuculline, and picrotoxin, the glycine antagonist, strychnine, and the NMDA receptor antagonist, memantine, on ethanol-induced behavioral sleep and body temperature were investigated. Pentylenetetrazol, bicuculline, and picrotoxin given prior and following ethanol reduced the behavioral sleep and potentiated the hypothermia caused by ethanol. However, convulsions appeared when bicuculline, but not pentylenetetrazol and picrotoxin, were given following ethanol. After the reversal of unconsciousness in rats without convulsions the animals remained awake throughout the experiments without motor incoordination, hyperexcitability, and sedation, but they were in hypothermia within 12 h. The glycine antagonist, strychnine, given prior or after ethanol had virtually no effect on ethanol-induced behavioral sleep and hypothermia. Ethanol given prior or following strychnine failed to antagonize strychnine-induced convulsions. The NMDA receptor antagonist, memantine, given following ethanol potentiated the behavioral sleep and had virtually no effect on hypothermia induced by ethanol. It is suggested that the ethanol-induced behavioral sleep may be attributed to its ability to enhance the GABAergic mechanisms and to inhibit NMDA-mediated excitatory responses. However, the ethanol-induced hypothermia may be ascribed solely to the facilitation of GABAergic transmission. Further, it is postulated that a bidirectional inhibitory system subserves the regulation of behavioral sleep and convulsions. However, one-way inhibitory system underlies the ethanol-induced hypothermia. PMID:9085718

  5. Andrographis paniculata ameliorates carbon tetrachloride (CCl(4))-dependent hepatic damage and toxicity: diminution of oxidative stress.

    PubMed

    Koh, Pei Hoon; Mokhtar, Ruzaidi Azli Mohd; Iqbal, Mohammad

    2011-01-01

    Andrographis paniculata (hempedu bumi) is a plant that possesses many medicinal values in treating several diseases and for health care maintenance. However, its hepatoprotective activity and mechanism of action have not been fully investigated. Therefore, this study aimed to evaluate the hepatoprotective effects of A. paniculata and its mechanism of action in rats. Carbon tetrachloride (CCl(4)) challenge of rats at a dose of 1.2 ml/kg body weight-induced oxidative stress in the liver. This was evidenced by augmentation in lipid peroxidation, which was accompanied by a decrease in the activities of antioxidant enzymes and depletion in the level of reduced glutathione (P < 0.05). Parrallel to these changes, CCl(4) challenge too, enhanced hepatic damage as evidenced by sharp increase in serum transaminases (e.g. alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase) (P < 0.05). Additionally, the impairment of liver function corresponded to histolopathological changes. However, most of these changes were reversed in a dose-dependent fashion by pre-treatment of animals with A. paniculata (P < 0.05). The ability of A. paniculata to scavenge the 2,2-Diphenyl-2-picrylhydrazyl radical was determined through its EC(50) value. The EC(50) value of A. paniculata was 583.60 ± 4.25 µg/ml. In addition, A. paniculata was found to contain 65.37 ± 1.20 mg/g total phenolics expressed as gallic acid equivalent. From these studies, it is concluded that A. paniculata could be used as a hepatoprotective agent and possesses the potential to treat or prevent degenerative diseases where oxidative stress is implicated. PMID:21801496

  6. Glycine inhibits ethanol-induced oxidative stress, neuroinflammation and apoptotic neurodegeneration in postnatal rat brain.

    PubMed

    Amin, Faiz Ul; Shah, Shahid Ali; Kim, Myeong Ok

    2016-06-01

    Here we investigated for the first time the inhibitory potential of Glycine (Gly) against ethanol-induced oxidative stress, neuroinflammation and apoptotic neurodegeneration in human neuroblastoma SH-SY5Y cells and in the developing rat brain. The Gly co-treatment significantly increased the cell viability, inhibited the expression of phospho-Nuclear Factor kappa B (p-NF-kB) and caspase-3 and reduced the oxidative stress in ethanol-treated SH-SY5Y cells in a PI3K-dependent manner. Seven days old male rat pups were injected with ethanol (5 g/kg subcutaneously, prepared in a 20% saline solution) and Gly (1 g/kg). Gly co-treatment stimulated the PI3K/Akt signaling pathway to limit the ethanol induced reactive oxygen species (ROS) production in the developing rat brain. It lowered the ethanol-elevated levels of phospho-c Jun N terminal kinase (p-JNK) and its various downstream apoptotic markers, including Bax, cytochrome C, caspase-3 and PARP-1. Additionally, the Gly treatment upregulated antiapoptotic Bcl-2 proteins and prevented ethanol-induced neurodegeneration as assessed by Fluoro-Jade-B (FJB) and Nissl staining. Furthermore, the Gly administration caused significant reduction in the ethanol-induced neuroinflammation by inhibiting the expression of inflammatory markers such as p-NF-kB, cyclooxygenase 2 (COX2) and tumor necrosis factor-α (TNF-α) and reversed the ethanol-induced synaptic protein markers expression. The results suggest that acute Gly treatment reduces ethanol-induced oxidative stress and neuronal cell loss in SH-SY5Y cells and in the developing rat brain. Therefore, Gly may be considered as potential treatment in ethanol-intoxicated newborns and infants. PMID:27058626

  7. Risk factors for damaged liver function after chemotherapy in hepatitis B virus carriers with non-Hodgkin lymphoma.

    PubMed

    Li, X; Fan, X W; Liu, W; Guo, L; Li, Y; Hu, X; Liang, X; Ma, X P; Yang, S E

    2015-01-01

    The goal of this study was to investigate damaged liver function after chemotherapy in hepatitis B virus (HBV) carriers with non-Hodgkin lymphoma (NHL) and to evaluate risk factors associated with a high risk of damaged liver function. Clinical histories of 134 HBV carriers with NHL who were treated with chemotherapy were obtained and analyzed for the occurrence of damaged liver function and other related high-risk factors. Analysis showed that 76 patients (56.7%) had damaged liver function after chemotherapy: 6 patients (7.9%) had I degree, 17 patients (22.4%) had II degree, 20 patients (26.3%) had III degree, and 33 patients (43.4%) had IV degree damage. After treatment, 18 patients (23.7%) continued to receive chemotherapy according to their original schedule, 39 patients (51.3%) delayed chemotherapy, 16 patients (21.1%) stopped chemotherapy, and 3 patients (3.9%) died. Analysis of a binary multivariate logistic regression model showed that administration of steroids was a high-risk factor for damaged liver function after chemotherapy in NHL patients. The incidence of damaged liver function after chemotherapy is high among HBV carriers with NHL; therefore, administration of steroid chemotherapy is a high-risk factor. PMID:25867413

  8. Early maternal separation affects ethanol-induced conditioning in a nor-BNI insensitive manner, but does not alter ethanol-induced locomotor activity.

    PubMed

    Pautassi, Ricardo Marcos; Nizhnikov, Michael E; Fabio, Ma Carolina; Spear, Norman E

    2012-01-01

    Early environmental stress significantly affects the development of offspring. This stress has been modeled in rats through the maternal separation (MS) paradigm, which alters the functioning of the HPA axis and can enhance ethanol intake at adulthood. Infant rats are sensitive to ethanol's reinforcing effects, which modulate ethanol seeking and intake. Little is known about the impact of MS on sensitivity to ethanol's appetitive and aversive effects during infancy. The present study assessed ethanol-induced conditioned place preference established through second-order conditioning (SOC), spontaneous or ethanol-induced locomotor activity and ethanol intake in preweanling rats that experienced normal animal facility rearing (AFR) or daily episodes of maternal separation (MS) during postnatal days 1-13 (PDs 1-13). Low-ethanol dose (0.5 g/kg) induced appetitive conditioned place preference (via SOC) in control rats given conventional rearing but not in rats given maternal separation in early infancy, whereas 2.0 g/kg ethanol induced aversive conditioned place preference in the former but not the latter. The administration of a kappa antagonist at PD 1 or immediately before testing did not alter ethanol-induced reinforcement. High (i.e., 2.5 and 2.0 g/kg) but not low (i.e., 0.5 g/kg) ethanol dose induced reliable motor stimulation, which was independent of early maternal separation. Ethanol intake and blood alcohol levels during conditioning were unaffected by rearing conditions. Pups given early maternal separation had lower body weights than controls and showed an altered pattern of exploration when placed in an open field. These results indicate that, when assessed in infant rats, earlier maternal separation alters the balance between the appetitive and aversive motivational effects of ethanol but has no effect on the motor activating effects of the drug. PMID:22108648

  9. The Preventive Effect on Ethanol-Induced Gastric Lesions of the Medicinal Plant Plumeria rubra: Involvement of the Latex Proteins in the NO/cGMP/K ATP Signaling Pathway.

    PubMed

    de Alencar, Nylane Maria Nunes; Pinheiro, Rachel Sindeaux Paiva; de Figueiredo, Ingrid Samantha Tavares; Luz, Patrícia Bastos; Freitas, Lyara Barbosa Nogueira; de Souza, Tamiris de Fátima Goebel; do Carmo, Luana David; Marques, Larisse Mota; Ramos, Marcio Viana

    2015-01-01

    Plumeria rubra (Apocynaceae) is frequently used in folk medicine for the treatment of gastrointestinal disorders, hepatitis, and tracheitis, among other infirmities. The aim of this study was to investigate the gastroprotective potential of a protein fraction isolated from the latex of Plumeria rubra (PrLP) against ethanol-induced gastric lesions and describe the underlying mechanisms. In a dose-dependent manner, the pretreatment with PrLP prevented ethanol-induced gastric lesions in mice after single intravenous administration. The gastroprotective mechanism of PrLP was associated with the involvement of prostaglandins and balance of oxidant/antioxidant factors. Secondarily, the NO/cGMP/KATP pathway and activation of capsaicin-sensitive primary afferents were also demonstrated as part of the mechanism. This study shows that proteins extracted from the latex of P. rubra prevent gastric lesions induced in experimental animals. Also, the results support the use of the plant in folk medicine. PMID:26788111

  10. The Preventive Effect on Ethanol-Induced Gastric Lesions of the Medicinal Plant Plumeria rubra: Involvement of the Latex Proteins in the NO/cGMP/KATP Signaling Pathway

    PubMed Central

    de Alencar, Nylane Maria Nunes; Pinheiro, Rachel Sindeaux Paiva; de Figueiredo, Ingrid Samantha Tavares; Luz, Patrícia Bastos; Freitas, Lyara Barbosa Nogueira; de Souza, Tamiris de Fátima Goebel; do Carmo, Luana David; Marques, Larisse Mota; Ramos, Marcio Viana

    2015-01-01

    Plumeria rubra (Apocynaceae) is frequently used in folk medicine for the treatment of gastrointestinal disorders, hepatitis, and tracheitis, among other infirmities. The aim of this study was to investigate the gastroprotective potential of a protein fraction isolated from the latex of Plumeria rubra (PrLP) against ethanol-induced gastric lesions and describe the underlying mechanisms. In a dose-dependent manner, the pretreatment with PrLP prevented ethanol-induced gastric lesions in mice after single intravenous administration. The gastroprotective mechanism of PrLP was associated with the involvement of prostaglandins and balance of oxidant/antioxidant factors. Secondarily, the NO/cGMP/KATP pathway and activation of capsaicin-sensitive primary afferents were also demonstrated as part of the mechanism. This study shows that proteins extracted from the latex of P. rubra prevent gastric lesions induced in experimental animals. Also, the results support the use of the plant in folk medicine. PMID:26788111

  11. Gastroprotective effects of Corchorus olitorius leaf extract against ethanol-induced gastric mucosal hemorrhagic lesions in rats

    PubMed Central

    Al Batran, Rami; Al-Bayaty, Fouad; Ameen Abdulla, Mahmood; Jamil Al-Obaidi, Mazen M; Hajrezaei, Maryam; Hassandarvish, Pouya; Fouad, Mustafa; Golbabapour, Shahram; Talaee, Samaneh

    2013-01-01

    Background and AimCorchorus olitorius is a medicinal plant traditionally utilized as an antifertility, anti-convulsive, and purgative agent. This study aimed to evaluate the gastroprotective effect of an ethanolic extract of C. olitorius against ethanol-induced gastric ulcers in adult Sprague Dawley rats. MethodsThe rats were divided into seven groups according to their pretreatment: an untreated control group, an ulcer control group, a reference control group (20 mg/kg omeprazole), and four experimental groups (50, 100, 200, or 400 mg/kg of extract). Carboxymethyl cellulose was the vehicle for the agents. Prior to the induction of gastric ulcers with absolute ethanol, the rats in each group were pretreated orally. An hour later, the rats were sacrificed, and gastric tissues were collected to evaluate the ulcers and to measure enzymatic activity. The tissues were subjected to histological and immunohistochemical evaluations. ResultsCompared with the extensive mucosal damage in the ulcer control group, gross evaluation revealed a marked protection of the gastric mucosa in the experimental groups, with significantly preserved gastric wall mucus. In these groups, superoxide dismutase and malondialdehyde levels were significantly increased (P < 0.05) and reduced (P < 0.05), respectively. In addition to the histologic analyses (HE and periodic acid-Schiff staining), immunohistochemistry confirmed the protection through the upregulation of Hsp70 and the downregulation of Bax proteins. The gastroprotection of the experimental groups was comparable to that of the reference control medicine omeprazole. ConclusionsOur study reports the gastroprotective property of an ethanolic extract of C. olitorius against ethanol-induced gastric mucosal hemorrhagic lesions in rats. PMID:23611708

  12. Effect of betaine on the hepatic damage from orotic acid-induced fatty liver development in rats.

    PubMed

    Cha, Jae-Young; Kim, Hyeong-Soo; Moon, Hyung-In; Cho, Young-Su

    2011-12-13

    Betaine prevents hepatic damage caused by ethanol and carbone tetrachloride (CCl4) in rats. Present study was to investigate the effect of betaine on the hepatic microsomal triglyceride transfer protein (MTP) mRNA expression in orotic acid (OA)-induced fatty liver in rats. OA feeding was attributed to the significant increase in the hepatic levels of triglyceride and the serum levels of ALT and AST and resulted in typical histology of fatty liver contained numerous largely fat droplets. While concomitant supplementation of betaine to OA diet was slightly reduced the hepatic triglyceride concentrations and was significantly decreased ALT activity. Hepatic MTP mRNA expression by OA treatment increased by 14% despite triglyceride accumulation in the liver in OA treatment rats relative to rats fed a normal diet without OA supplemented, but MTP expression by simultaneous supplementation of OA and betaine was slightly decreased by 7.9% as compared to the OA-feeding rats. A significant elevation of TBARS contents in the liver homogenate, microsome, and mitochondrial fractions of the OA-feeding rats compared with the normal rats, however, these increases were significantly or slightly decreased by simultaneous addition of OA and betaine. The increases of hepatic OA and betaine levels in OA feeding rats was also found when compared to the normal rats, but these increases were significantly lowered in the concomitant supplementation OA and betaine. The content of Fe was significantly increased in the OA feeding rats, but this elevation showed significantly recovered as low as the normal level by concomitant with OA and betaine. Zinc content was also significantly decreased in the OA feeding rats compared with the normal rats, but this reduction was more significantly elevated by concomitant with OA and betaine. Hepatic glutathione content in the OA feeding rats was similar to that of the normal rats, but this content was slightly reduced without statistically significant

  13. Curcuma aromatica Water Extract Attenuates Ethanol-Induced Gastritis via Enhancement of Antioxidant Status

    PubMed Central

    Jeon, Woo-Young; Lee, Mee-Young; Shin, In-Sik; Jin, Seong Eun; Ha, Hyekyung

    2015-01-01

    Curcuma aromatica is an herbal medicine and traditionally used for the treatment of various diseases in Asia. We investigated the effects of C. aromatica water extract (CAW) in the stomach of rats with ethanol-induced gastritis. Gastritis was induced in rats by intragastric administration of 5 mL/kg body weight of absolute ethanol. The CAW groups were given 250 or 500 mg of extract/kg 2 h before administration of ethanol, respectively. To determine the antioxidant effects of CAW, we determined the level of lipid peroxidation, the level of reduced glutathione (GSH), the activities of catalase, degree of inflammation, and mucus production in the stomach. CAW reduced ethanol-induced inflammation and loss of epithelial cells and increased the mucus production in the stomach. CAW reduced the increase in lipid peroxidation associated with ethanol-induced gastritis (250 and 500 mg/kg, p < 0.01, resp.) and increased mucosal GSH content (500 mg/kg, p < 0.01) and the activity of catalase (250 and 500 mg/kg, p < 0.01, resp.). CAW increased the production of prostaglandin E2. These findings suggest that CAW protects against ethanol-induced gastric mucosa injury by increasing antioxidant status. We suggest that CAW could be developed for the treatment of gastritis induced by alcohol. PMID:26483844

  14. Lithium blocks ethanol-induced modulation of protein kinases in the developing brain

    SciTech Connect

    Chakraborty, Goutam; Saito, Mitsuo; Mao, Rui-Fen; Wang, Ray; Vadasz, Csaba; Saito, Mariko

    2008-03-14

    Lithium has been shown to be neuroprotective against various insults including ethanol exposure. We previously reported that ethanol-induced apoptotic neurodegeneration in the postnatal day 7 (P7) mice is associated with decreases in phosphorylation levels of Akt, glycogen synthase kinase-3{beta} (GSK-3{beta}), and AMP-activated protein kinase (AMPK), and alteration in lipid profiles in the brain. Here, P7 mice were injected with ethanol and lithium, and the effects of lithium on ethanol-induced alterations in phosphorylation levels of protein kinases and lipid profiles in the brain were examined. Immunoblot and immunohistochemical analyses showed that lithium significantly blocked ethanol-induced caspase-3 activation and reduction in phosphorylation levels of Akt, GSK-3{beta}, and AMPK. Further, lithium inhibited accumulation of cholesterol ester (ChE) and N-acylphosphatidylethanolamine (NAPE) triggered by ethanol in the brain. These results suggest that Akt, GSK-3{beta}, and AMPK are involved in ethanol-induced neurodegeneration and the neuroprotective effects of lithium by modulating both apoptotic and survival pathways.

  15. ALTERED RA SIGNALING IN THE GENESIS OF ETHANOL-INDUCED LIMB DEFECTS

    EPA Science Inventory

    Altered RA Signaling in the Genesis of Ethanol-Induced Limb Defects

    Johnson CS(1), Sulik KK(1,2) Hunter, ES III(3)
    (1) Dept of Cell and Developmental Biology, UNC-Chapel Hill (2) Bowles Center for Alcohol Studies, UNC-CH (3) NHEERL, ORD, US EPA, RTP, NC

    Administr...

  16. Ethanol-Induced Alterations in Purkinje Neuron Dendrites in Adult and Aging Rats: a Review.

    PubMed

    Dlugos, Cynthia A

    2015-08-01

    Uncomplicated alcoholics suffer from discrete motor dysfunctions that become more pronounced with age. These deficits involve the structure and function of Purkinje neurons (PN), the sole output neurons from the cerebellar cortex. This review focuses on alterations to the PN dendritic arbor in the adult and aging Fischer 344 rat following lengthy alcohol consumption. It describes seminal studies using the Golgi-Cox method which proposed a model for ethanol-induced dendritic regression. Subsequent ultrastructural studies of PN dendrites showed dilation of the extensive smooth endoplasmic reticulum (SER) which preceded and accompanied dendritic regression. The component of the SER that was most affected by ethanol was the sarco/endoplasmic reticulum Ca(2+) ATPase pump (SERCA) responsible for resequestration of calcium into the SER. Ethanol-induced decreases in SERCA pump levels, similar to the finding of SER dilation, preceded and occurred concomitantly with dendritic regression. Discrete ethanol-induced deficits in balance also accompanied these decreases. Ethanol-induced ER stress within the SER of PN dendrites was proposed as an underlying cause of dendritic regression. It was recently shown that increased activation of caspase 12, inherent to the ER, occurred in PN of acute slices in ethanol-fed rats and was most pronounced following 40 weeks of ethanol treatment. These findings shed new light into alcohol-induced disruption in PN dendrites providing a new model for the discrete but critical changes in motor function in aging, adult alcoholics. PMID:25648753

  17. Zinc inhibits ethanol-induced HepG2 cell apoptosis

    SciTech Connect

    Szuster-Ciesielska, Agnieszka Plewka, Krzysztof; Daniluk, Jadwiga; Kandefer-Szerszen, Martyna

    2008-05-15

    Alcohol consumption produces a variety of metabolic alterations in liver cells, associated with ethanol oxidation and with nonoxidative metabolism of ethanol, among others apoptosis of hepatocytes. As zinc is known as a potent antioxidant and an inhibitor of cell apoptosis, the aim of this paper was to investigate whether zinc supplementation could inhibit ethanol-induced HepG2 apoptosis, and whether this inhibition was connected with attenuation of oxidative stress and modulation of FasR/FasL system expression. The results indicated that zinc supplementation significantly inhibited ethanol-induced HepG2 cell apoptosis (measured by cytochrome c release from mitochondria and caspase-3 activation) by attenuation of reactive oxygen species (ROS) production, increase in the cellular level of GSH, inhibition of ethanol-induced sFasR and FasL overexpression and caspase-8 activation. These results indicate that zinc can inhibit ethanol-induced hepatocyte apoptosis by several independent mechanisms, among others by an indirect antioxidative effect and probably by inhibition of caspase-8 and caspase-9 activation.

  18. Attrition of Hepatic Damage Inflicted by Angiotensin II with α-Tocopherol and β-Carotene in Experimental Apolipoprotein E Knock-out Mice.

    PubMed

    Gopal, Kaliappan; Gowtham, Munusamy; Sachin, Singh; Ravishankar Ram, Mani; Shankar, Esaki M; Kamarul, Tunku

    2015-01-01

    Angiotensin II is one of the key regulatory peptides implicated in the pathogenesis of liver disease. The mechanisms underlying the salubrious role of α-tocopherol and β-carotene on liver pathology have not been comprehensively assessed. Here, we investigated the mechanisms underlying the role of Angiotensin II on hepatic damage and if α-tocopherol and β-carotene supplementation attenuates hepatic damage. Hepatic damage was induced in Apoe(-/-)mice by infusion of Angiotensin II followed by oral administration with α-tocopherol and β-carotene-enriched diet for 60 days. Investigations showed fibrosis, kupffer cell hyperplasia, hepatocyte degeneration and hepatic cell apoptosis; sinusoidal dilatation along with haemorrhages; evidence of fluid accumulation; increased ROS level and increased AST and ALT activities. In addition, tPA and uPA were down-regulated due to 42-fold up-regulation of PAI-1. MMP-2, MMP-9, MMP-12, and M-CSF were down-regulated in Angiotensin II-treated animals. Notably, α-tocopherol and β-carotene treatment controlled ROS, fibrosis, hepatocyte degeneration, kupffer cell hyperplasia, hepatocyte apoptosis, sinusoidal dilatation and fluid accumulation in the liver sinusoids, and liver enzyme levels. In addition, PAI-1, tPA and uPA expressions were markedly controlled by β-carotene treatment. Thus, Angiotensin II markedly influenced hepatic damage possibly by restraining fibrinolytic system. We concluded that α-tocopherol and β-carotene treatment has salubrious role in repairing hepatic pathology. PMID:26670291

  19. Attrition of Hepatic Damage Inflicted by Angiotensin II with α-Tocopherol and β-Carotene in Experimental Apolipoprotein E Knock-out Mice

    PubMed Central

    Gopal, Kaliappan; Gowtham, Munusamy; Sachin, Singh; Ravishankar Ram, Mani; Shankar, Esaki M.; Kamarul, Tunku

    2015-01-01

    Angiotensin II is one of the key regulatory peptides implicated in the pathogenesis of liver disease. The mechanisms underlying the salubrious role of α-tocopherol and β-carotene on liver pathology have not been comprehensively assessed. Here, we investigated the mechanisms underlying the role of Angiotensin II on hepatic damage and if α-tocopherol and β-carotene supplementation attenuates hepatic damage. Hepatic damage was induced in Apoe−/−mice by infusion of Angiotensin II followed by oral administration with α-tocopherol and β-carotene-enriched diet for 60 days. Investigations showed fibrosis, kupffer cell hyperplasia, hepatocyte degeneration and hepatic cell apoptosis; sinusoidal dilatation along with haemorrhages; evidence of fluid accumulation; increased ROS level and increased AST and ALT activities. In addition, tPA and uPA were down-regulated due to 42-fold up-regulation of PAI-1. MMP-2, MMP-9, MMP-12, and M-CSF were down-regulated in Angiotensin II-treated animals. Notably, α-tocopherol and β-carotene treatment controlled ROS, fibrosis, hepatocyte degeneration, kupffer cell hyperplasia, hepatocyte apoptosis, sinusoidal dilatation and fluid accumulation in the liver sinusoids, and liver enzyme levels. In addition, PAI-1, tPA and uPA expressions were markedly controlled by β-carotene treatment. Thus, Angiotensin II markedly influenced hepatic damage possibly by restraining fibrinolytic system. We concluded that α-tocopherol and β-carotene treatment has salubrious role in repairing hepatic pathology. PMID:26670291

  20. Suppression of intralysosomal proteolysis aggravates structural damage and functional impairment of liver lysosomes in rats with toxic hepatitis

    SciTech Connect

    Korolenko, T.A.; Gavrilova, N.I.; Kurysheva, N.G.; Malygin, A.E.; Pupyshev, A.B.

    1986-01-01

    This paper estimates the effect of lowering protein catabolism in the lysosomes on structural and functional properties of the latter during liver damage. For comparison, polyvinylpyrrolidone (PVP), which is inert relative to intralysosomal proteolysis, and which also accumulates largely in lysosomes of the kupffer cells of the liver, was used. The uptake of labeled bovine serum albuman (C 14-BSA) by the liver is shown and the rate of intralysosomal proteolysis is given 24 hours after administration of suramin an CCl/sub 4/ to rats. It is suggested that it is risky to use drugs which inhibit intralysosomal proteolysis in the treatment of patients with acute hepatitis.

  1. Aripiprazole an atypical antipsychotic protects against ethanol induced gastric ulcers in rats

    PubMed Central

    Asmari, Abdulrahman Al; Arshaduddin, Mohammed; Elfaki, Ibrahim; Kadasah, Saeed; Robayan, Abdulrahman Al; Asmary, Saeed Al

    2014-01-01

    The present investigation was undertaken, to study the gastro-protective potential of aripiprazole (ARI) an atypical antipsychotic drug in ethanol induced gastric ulcers in rats. ARI (10, 30, 100 mg/kg) was tested for gastric secretion and antiulcer activity in different groups of male Sprague Dawley rats. Gastric secretion and acidity studies were performed in pylorus ligated rats while indices of gastric ulcers were measured in ethanol (1 ml-100%) induced gastric ulcers. Histological changes and the levels of gastric wall mucus, malondialdehyde (MDA), non-protein sulfhydryls (NP-SH), myeloperoxidase (MPO), and serotonin were used to assess ethanol induced gastric mucosal injuries. Exposure of rats to ethanol resulted in gastric mucosal injury and a high index of ulcer. Pretreatment with ARI significantly (P < 0.001), reduced the gastric lesions induced by ethanol and also resulted in a significant decrease in the gastric secretion, and total acidity in pylorus ligated rats. ARI also significantly attenuated the ethanol induced reduction in the levels of gastric wall mucus, and NP-SH (P < 0.001). The histological changes and the increased MDA and MPO activity were also significantly (P < 0.001) inhibited by ARI. Ethanol induced depletion in the levels of serotonin in the gastric tissue were also significantly restored by pretreatment with ARI (p < 0.001). ARI showed significant antiulcer and gastroprotective activity against ethanol induced gastric ulcers. The gastroprotective effects of ARI may be due to its anti-secretory, antioxidant and anti-inflammatory action and also due to the restoration of the depleted gastric serotonin levels. PMID:25232384

  2. Metabolic basis of ethanol-induced cytotoxicity in recombinant HepG2 cells: Role of nonoxidative metabolism

    SciTech Connect

    Wu Hai; Cai Ping; Clemens, Dahn L.; Jerrells, Thomas R.; Ansari, G.A. Shakeel; Kaphalia, Bhupendra S. . E-mail: bkaphali@utmb.edu

    2006-10-15

    Chronic alcohol abuse, a major health problem, causes liver and pancreatic diseases and is known to impair hepatic alcohol dehydrogenase (ADH). Hepatic ADH-catalyzed oxidation of ethanol is a major pathway for the ethanol disposition in the body. Hepatic microsomal cytochrome P450 (CYP2E1), induced in chronic alcohol abuse, is also reported to oxidize ethanol. However, impaired hepatic ADH activity in a rat model is known to facilitate a nonoxidative metabolism resulting in formation of nonoxidative metabolites of ethanol such as fatty acid ethyl esters (FAEEs) via a nonoxidative pathway catalyzed by FAEE synthase. Therefore, the metabolic basis of ethanol-induced cytotoxicity was determined in HepG2 cells and recombinant HepG2 cells transfected with ADH (VA-13), CYP2E1 (E47) or ADH + CYP2E1 (VL-17A). Western blot analysis shows ADH deficiency in HepG2 and E47 cells, compared to ADH-overexpressed VA-13 and VL-17A cells. Attached HepG2 cells and the recombinant cells were incubated with ethanol, and nonoxidative metabolism of ethanol was determined by measuring the formation of FAEEs. Significantly higher levels of FAEEs were synthesized in HepG2 and E47 cells than in VA-13 and VL-17A cells at all concentrations of ethanol (100-800 mg%) incubated for 6 h (optimal time for the synthesis of FAEEs) in cell culture. These results suggest that ADH-catalyzed oxidative metabolism of ethanol is the major mechanism of its disposition, regardless of CYP2E1 overexpression. On the other hand, diminished ADH activity facilitates nonoxidative metabolism of ethanol to FAEEs as found in E47 cells, regardless of CYP2E1 overexpression. Therefore, CYP2E1-mediated oxidation of ethanol could be a minor mechanism of ethanol disposition. Further studies conducted only in HepG2 and VA-13 cells showed lower ethanol disposition and ATP concentration and higher accumulation of neutral lipids and cytotoxicity (apoptosis) in HepG2 cells than in VA-13 cells. The apoptosis observed in HepG2 vs

  3. Multiphoton microscopy can visualize zonal damage and decreased cellular metabolic activity in hepatic ischemia-reperfusion injury in rats

    NASA Astrophysics Data System (ADS)

    Thorling, Camilla A.; Liu, Xin; Burczynski, Frank J.; Fletcher, Linda M.; Gobe, Glenda C.; Roberts, Michael S.

    2011-11-01

    Ischemia-reperfusion (I/R) injury is a common occurrence in liver surgery. In orthotopic transplantation, the donor liver is exposed to periods of ischemia and when oxygenated blood is reintroduced to the liver, oxidative stress may develop and lead to graft failure. The aim of this project was to investigate whether noninvasive multiphoton and fluorescence lifetime imaging microscopy, without external markers, were useful in detecting early liver damage caused by I/R injury. Localized hepatic ischemia was induced in rats for 1 h followed by 4 h reperfusion. Multiphoton and fluorescence lifetime imaging microscopy was conducted prior to ischemia and up to 4 h of reperfusion and compared to morphological and biochemical assessment of liver damage. Liver function was significantly impaired at 2 and 4 h of reperfusion. Multiphoton microscopy detected liver damage at 1 h of reperfusion, manifested by vacuolated cells and heterogeneous spread of damage over the liver. The damage was mainly localized in the midzonal region of the liver acinus. In addition, fluorescence lifetime imaging showed a decrease in cellular metabolic activity. Multiphoton and fluorescence lifetime imaging microscopy detected evidence of early I/R injury both structurally and functionally. This provides a simple noninvasive technique useful for following progressive liver injury without external markers.

  4. Epigallocatechin-3-O-Gallate Protects Against Hepatic Damage and Testicular Toxicity in Male Mice Exposed to Di-(2-Ethylhexyl) Phthalate.

    PubMed

    Ge, Jian; Han, Baoyu; Hu, Huajun; Liu, Jun; Liu, Yang

    2015-07-01

    The aim of this study was to examine the effects of epigallocatechin-3-O-gallate (EGCG) on hepatic damage and testicular toxicity in male mice exposed to daily oral administration of di-(2-ethylhexyl) phthalate (DEHP). A mouse model was used to assess the effects of daily intraperitoneal EGCG injection on hepatic and testicular damage. Histological and mitochondrial membrane potential results revealed that EGCG treatment significantly arrested the progression of hepatic damage. EGCG treatment resulted in significant suppression of liver injury (i.e., reduced activities of alanine aminotransferase [ALT] and aspartate aminotransferase [AST]). The development of DEHP-induced hepatic and testicular damage altered the testosterone concentration in mouse serum, which could affect the reproductive ability of male mice. Moreover, EGCG treatment markedly attenuated testes lesions, sperm deformity, and spermatogenic cell apoptosis. At the molecular level, hepatic CYP3A4 expression was substantially reduced by EGCG treatment in mice exposed to DEHP compounds, whereas testicular aromatase expression was increased significantly in testes. Thus, these results demonstrate that EGCG administration may protect against liver damage and reproductive toxicity in males exposed to DEHP. PMID:25789634

  5. Reversing gastric mucosal alterations during ethanol-induced chronic gastritis in rats by oral administration of Opuntia ficus-indica mucilage

    PubMed Central

    Vázquez-Ramírez, Ricardo; Olguín-Martínez, Marisela; Kubli-Garfias, Carlos; Hernández-Muñoz, Rolando

    2006-01-01

    AIM: To study the effect of mucilage obtained from cladodes of Opuntia ficus-indica (Cactaceae) on the healing of ethanol-induced gastritis in rats. METHODS: Chronic gastric mucosa injury was treated with mucilage (5 mg/kg per day) after it was induced by ethanol. Lipid composition, activity of 5’-nucleotidase (a membrane-associated ectoenzyme) and cytosolic activities of lactate and alcohol dehydrogenases in the plasma membrane of gastric mucosa were determined. Histological studies of gastric samples from the experimental groups were included. RESULTS: Ethanol elicited the histological profile of gastritis characterized by loss of the surface epithelium and infiltration of polymorphonuclear leukocytes. Phosphatidylcholine (PC) decreased and cholesterol content increased in plasma membranes of the gastric mucosa. In addition, cytosolic activity increased while the activity of alcohol dehydrogenases decreased. The administration of mucilage promptly corrected these enzymatic changes. In fact, mucilage readily accelerated restoration of the ethanol-induced histological alterations and the disturbances in plasma membranes of gastric mucosa, showing a univocal anti-inflammatory effect. The activity of 5’-nucleotidase correlated with the changes in lipid composition and the fluidity of gastric mucosal plasma membranes. CONCLUSION: The beneficial action of mucilage seems correlated with stabilization of plasma membranes of damaged gastric mucosa. Molecular interactions between mucilage monosaccharides and membrane phospholipids, mainly PC and phosphatidylethanolamine (PE), may be the relevant features responsible for changing activities of membrane-attached proteins during the healing process after chronic gastric mucosal damage. PMID:16865772

  6. Drug-induced hepatitis

    MedlinePlus

    Toxic hepatitis ... to get liver damage. Some drugs can cause hepatitis with small doses, even if the liver breakdown ... liver. Many different drugs can cause drug-induced hepatitis. Painkillers and fever reducers that contain acetaminophen are ...

  7. Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection.

    PubMed

    Larrubia, Juan R; Benito-Martínez, Selma; Calvino, Miryam; Sanz-de-Villalobos, Eduardo; Parra-Cid, Trinidad

    2008-12-21

    Chemokines produced in the liver during hepatitis C virus (HCV) infection induce migration of activated T cells from the periphery to infected parenchyma. The milieu of chemokines secreted by infected hepatocytes is predominantly associated with the T-helper cell/Tc1 T cell (Th1/Tc1) response. These chemokines consist of CCL3 (macrophage inflammatory protein-1 alpha; MIP-1 alpha), CCL4 (MIP-1 beta), CCL5 (regulated on activation normal T cell expressed and secreted; RANTES), CXCL10 (interferon-gamma-inducible protein-10; IP-10), CXCL11 (interferon-inducible T-cell alpha chemoattractant; I-TAC), and CXCL9 (monokine induced by interferon gamma; Mig) and they recruit T cells expressing either CCR5 or CXCR3 chemokine receptors. Intrahepatic and peripheral blood levels of these chemokines are increased during chronic hepatitis C. The interaction between chemokines and their receptors is essential in recruiting HCV-specific T cells to control the infection. When the adaptive immune response fails in this task, non-specific T cells without the capacity to control the infection are also recruited to the liver, and these are ultimately responsible for the persistent hepatic damage. The modulation of chemokine receptor expression and chemokine secretion could be a viral escape mechanism to avoid specific T cell migration to the liver during the early phase of infection, and to maintain liver viability during the chronic phase, by impairing non-specific T cell migration. Some chemokines and their receptors correlate with liver damage, and CXCL10 (IP-10) and CXCR3 levels have shown a clinical utility as predictors of treatment response outcome. The regulation of chemokines and their receptors could be a future potential therapeutic target to decrease liver inflammation and to increase specific T cell migration to the infected liver. PMID:19084927

  8. Influence of cytokine and cytokine receptor gene polymorphisms on the degree of liver damage in patients with chronic hepatitis C.

    PubMed

    Moreira, Sara Tatiana; Silva, Giovanni Faria; de Moraes, Camila Fernanda Verdichio; Grotto, Rejane Maria Tomasini; de Moura Campos Pardini, Maria Inês; Bicalho, Maria da Graça; Moliterno, Ricardo Alberto

    2016-09-01

    Hepatic fibrosis may be the result of repetitive injury to hepatocytes caused by HCV infection and the immune response to it. Cytokines regulate the inflammatory response to injury and modulate hepatic fibrogenesis. Single nucleotide polymorphisms (SNPs) located in cytokine genes may influence the cytokine expression and secretion that may contribute to hepatic fibrogenesis in HCV infection. The aim of this study was to determine the genotype of 22 SNPs found in the genes of 13 cytokines/cytokine receptors to assess the influence of polymorphic variants on the stage of liver damage in Brazilian patients chronically infected with HCV genotype 1 only. 141 unrelated patients were grouped according to their stage of fibrosis: absence of fibrosis or patients in the initial stages of fibrosis (F0-F2, n = 84), patients with advanced stages of fibrosis or cirrhosis (F3-F4, n = 57), without cirrhosis (F0-F3, n = 103), and with cirrhosis (F4, n = 38). The comparison of frequencies in each sub-sample was performed by 2 × 2 contingency tables using the chi-square or Fisher's exact test. Stepwise logistic regression was also used to assess independent associations between cirrhosis or fibrosis with polymorphic variants. The TNFA-308G:A genotype conferred increased risk of fibrosis and cirrhosis. The TNFA-238G:G genotype was associated with protection from cirrhosis. The IL10-819C:T genotype conferred protection from fibrosis and the IL1B-511C:T genotype conferred increased risk of cirrhosis. Some of these genotypes showed results on the borderline of statistical significance in the bivariate analysis. We conclude that gene variants of cytokines/receptors may influence liver damage in patients chronically infected by HCV genotype 1. PMID:27200267

  9. Influence of cytokine and cytokine receptor gene polymorphisms on the degree of liver damage in patients with chronic hepatitis C

    PubMed Central

    Moreira, Sara Tatiana; Silva, Giovanni Faria; de Moraes, Camila Fernanda Verdichio; Grotto, Rejane Maria Tomasini; de Moura Campos Pardini, Maria Inês; Bicalho, Maria da Graça; Moliterno, Ricardo Alberto

    2016-01-01

    Hepatic fibrosis may be the result of repetitive injury to hepatocytes caused by HCV infection and the immune response to it. Cytokines regulate the inflammatory response to injury and modulate hepatic fibrogenesis. Single nucleotide polymorphisms (SNPs) located in cytokine genes may influence the cytokine expression and secretion that may contribute to hepatic fibrogenesis in HCV infection. The aim of this study was to determine the genotype of 22 SNPs found in the genes of 13 cytokines/cytokine receptors to assess the influence of polymorphic variants on the stage of liver damage in Brazilian patients chronically infected with HCV genotype 1 only. 141 unrelated patients were grouped according to their stage of fibrosis: absence of fibrosis or patients in the initial stages of fibrosis (F0-F2, n = 84), patients with advanced stages of fibrosis or cirrhosis (F3-F4, n = 57), without cirrhosis (F0-F3, n = 103), and with cirrhosis (F4, n = 38). The comparison of frequencies in each sub-sample was performed by 2 × 2 contingency tables using the chi-square or Fisher's exact test. Stepwise logistic regression was also used to assess independent associations between cirrhosis or fibrosis with polymorphic variants. The TNFA-308G:A genotype conferred increased risk of fibrosis and cirrhosis. The TNFA-238G:G genotype was associated with protection from cirrhosis. The IL10-819C:T genotype conferred protection from fibrosis and the IL1B-511C:T genotype conferred increased risk of cirrhosis. Some of these genotypes showed results on the borderline of statistical significance in the bivariate analysis. We conclude that gene variants of cytokines/receptors may influence liver damage in patients chronically infected by HCV genotype 1. PMID:27200267

  10. Causes of death in fulminant hepatic failure and relationship to quantitative histological assessment of parenchymal damage.

    PubMed

    Gazzard, B G; Portmann, B; Murray-Lyon, I M; Williams, R

    1975-10-01

    The clinical course and causes of death in 132 consecutive patients with fulminant hepatic failure and grade III or IV encephalopathy have been reviewed. 105 patients died and in 96 of these an autopsy examination was performed. In 36 patients there was cerebral oedema and the mean age of this group was significantly younger than the other fatal cases. In 28 patients death was attributed to major haemorrhage which originated in the gastrointestinal tract in 25. The prothrombin time ratio was not significantly greater in patients with major bleeding than in those without but they did have a significantly lower platelet count. Sepsis contributed to death in 12 patients. In 25 patients massive hepatic necrosis only was found at autopsy and death was considered to be due solely to hepatic failure. The degree of hepatocyte loss was assessed in 80 fatal cases by a histological morphometric technique on a needle specimen of liver taken immediately post-mortem. The proportion of the liver volume occupied by hepatocytes (hepatocyte volume fraction, HVF) was greatly reduced in all patients (normal 85+/-SD 5 percent) but the mean value was significantly higher in the patients dying with sepsis, cerebral oedema or haemorrhage than in the group in whom death was attributed solely to hepatic failure. There were ten patients in whom liver function was improving at the time of death which was due to cerebral (9) or haemorrhage (1). These observations suggest that many patients presently dying from fulminant hepatic failure may be expected to survive, once more effective therapy is available for the complications of the illness. PMID:172938

  11. Comparative study of the damage produced by acute ethanol and acetaldehyde treatment in a human fetal hepatic cell line.

    PubMed

    Olivares, I P; Bucio, L; Souza, V; Cárabez, A; Gutiérrez-Ruiz, M C

    1997-06-27

    The effects of acute ethanol and acetaldehyde treatment on cell proliferation, cell adhesion capacity, neutral red incorporation into lysosomes, glutathione content, protein sulfhydryl compounds, lipid peroxidation, inner mitochondrial membrane integrity (MTT test), lactate dehydrogenase activity (LDH) and ultrastructural alterations were investigated in a human fetal hepatic cell line (WRL-68 cells). WRL-68 cells were used, due to the fact that, although this cell line expresses some hepatic characteristics, it does not express alcohol dehydrogenase or cytochrome P450 activity, so it could be a good model to study the effect of the toxic agents per se. Cells were exposed during 120 min with 200 mM ethanol or 10 mM acetaldehyde. Under these conditions, cells presented 100% viability and no morphological alteration was observed by light microscopy. Acetaldehyde-treated cells reduced their proliferative capacity drastically while the ethanol-treated ones presented no difference with control cells. Cell adhesion to substrate, measured as time required to adhere to the substrate and time required to detach from the substrate, was diminished in acetaldehyde WRL-68-treated cells. Cytotoxicity measures as neutral red and MTT test showed that acetaldehyde-treated cells presented more damage than ethanol-treated ones. Cellular respiratory capacity was compromised by acetaldehyde treatment due to 40% less oxygen consumption than control cells. Lipid peroxidation values, measured as malondialdehyde production, were higher in ethanol-treated WRL-68 cells (127%) than in acetaldehyde-treated ones (60%) to control cell values. Lactate dehydrogenase activity (LDH) in extracellular media of ethanol-treated cells presented the highest values. GSH content was reduced 95% and thiol protein content was diminished severely in acetaldehyde-treated cells. Transmission electron microscopy showed more ultrastructural alterations in cells treated with acetaldehyde. The results indicate that

  12. Resveratrol mitigate structural changes and hepatic stellate cell activation in N'-nitrosodimethylamine-induced liver fibrosis via restraining oxidative damage.

    PubMed

    Ahmad, Areeba; Ahmad, Riaz

    2014-09-25

    Resveratrol, a polyphenol, found in skin of red grapes, peanuts and berries possesses anti-inflammatory, anti-carcinogenic and lipid modulation properties. Here, we demonstrate in vivo antifibrotic activity of resveratrol in a mammalian model, wherein hepatic fibrosis was induced by N'-nitrosodimethylamine (NDMA) administration. Apart from being a potent hepatotoxin, NDMA is a known mutagen and carcinogen, as well. To induce hepatic fibrosis, rats were administered NDMA (i.p.) in 10mg/kgb.wt thrice/week for 21 days. Another group of animals received resveratrol supplement (10mg/kgb.wt) subsequent to NDMA administration and were sacrificed weekly. The changes in selected biomarkers were monitored to compare profibrotic effects of NDMA and antifibrotic activity of resveratrol. The selected biomarkers were: sera transaminases, ALP, bilirubin, liver glycogen, LPO, SOD, protein carbonyl content, ATPases (Ca(2+), Mg(2+), Na(+)/K(+)) and hydroxyproline/collagen content. Alterations in liver architecture were assessed by H&E, Masson's trichrome and reticulin staining of liver biopsies. Immuno-histochemistry and immunoblotting were employed to examine expression of α-SMA. Our results demonstrate that during NDMA-induced liver fibrosis transaminases, ALP, bilirubin, hydroxyproline and liver collagen increases, while liver glycogen is depleted. The decline in SOD (>65%) and ATPases, which were concomitant with the elevation in MDA and protein carbonyls, strongly indicate oxidative damage. Fibrotic transformation of liver in NDMA-treated rats was verified by histopathology, immuno-histochemistry and immunoblotting data, with the higher expressivity of α-SMA-positive HSCs being most established diagnostic immuno-histochemical marker of HSCs. Resveratrol-supplement refurbished liver architecture by significantly restoring levels of biomarkers of oxidative damage (MDA, SOD, protein carbonyls and membrane-bound ATPases). Therefore, we conclude that antifibrotic effect of

  13. Naltrexone Reverses Ethanol-Induced Rat Hippocampal and Serum Oxidative Damage

    PubMed Central

    Almansa, Inmaculada; Barcia, Jorge M.; López-Pedrajas, Rosa; Muriach, María; Miranda, María; Romero, Francisco Javier

    2013-01-01

    Naltrexone, an antagonist of μ-opioid receptors, is clinically used as adjuvant therapy of alcohol dishabituation. The aim of the present work was to test the effect of 1 mg/kg body weight of naltrexone to revert oxidative stress-related biochemical alterations, in the hippocampus and serum of chronic alcoholic adult rats. Malondialdehyde concentration was increased and glutathione peroxidase activity was decreased in hippocampus and serum of alcohol-treated rats. Naltrexone treatment restored these alterations. The in vitro antioxidant ability of Ntx could not justify these effects considering the doses used. Thus this apparent protective effect of Ntx can only be attributed to its pharmacological effects, as herein discussed. PMID:24363821

  14. Assessing the role of the medial preoptic area in ethanol-induced hypothermia.

    PubMed

    Westerman, Ashley T; Roma, Peter G; Price, Rebecca C; Dominguez, Juan M

    2010-05-01

    Administration of ethanol produces hypothermia. The preoptic area/anterior hypothalamus (POA/AH) contains warm- and cold-sensitive neurons that are important for temperature regulation. The present study evaluated the effect of ethanol on Fos immunoreactivity (Fos-ir) in the medial preoptic area (MPOA) and the effect of lesions to the MPOA on ethanol-induced hypothermia. Rats receiving 1.5-g/kg ethanol showed an increase in Fos-ir in the MPOA. However, lesions to the MPOA did not affect core body temperature. These findings indicate that ethanol increases neural activity in the MPOA, but this increased activity does not influence ethanol-induced changes in core body temperature. PMID:20302915

  15. Mechanisms of ethanol-induced degeneration in the developing, mature, and aging cerebellum.

    PubMed

    Jaatinen, Pia; Rintala, Jyrki

    2008-01-01

    The adverse effects of acute and chronic ethanol exposure on cerebellar functions have been acknowledged for decades, in terms of impaired control of movement and balance. In addition to the motor impairment, cerebellar degeneration has recently been shown to contribute to distinct neuropsychological deficits in chronic alcoholics, as well as in children with prenatal ethanol exposure. The basic mechanisms underlying these ethanol-induced functional alterations and the related neuropathology in the cerebellum have mostly been clarified only recently. These mechanisms include: (i) excitotoxicity; (ii) dietary factors, especially thiamine depletion; (iii) glial abnormalities; (iv) changes in growth factors; (v) apoptotic mechanisms; (vi) oxidative stress; and (vii) compromised energy production. Although these mechanisms widely apply not only to the mature cerebellum, but also to the developing and the aging cerebella, the developing and the aged cerebellum have some special characteristics, which may make them even more vulnerable to ethanol-induced degeneration. These special instances will be discussed along with the general mechanisms of ethanol-induced cerebellar degeneration. PMID:18418667

  16. Ethanol-Induced Neurodegeneration and Glial Activation in the Developing Brain.

    PubMed

    Saito, Mariko; Chakraborty, Goutam; Hui, Maria; Masiello, Kurt; Saito, Mitsuo

    2016-01-01

    Ethanol induces neurodegeneration in the developing brain, which may partially explain the long-lasting adverse effects of prenatal ethanol exposure in fetal alcohol spectrum disorders (FASD). While animal models of FASD show that ethanol-induced neurodegeneration is associated with glial activation, the relationship between glial activation and neurodegeneration has not been clarified. This review focuses on the roles of activated microglia and astrocytes in neurodegeneration triggered by ethanol in rodents during the early postnatal period (equivalent to the third trimester of human pregnancy). Previous literature indicates that acute binge-like ethanol exposure in postnatal day 7 (P7) mice induces apoptotic neurodegeneration, transient activation of microglia resulting in phagocytosis of degenerating neurons, and a prolonged increase in glial fibrillary acidic protein-positive astrocytes. In our present study, systemic administration of a moderate dose of lipopolysaccharides, which causes glial activation, attenuates ethanol-induced neurodegeneration. These studies suggest that activation of microglia and astrocytes by acute ethanol in the neonatal brain may provide neuroprotection. However, repeated or chronic ethanol can induce significant proinflammatory glial reaction and neurotoxicity. Further studies are necessary to elucidate whether acute or sustained glial activation caused by ethanol exposure in the developing brain can affect long-lasting cellular and behavioral abnormalities observed in the adult brain. PMID:27537918

  17. Deficient PKR in RAX/PKR Association Ameliorates Ethanol-Induced Neurotoxicity in the Developing Cerebellum.

    PubMed

    Li, Hui; Chen, Jian; Qi, Yuanlin; Dai, Lu; Zhang, Mingfang; Frank, Jacqueline A; Handshoe, Jonathan W; Cui, Jiajun; Xu, Wenhua; Chen, Gang

    2015-08-01

    Ethanol-induced neuronal loss is closely related to the pathogenesis of fetal alcohol spectrum disorders. The cerebellum is one of the brain areas that are most sensitive to ethanol. The mechanism underlying ethanol neurotoxicity remains unclear. Our previous in vitro studies have shown that the double-stranded RNA (dsRNA)-activated protein kinase (PKR) regulates neuronal apoptosis upon ethanol exposure and ethanol activates PKR through association with its intracellular activator RAX. However, the role of PKR and its interaction with RAX in vivo have not been investigated. In the current study, by utilizing N-PKR-/- mice, C57BL/6J mice with a deficient RAX-binding domain in PKR, we determined the critical role of RAX/PKR association in PKR-regulated ethanol neurotoxicity in the developing cerebellum. Our data indicate that while N-PKR-/- mice have a similar BAC profile as wild-type mice, ethanol induces less brain/body mass reduction as well as cerebellar neuronal loss. In addition, ethanol promotes interleukin-1β (IL-1β) secretion, and IL-1β is a master cytokine regulating inflammatory response. Importantly, ethanol-promoted IL-1β secretion is inhibited in the developing cerebellum of N-PKR-/- mice. Thus, RAX/PKR interaction and PKR activation regulate ethanol neurotoxicity in the developing cerebellum, which may involve ethanol-induced neuroinflammation. Further, PKR could be a possible target for pharmacological intervention to prevent or treat fetal alcohol spectrum disorder (FASD). PMID:25592072

  18. Role of neutrophilic elastase in ethanol induced injury to the gastric mucosa

    SciTech Connect

    Kvietys, P.R.; Carter, P.R. )

    1990-02-26

    Intragastric administration of ethanol (at concentrations likely to be encountered by the mucosa during acute intoxication) produces gastritis. Recent studies have implicated neutrophils in the gastric mucosal injury induced by luminal ethanol. The objective of the present study was to assess whether neutrophilic elastase contributes to the ethanol-induced gastric mucosal injury. Sprague-Dawley rats were instrumented for perfusion of the gastric lumen with saline or ethanol. Mucosal injury was quantitated by continuously measuring the blood-to-lumen clearance of {sup 51}Cr-EDTA. The experimental protocol consisted of a 40 minute control period (saline perfusion) followed by three successive 40 minute experimental periods (ethanol perfusion). During the three experimental periods the concentration of ethanol was progressively increased to 10, 20, and 30%. The experiments were performed in untreated animals and in animals pretreated with either Eglin c (an inhibitor of elastase and cathepsin G activity) or L 658 (a specific inhibitor of elastase activity). The effects of ethanol on EDTA clearance (x control) in untreated (n = 9) and L658 treated (n = 5) animals are shown in the Table below. Pretreatment with L 658 significantly attenuated the ethanol-induced increases in EDTA clearance. Pretreatment with Eglin c (n = 6) also provided some protection against ethanol-induced injury, but not to the extent as that provided by L658. The results of the authors studies suggest that neutrophilic elastase contributes to a gastric mucosal injury induced by luminal perfusion of the stomach with physiologically relevant concentrations of ethanol.

  19. Ethanol-induced loss of brain cyclic AMP binding proteins: correlation with growth suppression

    SciTech Connect

    Pennington, S.; Kalmus, G.

    1987-05-01

    Brain hypoplasia secondary to maternal ethanol consumption is a common fetal defect observed in all models of fetal alcohol syndrome. The molecular mechanism by which ethanol inhibits growth is unknown but has been hypothesized to involve ethanol-induced changes in the activity of cyclic-AMP stimulated protein kinase. Acute and chronic alcohol exposure elevate cyclic AMP level in many tissues, including brain. This increase in cyclic AMP should increase the phosphorylating activity of kinase by increasing the amount of dissociated (active) kinase catalytic subunit. In 7-day embryonic chick brains, ethanol-induced growth suppression was correlated with increased brain cyclic AMP content but neither basal nor cyclic AMP stimulated kinase catalytic activity was increased. However, the levels of cyclic AMP binding protein (kinase regulatory subunit) were significantly lowered by ethanol exposure. Measured as either /sup 3/H cyclic AMP binding or as 8-azido cyclic AM/sup 32/P labeling, ethanol-exposed brains had significantly less cyclic AMP binding activity (51 +/- 14 versus 29 +/- 10 units/..mu..g protein for 8-azido cyclic AMP binding). These findings suggest that ethanol's effect on kinase activity may involve more than ethanol-induced activation of adenylate cyclase.

  20. Tacrine, an oral acetylcholinesterase inhibitor, induced hepatic oxidative damage, which was blocked by liquiritigenin through GSK3-beta inhibition.

    PubMed

    Park, Sang Mi; Ki, Sung Hwan; Han, Nu Ri; Cho, Il Je; Ku, Sae Kwang; Kim, Sang Chan; Zhao, Rong Jie; Kim, Young Woo

    2015-01-01

    Although the cholinesterase inhibitor tacrine has been successfully used for the treatment of Alzheimer's disease, it is known to have hepatotoxic effects. Liquiritigenin (LQ), an active flavonoid in Glycyrrhizae radix, exerts protective effects against liver damage. This study investigated the toxic effect of tacrine on hepatocytes and the beneficial effect of LQ on tacrine intoxication in vivo and in vitro, and the underlying mechanism involved. In hepatocyte cell lines, tacrine induced cell death and oxidative stress, as indicated by decreases in cell viability and glutathione (GSH) contents, which were blocked by pretreatment with LQ. Fluorescent activated cell sorter (FACS) analysis revealed that LQ inhibited cellular H2O2 production and mitochondrial dysfunction induced by tacrine in HepG2 cells. Furthermore, LQ promoted inhibitory phosphorylation of glycogen synthase kinase-3β (GSK3β) and prevented decreases in GSK3β phosphorylation induced by tacrine. In rats treatment with tacrine at 30 mg/kg increased hepatic damage as assessed by blood biochemistry and histopathology. Administration of LQ (10 or 30 mg/kg/d, per os (p.o.)) or the hepatoprotective drug sylimarin (100 mg/kg/d) for 3 d inhibited elevations in alanine aminotransferase, aspartate aminotransferase, and histological changes induced by tacrine. These results show that LQ efficaciously protects the rat liver against tacrine-induced liver damage, and suggest that LQ is a therapeutic candidate for ameliorating the hepatotoxic effects of tacrine. PMID:25747977

  1. An experimental study on drugs for improving blood circulation and removing blood stasis in treating mild chronic hepatic damage.

    PubMed

    Xie, F; Li, X; Sun, K; Chu, Y; Cao, H; Chen, N; Wang, W; Liu, M; Liu, W; Mao, D

    2001-09-01

    Large and small doses of drugs for improving blood circulation and removing blood stasis were used in model rats to treat mild chronic hepatic damage induced by carbon tetrachloride (CCl4). The results show that large dose of Dang Gui ([symbol: see text] Radix Angelicae Sinensis) and Dan Shen ([symbol: see text] Radix Salviae Miltiorrhizae) (drugs for regulating blood flow) and small dose of Yu Jin ([symbol: see text] Radix Curcumae) and Niu Xi ([symbol: see text] Radix Achyranthis Bidentatae) (drugs for activating blood flow) can significantly elevate the activity of SOD (P < 0.05) and/or lower the T/K ratio, markedly reduce the MDA content (P < 0.05 or P < 0.01) and significantly decrease the activities of ALT and AST (P < 0.05 or P < 0.01), demonstrating that these drugs are effective in combating oxygen free radicals (OFR) in chronic liver damage. On the contrary, large dose of Tu Bie Chong ([symbol: see text] Eupolyphaga seu Steleophaga) and E Zhu ([symbol: see text] Rhizoma Curcumae) (drugs for removing blood stasis) tend to increase the ALT and AST (P < 0.05) activities. The results suggest that the synergism of elevation of the SOD activity and reduction of T/K ratio contributes to the action of drugs for improving blood circulation and removing blood stasis in combating the liver damage induced by CCl4. PMID:11789334

  2. Hepatoprotective effect of carob against acute ethanol-induced oxidative stress in rat.

    PubMed

    Souli, Abdelaziz; Sebai, Hichem; Chehimi, Latifa; Rtibi, Kaïs; Tounsi, Haifa; Boubaker, Samir; Sakly, Mohsen; El-Benna, Jamel; Amri, Mohamed

    2015-09-01

    The present study was undertaken to determine whether subacute treatment with aqueous extract of carob (Ceratonia siliqua L.) pods (AECPs) protects against ethanol (EtOH)-induced oxidative stress in rat liver. Animals were divided into four groups: control, carob, EtOH and EtOH + carob. Wistar rats were intraperitoneally pretreated with AECP (600 mg/kg body weight (bw)) during 7 days and intoxicated for 6 h by acute oral administration of EtOH (6 g/kg bw) 24 h after the last injection. We found that acute administration of EtOH leads to hepatotoxicity as monitored by the increase in the levels of hepatic marker aspartate aminotransferase and alanine aminotransferase as well as hepatic tissue injury. EtOH also increased the formation of malondialdehyde in the liver, indicating an increase in lipid peroxidation and depletion of antioxidant enzyme activities as superoxide dismutase, catalase and glutathione peroxidase. Subacute carob pretreatment prevented all the alterations induced by EtOH and returned their levels to near normal. Importantly, we showed that acute alcohol increased hepatic and plasmatic hydrogen peroxide and free iron levels. The carob pretreatment reversed EtOH effects to near control levels. These data suggest that carob could have a beneficial effect in inhibiting the oxidative damage induced by acute EtOH administration and that its mode of action may involve an opposite effect on plasma and tissue-free iron accumulation. Indeed, carob can be offered as a food additive to protect against EtOH-induced oxidative damage. PMID:23363576

  3. The gastroprotective effects of hydroalcoholic extract of Monolluma quadrangula against ethanol-induced gastric mucosal injuries in Sprague Dawley rats

    PubMed Central

    Ibrahim, Ibrahim Abdel Aziz; Abdulla, Mahmood Ameen; Hajrezaie, Maryam; Bader, Ammar; Shahzad, Naiyer; Al-Ghamdi, Saeed S; Gushash, Ahmad S; Hasanpourghadi, Mohadeseh

    2016-01-01

    Monolluma quadrangula (Forssk.) Plowes is used in Saudi traditional medicines to treat gastric ulcers. The hydroalcoholic extract of M. quadrangula (MHAE) was used in an in vivo model to investigate its gastroprotective effects against ethanol-induced acute gastric lesions in rats. Five groups of Sprague Dawley rats were used. The first group was treated with 10% Tween 20 as a control. The other four groups included rats treated with absolute ethanol (5 mL/kg) to induce an ulcer, rats treated with 20 mg/kg omeprazole as a reference drug, and rats treated with 150 or 300 mg/kg MHAE. One hour later, the rats were administered absolute ethanol (5 mL/kg) orally. Animals fed with MHAE exhibited a significantly increased pH, gastric wall mucus, and flattening of the gastric mucosa, as well as a decreased area of gastric mucosal damage. Histology confirmed the results; extensive destruction of the gastric mucosa was observed in the ulcer control group, and the lesions penetrated deep into the gastric mucosa with leukocyte infiltration of the submucosal layer and edema. However, gastric protection was observed in the rats pre-fed with plant extracts. Periodic acid–Schiff staining of the gastric wall revealed a remarkably intensive uptake of magenta color in the experimental rats pretreated with MHAE compared to the ulcer control group. Immunohistochemistry staining revealed an upregulation of the Hsp70 protein and a downregulation of the Bax protein in rats pretreated with MHAE compared with the control rats. Gastric homogenate showed significantly increased catalase and superoxide dismutase, and the level of malondialdehyde (MDA) was reduced in the rats pretreated with MHAE compared to the control group. In conclusion, MHAE exhibited a gastroprotective effect against ethanol-induced gastric mucosal injury in rats. The mechanism of this gastroprotection included an increase in pH and gastric wall mucus, an increase in endogenous enzymes, and a decrease in the level of

  4. Histopathological, oxidative damage, biochemical, and genotoxicity alterations in hepatic rats exposed to deltamethrin: modulatory effects of garlic (Allium sativum).

    PubMed

    Ncir, Marwa; Ben Salah, Ghada; Kamoun, Hassen; Makni Ayadi, Fatma; Khabir, Abdelmajid; El Feki, Abdelfattah; Saoudi, Mongi

    2016-06-01

    Deltamethrin is a pesticide widely used as a synthetic pyrethroid. The aim of this study was undertaken to investigate the effects of deltamethrin to induce oxidative stress and changes in biochemical parameters, hepatotoxicity and genotoxicity in female rats following a short-term (30 days) oral exposure and attenuation of these effects by Allium sativum extract. Indeed, Allium sativum is known to be a good antioxidant food resource which helps destroy free radical particles. Our results showed that deltamethrin treatment caused an increase in liver enzyme activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH); and hepatic lipid peroxidation (LPO) level. However, it induced a decrease in activities of hepatic catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) (p < 0.01). Allium sativum extract normalized significantly (p < 0.01) the mentioned parameters in deltamethrin-treated rats. For genotoxic evaluation, deltamethrin treatment showed a significant increase in frequencies of micronucleus in bone-marrow cells. Micronucleus formation is an indicator of chromosomal damage which has been increasingly used to detect the genotoxic potential of environmental pests. The present study showed that Allium sativum diminished the adverse effects induced by this synthetic pyrethroid insecticide. PMID:26974685

  5. Epigallocatechin-3-Gallate Inhibits Ethanol-Induced Apoptosis Through Neurod1 Regulating CHOP Expression in Pancreatic β-Cells.

    PubMed

    Wu, Tijun; Xiang, Jie; Shan, Wei; Li, Mengxiao; Zhou, Wenbo; Han, Xiao; Chen, Fang

    2016-05-01

    Epiga-llocatechin-3-gallate (EGCG) is one kind of polyphenol abundant extracted from green tea which has a potent antidiabetic activity. However, the molecular mechanisms mediating the protection procession of EGCG are still unclear. The aim of this study was to investigate the protective effect of EGCG on pancreatic β-cells exposed to ethanol and the possible underlying mechanisms. To observe the effect of EGCG, we assessed apoptosis in βTC-6 and INS-1 cells, which were in complete medium containing 60 mM ethanol, or coincubation with different concentration of EGCG. We also evaluated the roles of Neurod1 in CHOP expression and ethanol-mediated damage through plasmid overexpression. Treatment with EGCG decreased CHOP expression and apoptosis, whereas its treatment increased Neurod1 expression in ethanol-treated βTC-6 and INS-1 cells. Overexpression of Neurod1 caused the decrease of CHOP expression and apoptosis in ethanol-treated cells. Furthermore, Neurod1 inhibited CHOP expression by deacetylation of Histone H4 at the CHOP gene promoter. In addition, EGCG partially restores the activity of Neurod1 binding to CHOP promoter in ethanol-treated cells. In conclusion, EGCG protected β-cell against ethanol-induced β-cell apoptosis by Neurod1 regulating CHOP expression. Anat Rec, 299:573-582, 2016. © 2016 Wiley Periodicals, Inc. PMID:26916663

  6. Protective Effect of Areca catechu Leaf Ethanol Extract Against Ethanol-Induced Gastric Ulcers in ICR Mice.

    PubMed

    Lee, Kang Pa; Choi, Nan Hee; Sudjarwo, Giftania Wardani; Ahn, Sang-Hyun; Park, In-Sik; Lee, Sang-Rak; Hong, Heeok

    2016-02-01

    Gastric ulcer is a common digestive disorder that results in considerable suffering. Hence, this digestive pathology has been the focus of a number of recent studies. Although numerous drugs have been developed to treat gastric ulcers, therapeutic approaches for many of the complications associated with these drugs remain to be identified. For this reason, many natural compounds have been explored as alternatives for these drugs. In this study, we have investigated the effectiveness of Areca catechu leaf ethanol extract (ACE) for treating ethanol-induced gastric ulcers in mice. We performed histological as well as immunohistochemical examinations to explore the therapeutic properties of ACE. We also examined the levels of inflammatory signaling molecules to confirm the anti-inflammatory effects of ACE. The histochemical data demonstrate that ACE can protect the mucosal epithelium as well as the vascular supply in the gastric tract. Furthermore, ACE significantly reduced the expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 receptor (IL-6R), inducible NO synthase (iNOS), cyclooxygenase 2 (COX2), and nuclear factor-kappa B (NF-κB). Taken together, these data suggest that ACE administration may have the potential as an alternative treatment for gastric ulcer because of its cytoprotective and anti-inflammatory effects and ability to promote the rejuvenation and revascularization of the damaged gastric epithelium. PMID:26540449

  7. Antioxidant Properties and Gastroprotective Effects of 2-(Ethylthio)Benzohydrazones on Ethanol-Induced Acute Gastric Mucosal Lesions in Rats

    PubMed Central

    Ariffin, Azhar; Abdulla, Mahmood A.; Abdullah, Zanariah

    2016-01-01

    A series of new 2-(ethylthio)benzohydrazone derivatives (1–6) were prepared and characterised by IR, 1H NMR, and 13C NMR spectroscopy and mass spectrometry. The newly prepared compounds were screened for their in vitro antioxidant activities using free radical scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. Among them, most powerful antioxidant, compound 1 has been selected in order to illustrate anti-ulcer effect on ethanol-induced gastric mucosal lesions in rats. Four groups of Sprague Dawley rats were respectively treated with 10% Tween 20 as ulcer control group, 20 mg/kg omeprazole as reference group, 50 mg/kg and 100 mg/kg compound 1 as experimental animals. Macroscopically, ulcer control group showed extensive hemorrhagic lesions of gastric mucosa compared with omeprazole or compound 1. Rats pre-treated with compound 1 showed increased in gastric pH and gastric mucus. Histologically, ulcer control group showed severe damage to gastric mucosa with edema and leucocytes infiltration of submucosal layer. In immunohistochemical analysis, rats which were pre-treated with compound 1 showed up-regulation of HSP70 and down-regulation of Bax proteins. In conclusion, the gastroprotective effect of compound 1 may be due to its antioxidant activity, and/or due to up-regulation of HSP70 and down-regulation of Bax protein in stained tissue section. PMID:27272221

  8. Acute Toxicity and Gastroprotective Role of M. pruriens in Ethanol-Induced Gastric Mucosal Injuries in Rats

    PubMed Central

    Hassandarvish, Pouya; Abdul Majid, Nazia; Hadi, A. Hamid A.; Nordin, Noraziah; Abdulla, Mahmood A.

    2013-01-01

    The investigation was to evaluate gastroprotective effects of ethanolic extract of M. pruriens leaves on ethanol-induced gastric mucosal injuries in rats. Forty-eight rats were divided into 8 groups: negative control, extract control, ulcer control, reference control, and four experimental groups. As a pretreatment, the negative control and the ulcer control groups were orally administered carboxymethylcellulose (CMC). The reference control was administered omeprazole orally (20 mg/kg). The ethanolic extract of M. pruriens leaves was given orally to the extract control group (500 mg/kg) and the experimental groups (62.5, 125, 250, and 500 mg/kg). After 1 h, CMC was given orally to the negative and the extract control groups. The other groups received absolute ethanol. The rats were sacrificed after 1 h. The ulcer control group exhibited significant mucosal injuries with decreased gastric wall mucus and severe damage to the gastric mucosa. The extract caused upregulation of Hsp70 protein, downregulation of Bax protein, and intense periodic acid schiff uptake of glandular portion of stomach. Gastric mucosal homogenate showed significant antioxidant properties with increase in synthesis of PGE2, while MDA was significantly decreased. The ethanolic extract of M. pruriens leaves was nontoxic (<5 g/kg) and could enhance defensive mechanisms against hemorrhagic mucosal lesions. PMID:23781513

  9. Gastroprotective Activity of Polygonum chinense Aqueous Leaf Extract on Ethanol-Induced Hemorrhagic Mucosal Lesions in Rats

    PubMed Central

    Ismail, Iza Farhana; Abdul Majid, Nazia; Kadir, Farkaad A.; Al-Bayaty, Fouad; Awang, Khalijah

    2012-01-01

    Polygonum chinense is a Malaysian ethnic plant with various healing effects. This study was to determine preventive effect of aqueous leaf extract of P. chinense against ethanol-induced gastric mucosal injury in rats. Sprague Dawley rats were divided into seven groups. The normal and ulcer control groups were orally administered with distilled water. The reference group was orally administered with 20 mg/kg omeprazole. The experimental groups received the extracts 62.5, 125, 250, and 500 mg/kg, accordingly. After sixty minutes, distilled water and absolute ethanol were given (5 mL/kg) to the normal control and the others, respectively. In addition to histology, immunohistochemical and periodic acid schiff (PAS) stains, levels of lipid peroxidation, malondialdehyde (MDA), antioxidant enzymes, and superoxide dismutase (SOD) were measured. The ulcer group exhibited severe mucosal damages. The experimental groups significantly reduced gastric lesions and MDA levels and increased SOD level. Immunohistochemistry of the experimental groups showed upregulation and downregulation of Hsp70 and Bax proteins, respectively. PAS staining in these groups exhibited intense staining as compared to the ulcer group. Acute toxicity study revealed the nontoxic nature of the extract. Our data provide first evidence that P. chinense extract could significantly prevent gastric ulcer. PMID:23365597

  10. Acute toxicity and gastroprotective role of M. pruriens in ethanol-induced gastric mucosal injuries in rats.

    PubMed

    Golbabapour, Shahram; Hajrezaie, Maryam; Hassandarvish, Pouya; Abdul Majid, Nazia; Hadi, A Hamid A; Nordin, Noraziah; Abdulla, Mahmood A

    2013-01-01

    The investigation was to evaluate gastroprotective effects of ethanolic extract of M. pruriens leaves on ethanol-induced gastric mucosal injuries in rats. Forty-eight rats were divided into 8 groups: negative control, extract control, ulcer control, reference control, and four experimental groups. As a pretreatment, the negative control and the ulcer control groups were orally administered carboxymethylcellulose (CMC). The reference control was administered omeprazole orally (20 mg/kg). The ethanolic extract of M. pruriens leaves was given orally to the extract control group (500 mg/kg) and the experimental groups (62.5, 125, 250, and 500 mg/kg). After 1 h, CMC was given orally to the negative and the extract control groups. The other groups received absolute ethanol. The rats were sacrificed after 1 h. The ulcer control group exhibited significant mucosal injuries with decreased gastric wall mucus and severe damage to the gastric mucosa. The extract caused upregulation of Hsp70 protein, downregulation of Bax protein, and intense periodic acid schiff uptake of glandular portion of stomach. Gastric mucosal homogenate showed significant antioxidant properties with increase in synthesis of PGE2, while MDA was significantly decreased. The ethanolic extract of M. pruriens leaves was nontoxic (<5 g/kg) and could enhance defensive mechanisms against hemorrhagic mucosal lesions. PMID:23781513

  11. Acetaminophen increases the risk of arsenic-mediated development of hepatic damage in rats by enhancing redox-signaling mechanism.

    PubMed

    Majhi, Chhaya Rani; Khan, Saleem; Leo, Marie Dennis Marcus; Prawez, Shahid; Kumar, Amit; Sankar, Palanisamy; Telang, Avinash Gopal; Sarkar, Souvendra Nath

    2014-02-01

    We evaluated whether the commonly used analgesic-antipyretic drug acetaminophen can modify the arsenic-induced hepatic oxidative stress and also whether withdrawal of acetaminophen administration during the course of long-term arsenic exposure can increase susceptibility of liver to arsenic toxicity. Acetaminophen was co-administered orally to rats for 3 days following 28 days of arsenic pre-exposure (Phase-I) and thereafter, acetaminophen was withdrawn, but arsenic exposure was continued for another 28 days (Phase-II). Arsenic increased lipid peroxidation and reactive oxygen species (ROS) generation, depleted glutathione (GSH), and decreased superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione reductase (GR) activities. Acetaminophen caused exacerbation of arsenic-mediated lipid peroxidation and ROS generation and further enhancement of serum alanine aminotransferase and aspartate aminotransferase activities. In Phase-I, acetaminophen caused further GSH depletion and reduction in SOD, catalase, GPx and GR activities, but in Phase-II, only GPx and GR activities were more affected. Arsenic did not alter basal and inducible nitric oxide synthase (iNOS)-mediated NO production, but decreased constitutive NOS (cNOS)-mediated NO release. Arsenic reduced expression of endothelial NOS (eNOS) and iNOS genes. Acetaminophen up-regulated eNOS and iNOS expression and NO production in Phase-I, but reversed these effects in Phase-II. Results reveal that acetaminophen increased the risk of arsenic-mediated hepatic oxidative damage. Withdrawal of acetaminophen administration also increased susceptibility of liver to hepatotoxicity. Both ROS and NO appeared to mediate lipid peroxidation in Phase-I, whereas only ROS appeared responsible for peroxidative damage in Phase-II. PMID:22120977

  12. Uptake, cellular distribution and DNA damage produced by mercuric chloride in a human fetal hepatic cell line.

    PubMed

    Bucio, L; García, C; Souza, V; Hernández, E; González, C; Betancourt, M; Gutiérrez-Ruiz, M C

    1999-01-25

    A human hepatic cell line (WRL-68 cells) was employed to investigate the uptake of the toxic heavy metal mercury. Hg accumulation in WRL-68 cells is a time and concentration dependent process. A rapid initial phase of uptake was followed by a second slower phase. The transport does not require energy and at low HgCl2 concentrations (<50 microM) Hg transport occurs by temperature-insensitive processes. Subcellular distribution of Hg was: 48% in mitochondria, 38% in nucleus and only 8% in cytosolic fraction and 7% in microsomes. Little is known at the molecular level concerning the genotoxic effects following the acute exposure of eucaryotic cells to low concentrations of Hg. Our results showed that Hg induced DNA single-strand breaks or alkali labile sites using the single-cell gel electrophoresis assay (Comet assay). The percentage of damaged nucleus and the average length of DNA migration increased as metal concentration and time exposure increased. Lipid peroxidation, determined as malondialdehyde production in the presence of thiobarbituric acid, followed the same tendency, increased as HgCl2 concentration and time of exposure increased. DNA damage recovery took 8 h after partial metal removed with PBS-EGTA. PMID:10029678

  13. Ambient temperature effects on taste aversion conditioned by ethanol: contribution of ethanol-induced hypothermia.

    PubMed

    Cunningham, C L; Niehus, J S; Bachtold, J F

    1992-12-01

    Six experiments examined the effects of low (5-10 degrees C), normal (21 degrees C), or high (32 degrees) ambient temperature on conditioned taste aversion and body temperature changes produced by ethanol, lithium chloride, or morphine sulfate. Fluid-deprived rats received five to seven taste conditioning trials at 48-hr intervals. On each trial, access to saccharin at normal ambient temperature was followed by injection of drug or saline and placement for 6 hr into a temperature-controlled enclosure. Exposure to low ambient temperature facilitated, whereas exposure to high ambient temperature retarded acquisition of ethanol-induced conditioned taste aversion. The ability of an alteration in ambient temperature to influence conditioned taste aversion varied as a function of ethanol dose and was related to ambient temperature's effect on ethanol-induced hypothermia. More specifically, strength of conditioned taste aversion was negatively correlated with core body temperature after ethanol injection. Alterations in ambient temperature alone did not affect ingestion of a paired flavor solution in the absence of drug. Moreover, alterations in ambient temperature did not appear to influence conditioned taste aversion by changing ethanol pharmacokinetics. Finally, high and low ambient temperature did not affect development of taste aversion conditioned by lithium chloride or morphine sulfate. The overall pattern of data presented by these experiments supports the hypothesis that ambient-temperature influences strength of ethanol-induced conditioned taste aversion by altering the hypothermic response to ethanol. More generally, these data support the suggestion that body temperature change induced by ethanol is related to ethanol's aversive motivational effects and may be involved in modulating ethanol intake. PMID:1471766

  14. Nicotinamide Protects against Ethanol-Induced Apoptotic Neurodegeneration in the Developing Mouse Brain

    PubMed Central

    Ieraci, Alessandro; Herrera, Daniel G

    2006-01-01

    Background Exposure to alcohol during brain development may cause a neurological syndrome called fetal alcohol syndrome (FAS). Ethanol induces apoptotic neuronal death at specific developmental stages, particularly during the brain-growth spurt, which occurs from the beginning of third trimester of gestation and continues for several years after birth in humans, whilst occuring in the first two postnatal weeks in mice. Administration of a single dose of ethanol in 7-d postnatal (P7) mice triggers activation of caspase-3 and widespread apoptotic neuronal death in the forebrain, providing a possible explanation for the microencephaly observed in human FAS. The present study was aimed at determining whether nicotinamide may prevent ethanol-induced neurodegeneration. Methods and Findings P7 mice were treated with a single dose of ethanol (5g/kg), and nicotinamide was administered from 0 h to 8 h after ethanol exposure. The effects of nicotinamide on ethanol-induced activation of caspase-3 and release of cytochrome-c from the mitochondria were analyzed by Western blot ( n = 4–7/group). Density of Fluoro-Jade B–positive cells and NeuN-positive cells was determined in the cingulated cortex, CA1 region of the hippocampus, and lateral dorsal nucleus of the thalamus ( n = 5–6/group). Open field, plus maze, and fear conditioning tests were used to study the behavior in adult mice ( n = 31–34/group). Nicotinamide reduced the activation of caspase-3 (85.14 ± 4.1%) and the release of cytochrome-c (80.78 ± 4.39%) in postnatal mouse forebrain, too. Nicotinamide prevented also the ethanol-induced increase of apoptosis. We demonstrated that ethanol-exposed mice showed impaired performance in the fear conditioning test and increased activity in the open field and in the plus maze. Administration of nicotinamide prevented all these behavioral abnormalities in ethanol-exposed mice. Conclusions Our findings indicate that nicotinamide can prevent some of the deleterious effects

  15. Protective effect of dieckol isolated from Ecklonia cava against ethanol caused damage in vitro and in zebrafish model.

    PubMed

    Kang, Min-Cheol; Kim, Kil-Nam; Kang, Sung-Myung; Yang, Xiudong; Kim, Eun-A; Song, Choon Bok; Nah, Jae-Woon; Jang, Mi-Kyeong; Lee, Jung-Suck; Jung, Won-Kyo; Jeon, You-Jin

    2013-11-01

    In the present study, the protective effects of phlorotannins isolated from Ecklonia cava against ethanol-induced cell damage and apoptosis were investigated both in vitro and in vivo. Three phlorotannin compounds, namely phloroglucinol, eckol and dieckol, were successively isolated and identified from the extract. Dieckol showed the strongest protective effect against ethanol-induced cell apoptosis in Chang liver cells, with the lowest cytotoxicity. It was observed that dieckol reduced cell apoptosis through activation of Bcl-xL and PARP, and down-regulation of Bax and caspase-3 in Western blot analyses. In the in vivo study, the protective effect of ethanol induced by dieckol was investigated in a zebrafish model. The dieckol treated group scavenged intracellural reactive oxygen species and prevented lipid peroxidation and ethanol induced cell death in the zebrafish embryo. In conclusion, dieckol isolated from E. cava might possess a potential protective effect against ethanol-induced liver diseases. PMID:24189014

  16. Acquisition and reinstatement of ethanol-induced conditioned place preference in rats: Effects of the cholinesterase inhibitors donepezil and rivastigmine.

    PubMed

    Gawel, Kinga; Labuz, Krzysztof; Gibula-Bruzda, Ewa; Jenda, Malgorzata; Marszalek-Grabska, Marta; Silberring, Jerzy; Kotlinska, Jolanta H

    2016-07-01

    The present study examined the influence of the cholinesterase inhibitors donepezil (a selective inhibitor of acetylcholinesterase) and rivastigmine (also an inhibitor of butyrylcholinesterase) on the acquisition and reinstatement of ethanol-induced conditioned place preference (CPP) in rats. Before the CPP procedure, animals received a single injection of ethanol (0.5 g/kg, 10% w/v, intraperitoneally [i.p.]) for 15 days. The ethanol-induced CPP (biased method) was developed by four injections of ethanol (0.5 g/kg, 10% w/v, i.p.) every second day. Control rats received saline instead of ethanol. Donepezil (0.5, 1 or 3 mg/kg, i.p.) or rivastigmine (0.03, 0.5 or 1 mg/kg, i.p.) were administered before ethanol during conditioning or before the reinstatement of ethanol-induced CPP. The cholinesterase inhibitors were equally effective in increasing (dose dependently) the acquisition of ethanol-induced CPP. Furthermore, priming injections of both inhibitors reinstated (cross-reinstatement) the ethanol-induced CPP with similar efficacy. These effects of both cholinesterase inhibitors were reversed by mecamylamine (3 mg/kg, i.p.), a nicotinic acetylcholine receptor antagonist, but not by scopolamine (0.5 mg/kg, i.p.), a muscarinic acetylcholine receptor antagonist. Thus, our results show that the cholinergic system is involved in the reinforcing properties of ethanol, and nicotinic acetylcholine receptors play an important role in the relapse to ethanol-seeking behaviour. PMID:27097732

  17. Salvia miltiorrhiza Bunge Blocks Ethanol-Induced Synaptic Dysfunction through Regulation of NMDA Receptor-Dependent Synaptic Transmission

    PubMed Central

    Park, Hye Jin; Lee, Seungheon; Jung, Ji Wook; Lee, Young Choon; Choi, Seong-Min; Kim, Dong Hyun

    2016-01-01

    Consumption of high doses of ethanol can lead to amnesia, which often manifests as a blackout. These blackouts experienced by ethanol consumers may be a major cause of the social problems associated with excess ethanol consumption. However, there is currently no established treatment for preventing these ethanol-induced blackouts. In this study, we tested the ethanol extract of the roots of Salvia miltiorrhiza (SM) for its ability to mitigate ethanol-induced behavioral and synaptic deficits. To test behavioral deficits, an object recognition test was conducted in mouse. In this test, ethanol (1 g/kg, i.p.) impaired object recognition memory, but SM (200 mg/kg) prevented this impairment. To evaluate synaptic deficits, NMDA receptor-mediated excitatory postsynaptic potential (EPSP) and long-term potentiation (LTP) in the mouse hippocampal slices were tested, as they are known to be vulnerable to ethanol and are associated with ethanol-induced amnesia. SM (10 and 100 μg/ml) significantly ameliorated ethanol-induced long-term potentiation and NMDA receptor-mediated EPSP deficits in the hippocampal slices. Therefore, these results suggest that SM prevents ethanol-induced amnesia by protecting the hippocampus from NMDA receptor-mediated synaptic transmission and synaptic plasticity deficits induced by ethanol. PMID:27257009

  18. Salvia miltiorrhiza Bunge Blocks Ethanol-Induced Synaptic Dysfunction through Regulation of NMDA Receptor-Dependent Synaptic Transmission.

    PubMed

    Park, Hye Jin; Lee, Seungheon; Jung, Ji Wook; Lee, Young Choon; Choi, Seong-Min; Kim, Dong Hyun

    2016-07-01

    Consumption of high doses of ethanol can lead to amnesia, which often manifests as a blackout. These blackouts experienced by ethanol consumers may be a major cause of the social problems associated with excess ethanol consumption. However, there is currently no established treatment for preventing these ethanol-induced blackouts. In this study, we tested the ethanol extract of the roots of Salvia miltiorrhiza (SM) for its ability to mitigate ethanol-induced behavioral and synaptic deficits. To test behavioral deficits, an object recognition test was conducted in mouse. In this test, ethanol (1 g/kg, i.p.) impaired object recognition memory, but SM (200 mg/kg) prevented this impairment. To evaluate synaptic deficits, NMDA receptor-mediated excitatory postsynaptic potential (EPSP) and long-term potentiation (LTP) in the mouse hippocampal slices were tested, as they are known to be vulnerable to ethanol and are associated with ethanol-induced amnesia. SM (10 and 100 μg/ml) significantly ameliorated ethanol-induced long-term potentiation and NMDA receptor-mediated EPSP deficits in the hippocampal slices. Therefore, these results suggest that SM prevents ethanol-induced amnesia by protecting the hippocampus from NMDA receptor-mediated synaptic transmission and synaptic plasticity deficits induced by ethanol. PMID:27257009

  19. Combination of Alcohol and Fructose Exacerbates Metabolic Imbalance in Terms of Hepatic Damage, Dyslipidemia, and Insulin Resistance in Rats

    PubMed Central

    Schultze, Frank Christian; Wilting, Jörg; Mihm, Sabine; Raddatz, Dirk; Ramadori, Giuliano

    2014-01-01

    Although both alcohol and fructose are particularly steatogenic, their long-term effect in the development of a metabolic syndrome has not been studied in vivo. Consumption of fructose generally leads to obesity, whereas ethanol can induce liver damage in the absence of overweight. Here, Sprague-Dawley rats were fed ad libitum for 28 days on five diets: chow (control), liquid Lieber-DeCarli (LDC) diet, LDC +30%J of ethanol (L-Et) or fructose (L-Fr), and LDC combined with 30%J ethanol and 30%J fructose (L-EF). Body weight (BW) and liver weight (LW) were measured. Blood and liver samples were harvested and subjected to biochemical tests, histopathological examinations, and RT-PCR. Alcohol-containing diets substantially reduced the food intake and BW (≤3rd week), whereas fructose-fed animals had higher LW than controls (P<0.05). Additionally, leukocytes, plasma AST and leptin levels were the highest in the fructose-administered rats. Compared to the chow and LDC diets, the L-EF diet significantly elevated blood glucose, insulin, and total-cholesterol levels (also vs. the L-Et group). The albumin and Quick-test levels were the lowest, whereas ALT activity was the highest in the L-EF group. Moreover, the L-EF diet aggravated plasma triglyceride and reduced HDL-cholesterol levels more than 2.7-fold compared to the sum of the effects of the L-Et and L-Fr diets. The decreased hepatic insulin clearance in the L-EF group vs. control and LDC groups was reflected by a significantly decreased C-peptide:insulin ratio. All diets except the control caused hepatosteatosis, as evidenced by Nile red and H&E staining. Hepatic transcription of insulin receptor substrate-1/2 was mainly suppressed by the L-Fr and L-EF diets. The L-EF diet did not enhance the mitochondrial β-oxidation of fatty acids (Cpt1α and Ppar-α expressions) compared to the L-Et or L-Fr diet. Together, our data provide evidence for the coaction of ethanol and fructose with a high-fat-diet on dyslipidemia and

  20. Chronic ethanol treatment potientials ethanol-induced increases in interstitial nucleus accumbens endocannabinoid levels in rats

    PubMed Central

    Alvarez-Jaimes, Lily; Stouffer, David G.; Parsons, Loren H.

    2013-01-01

    We employed in vivo microdialysis to characterize the effect of an ethanol challenge injection on endocannabinoid levels in the nucleus accumbens of ethanol-naïve and chronic ethanol-treated rats. Ethanol (0.75 and 2 g/kg, i.p.) dose-dependently increased dialysate 2-arachidonoylglycerol (to a maximum 157 ± 20% of baseline) and decreased anandamide (to a minimum 52 ± 9% of baseline) in ethanol-naïve rats. The endocannabinoid clearance inhibitor N-(4-hydrophenyl) arachidonoylamide (AM404; 3 mg/kg) potentiated ethanol effects on 2-arachidonoylglycerol levels but did not alter ethanol-induced decreases in anandamide. AM404 alone did not alter dialysate levels of either endocannabinoid. Then, we characterized the effect of ethanol challenge on nucleus accumbens endocannabinoid levels in rats previously maintained on an ethanol-containing liquid diet. Ethanol challenge produced a greater and more prolonged increase in 2-arach-idonoylglycerol (to a maximum 394 ± 135% of baseline) in ethanol-experienced than in ethanol-naïve rats. The profile in ethanol-experienced rats was similar to that produced by AM404 pre-treatment in ethanol-naïve rats. AM404 in ethanol-experienced rats led to a further enhancement in the 2-arachidonoylglycerol response to ethanol challenge (to a maximum 704 ± 174% of baseline). Our findings demonstrate that ethanol-induced increases in nucleus accumbens 2-arachidonoylglycerol are potentiated in animals with a history of ethanol consumption. PMID:19650871

  1. Structure and preventive effects against ethanol-induced gastric ulcer of an expolysaccharide from Lachnum sp.

    PubMed

    Xu, Ping; Yang, Liu; Yuan, Ru-Yue; Ye, Zi-Yang; Ye, Hui-Ran; Ye, Ming

    2016-05-01

    An extracellular polysaccharide of Lachnum sp. (LEP) was purified by DEAE-cellulose 52 column chromatography and Sepharose CL-6B column chromatography. LEP-2a was identified to be a homogeneous component with an average molecular weight of 3.22×10(4)Da. The structure of LEP-2a was characterized by chemical and spectroscopic methods, including methylation analysis, periodate oxidation-smith degradation, infrared spectroscopy and NMR analysis. Results indicated that LEP-2a was a (1→3)-,(1→6)-β-D-Glcp, whose branch chain was consist of two d-glucopyranosyl residues linked by β-1,3-glycosidic linkage, which was linked at C6 of the backbone chain by β-1,6-glycosidic linkage. To study the protective effects of LEP-2a on the ethanol-induced gastric ulcer in mice, LEP-2a (100, 200 and 400mg/kg/d) was given to mice by gavage for 2 weeks. Results showed that LEP-2a significantly decreased the ulcer bleeding areas, pepsin activity, gastric juice volume, gastric juice total acidity and the malondialdehyde (MDA) content in serum. Meanwhile, the superoxide dismutase (SOD) increased significantly. The above findings suggested that LEP-2a had a significant preventive effect against the ethanol-induced gastric ulcer. PMID:26774377

  2. Acetaminophen fails to inhibit ethanol-induced subjective effects in human volunteers.

    PubMed

    Pickworth, W B; Klein, S A; George, F R; Henningfield, J E

    1992-01-01

    In animals, ethanol causes some of its CNS effects by releasing prostaglandins (PG); this is demonstrated by reports that prostaglandin synthetase inhibitors (PGSIs) diminish ethanol-induced effects. However, use of animals in these studies has precluded testing for subjective effects. We studied the interaction of ethanol and acetaminophen, a PGSI, in a double-blind crossover experiment. Six adult males were given no drug or acetaminophen (0, 325, 650, 1300 or 1950 mg) 75 min before ethanol (total dose = 0.625 g/kg; five divided doses). Physiologic, subjective and performance measures were collected. Compared to the no drug condition, ethanol significantly increased ratings of drug "liking," "drunk," "sluggish" and "drug strength" and decreased ratings of "sober." Ethanol increased heart rate and acetaminophen did not diminish or enhance this effect. The failure to antagonize ethanol-induced subjective and physiologic effects by acetaminophen in humans may be due to species differences or inadequate dosage of the PGSI. It is also possible that subjective and certain physiologic effects of ethanol in humans are not mediated by prostaglandin-dependent neural processes. Nevertheless, the finding that at greater than typical analgesic doses, acetaminophen failed to prevent subjective effects of ethanol is of clinical significance. PMID:1539069

  3. Ethanol induces calcium influx via the Cch1-Mid1 transporter in Saccharomyces cerevisiae.

    PubMed

    Courchesne, William E; Vlasek, Christopher; Klukovich, Rachel; Coffee, Sara

    2011-05-01

    Yeast suffers from a variety of environmental stresses, such as osmotic pressure and ethanol produced during fermentation. Since calcium ions are protective for high concentrations of ethanol, we investigated whether Ca(2+) flux occurs in response to ethanol stress. We find that exposure of yeast to ethanol induces a rise in the cytoplasmic concentration of Ca(2+). The response is enhanced in cells shifted to high-osmotic media containing proline, galactose, sorbitol, or mannitol. Suspension of cells in proline and galactose-containing media increases the Ca(2+) levels in the cytoplasm independent of ethanol exposure. The enhanced ability for ethanol to induce Ca(2+) flux after the hypertonic shift is transient, decreasing rapidly over a period of seconds to minutes. There is partial recovery of the response after zymolyase treatment, suggesting that cell wall integrity affects the ethanol-induced Ca(2+) flux. Acetate inhibits the Ca(2+) accumulation elicited by the ethanol/osmotic stress. The Ca(2+) flux is primarily via the Cch1 Ca(2+) influx channel because strains carrying deletions of the cch1 and mid1 genes show greater than 90% reduction in Ca(2+) flux. Furthermore, a functional Cch1 channel reduced growth inhibition by ethanol. PMID:21259000

  4. Cytochrome P450 2E1 inhibition prevents hepatic carcinogenesis induced by diethylnitrosamine in alcohol-fed rats

    PubMed Central

    Ye, Qinyuan; Lian, Fuzhi; Chavez, Pollyanna R.G.; Chung, Jayong; Ling, Wenhua; Qin, Hua; Seitz, Helmut K.

    2012-01-01

    Chronic alcohol ingestion increases hepatic cytochrome P450 2E1 (CYP2E1), which is associated with hepatocarcinogenesis. We investigated whether treatment with chlormethiazole (CMZ), a CYP2E1 inhibitor, protects against alcohol-associated hepatic carcinogenesis in rats. Rats were fed either an ethanol liquid diet or a non-ethanol liquid diet, with or without CMZ for one and ten months. A single intraperitoneal injection of diethylnitrosamine (DEN, 20 mg/kg) was given to initiate hepatic carcinogenesis. CYP2E1 expression, inflammatory proteins, cell proliferation, protein-bound 4-HNE, etheno-DNA adducts, 8-hydroxy-2'-deoxyguanosine (8-OHdG), retinoid concentrations, and hepatic carcinogenesis were examined. Ethanol feeding for 1 month with DEN resulted in significantly increased hepatic CYP2E1 levels and increased nuclear accumulation of NF-κB protein and TNF-α expression, which were associated with increased cyclin D1 expression and p-GST positive altered hepatic foci. All of these changes induced by ethanol feeding were significantly inhibited by the one month CMZ treatment. At 10-months of treatment, hepatocellular adenomas were detected in ethanol-fed rats only, but neither in control rats nor in animals receiving ethanol and CMZ. The 8-OHdG formation was found to be significantly increased in ethanol fed animals and normalized with CMZ treatment. In addition, alcohol-reduced hepatic retinol and retinoic acid concentrations were restored by CMZ treatment to normal levels in the rats at 10 months of treatment. These data demonstrate that the inhibition of ethanol-induced CYP2E1 as a key pathogenic factor can counteract the tumor-promoting action of ethanol by decreasing TNF-α expression, NF-κB activation, and oxidative DNA damage as well as restoring normal hepatic levels of retinoic acid in DEN-treated rats. PMID:23543859

  5. Cytochrome P450 2E1 inhibition prevents hepatic carcinogenesis induced by diethylnitrosamine in alcohol-fed rats.

    PubMed

    Ye, Qinyuan; Lian, Fuzhi; Chavez, Pollyanna R G; Chung, Jayong; Ling, Wenhua; Qin, Hua; Seitz, Helmut K; Wang, Xiang-Dong

    2012-12-01

    Chronic alcohol ingestion increases hepatic cytochrome P450 2E1 (CYP2E1), which is associated with hepatocarcinogenesis. We investigated whether treatment with chlormethiazole (CMZ), a CYP2E1 inhibitor, protects against alcohol-associated hepatic carcinogenesis in rats. Rats were fed either an ethanol liquid diet or a non-ethanol liquid diet, with or without CMZ for one and ten months. A single intraperitoneal injection of diethylnitrosamine (DEN, 20 mg/kg) was given to initiate hepatic carcinogenesis. CYP2E1 expression, inflammatory proteins, cell proliferation, protein-bound 4-HNE, etheno-DNA adducts, 8-hydroxy-2'-deoxyguanosine (8-OHdG), retinoid concentrations, and hepatic carcinogenesis were examined. Ethanol feeding for 1 month with DEN resulted in significantly increased hepatic CYP2E1 levels and increased nuclear accumulation of NF-κB protein and TNF-α expression, which were associated with increased cyclin D1 expression and p-GST positive altered hepatic foci. All of these changes induced by ethanol feeding were significantly inhibited by the one month CMZ treatment. At 10-months of treatment, hepatocellular adenomas were detected in ethanol-fed rats only, but neither in control rats nor in animals receiving ethanol and CMZ. The 8-OHdG formation was found to be significantly increased in ethanol fed animals and normalized with CMZ treatment. In addition, alcohol-reduced hepatic retinol and retinoic acid concentrations were restored by CMZ treatment to normal levels in the rats at 10 months of treatment. These data demonstrate that the inhibition of ethanol-induced CYP2E1 as a key pathogenic factor can counteract the tumor-promoting action of ethanol by decreasing TNF-α expression, NF-κB activation, and oxidative DNA damage as well as restoring normal hepatic levels of retinoic acid in DEN-treated rats. PMID:23543859

  6. The role of growth factors on hepatic damage in rats with obstructive jaundice.

    PubMed

    Turk, Ozgur; Badak, Bartu; Ates, Ersin; Dundar, Emine; Sutken, Emine

    2016-01-01

    In this study, we investigated the affect and the role of growth factors on liver damage. 110 Sprague-Dawley rats were divided into 11 groups: a sham group, a control group, HGF, EGF, IGF, TGF groups of irreversible jaundiced rats and a control group and HGF, EGF, IGF, and TGF groups of reversible jaundiced rats (n = 10). In the irreversible jaundiced groups, the common bile duct was explorated, double ligated, and cut. 150 μg/kg/day HGF, 5 μg/kg/day EGF, 5 μg/kg/day IGF, and 5 μg/kg/day TGF β-1 were injected intraperitoneally after the seventh post-operative day. In the reversible jaundiced group, the common bile duct was ligated and the ligation was resolved on the seventh post-operative day. For 5 days, growth factors were injected at the same dose. Ductal proliferation scores significantly decreased after growth factor administration in the EGF-A and TGF-A groups. Furthermore, ductal proliferation was decreased in the TGF-B group. As a result of this study, HGF was effective in the irreversible jaundiced groups and ineffective in the reversible jaundice groups. EGF was effective in the reversible jaundiced groups and ineffective in the irreversible jaundiced groups. In both the irreversible jaundiced and reversible jaundiced groups, IGF was ineffective, although TGF β-1 was effective. We believe that these results arise from the positive effects of effective doses of growth factor on liver damage. PMID:27540507

  7. Nelumbo nucifera leaves protect hydrogen peroxide-induced hepatic damage via antioxidant enzymes and HO-1/Nrf2 activation.

    PubMed

    Je, Jae-Young; Lee, Da-Bin

    2015-06-01

    Naturally occurring phenolic compounds are widely found in plants. Here, the phenolic composition and hepatoprotective effect of the butanolic extract (BE) from Nelumbo nucifera leaves against H2O2-induced hepatic damage in cultured hepatocytes were investigated. BE showed high total phenol and flavonoid contents, and major phenolic compounds are quercetin, catechin, ferulic acid, rutin, and protocatechuic acid by HPLC analysis. BE effectively scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-azino-bis(3-ethylbenzthiazoline)-6-sulfonic acid (ABTS) cation radicals (IC50 values of 5.21 μg mL(-1) for DPPH and 6.22 μg mL(-1) for ABTS(+)) and showed strong reducing power. Pretreatment of BE prior to 650 μM H2O2 exposure markedly increased cell viability and suppressed H2O2-induced intracellular reactive oxygen species generation and AAPH-induced cell membrane lipid peroxidation. In addition, BE up-regulated intracellular glutathione levels under normal and oxidative stress conditions. Notably, the hepatoprotective effect of BE was directly correlated with the increased expression of superoxide dismutase-1 (SOD-1) by 0.62-fold, catalase (CAT) by 0.42-fold, and heme oxygenase-1 (HO-1) by 2.4-fold. Pretreatment of BE also increased the nuclear accumulation of Nrf2 by 8.1-fold indicating that increased SOD-1, CAT, and HO-1 expressions are Nrf2-mediated. PMID:25962859

  8. Hepatoprotective potential of Lavandula coronopifolia extracts against ethanol induced oxidative stress-mediated cytotoxicity in HepG2 cells.

    PubMed

    Farshori, Nida Nayyar; Al-Sheddi, Ebtsam S; Al-Oqail, Mai M; Hassan, Wafaa H B; Al-Khedhairy, Abdulaziz A; Musarrat, Javed; Siddiqui, Maqsood A

    2015-08-01

    The present investigations were carried out to study the protective potential of four extracts (namely petroleum ether extract (LCR), chloroform extract (LCM), ethyl acetate extract (LCE), and alcoholic extract (LCL)) of Lavandula coronopifolia on oxidative stress-mediated cell death induced by ethanol, a known hepatotoxin in human hapatocellular carcinoma (HepG2) cells. Cells were pretreated with LCR, LCM, LCE, and LCL extracts (10-50 μg/ml) of L. coronopifolia for 24 h and then ethanol was added and incubated further for 24 h. After the exposure, cell viability using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and neutral red uptake assays and morphological changes in HepG2 cells were studied. Pretreatment with various extracts of L. coronpifolia was found to be significantly effective in countering the cytotoxic responses of ethanol. Antioxidant properties of these L. coronopifolia extracts against reactive oxygen species (ROS) generation, lipid peroxidation (LPO), and glutathione (GSH) levels induced by ethanol were investigated. Results show that pretreatment with these extracts for 24 h significantly inhibited ROS generation and LPO induced and increased the GSH levels reduced by ethanol. The data from the study suggests that LCR, LCM, LCE, and LCL extracts of L. coronopifolia showed hepatoprotective activity against ethanol-induced damage in HepG2 cells. However, a comparative study revealed that the LCE extract was found to be the most effective and LCL the least effective. The hepatoprotective effects observed in the study could be associated with the antioxidant properties of these extracts of L. coronopifolia. PMID:23546397

  9. Anti-ulcerogenic effect of cavidine against ethanol-induced acute gastric ulcer in mice and possible underlying mechanism.

    PubMed

    Li, Weifeng; Wang, Xiumei; Zhang, Hailin; He, Zehong; Zhi, Wenbing; Liu, Fang; Wang, Yu; Niu, Xiaofeng

    2016-09-01

    Cavidine, a major alkaloid compound isolated from Corydalis impatiens, has various pharmacological effects but its effect on gastric ulcer has not been previously explored. The current study aimed to investigate the possible anti-ulcerogenic potential of cavidine in the model of ethanol-induced gastric ulcer. Mice received cavidine (1, 5 or 10mg/kg, ig), cimetidine (CMD, 100mg/kg, ig) or vehicle at 12h and 1h before absolute ethanol administration (0.5mL/100g), and animals were euthanized 3h after ethanol ingestion. Gross and histological gastric lesions, biochemical, immunological and Western blot parameters were taken into consideration. The results showed that ethanol administration produced apparent mucosal injuries with morphological and histological damage, whereas cavidine pre-treatment reduced the gastric injuries. Cavidine pre-treatment also ameliorated the contents of malonaldehyde (MDA) and myeloperoxidase (MPO) activity, and increased the mucosa levels of glutathione (GSH), superoxide dismutase (SOD) and prostaglandin E2 (PGE2), relative to the model group. Also cavidine was able to decrease the levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), inhibit the up-regulation of cyclo-oxygenase-2 (COX-2) expression and activation of Nuclear factor-kappa B (NF-κB) pathway. Taken together, these results indicated that cavidine exerts a gastroprotective effect against gastric ulceration, and the underlying mechanism might be associated with the stimulation of PGE2, reduction of oxidative stress, suppression of NF-κB expression and subsequent reduced COX-2 and pro-inflammatory cytokines. PMID:27380619

  10. Gastroprotective activity of Annona muricata leaves against ethanol-induced gastric injury in rats via Hsp70/Bax involvement

    PubMed Central

    Moghadamtousi, Soheil Zorofchian; Rouhollahi, Elham; Karimian, Hamed; Fadaeinasab, Mehran; Abdulla, Mahmood Ameen; Kadir, Habsah Abdul

    2014-01-01

    The popular fruit tree of Annona muricata L. (Annonaceae), known as soursop and graviola, is a widely distributed plant in Central and South America and tropical countries. Leaves of A. muricata have been reported to possess antioxidant and anti-inflammatory activities. In this study, the gastroprotective effects of ethyl acetate extract of A. muricata leaves (EEAM) were investigated against ethanol-induced gastric injury models in rats. The acute toxicity test of EEAM in rats, carried out in two doses of 1 g/kg and 2 g/kg, showed the safety of this plant, even at the highest dose of 2 g/kg. The antiulcer study in rats (five groups, n=6) was performed with two doses of EEAM (200 mg/kg and 400 mg/kg) and with omeprazole (20 mg/kg), as a standard antiulcer drug. Gross and histological features showed the antiulcerogenic characterizations of EEAM. There was significant suppression on the ulcer lesion index of rats pretreated with EEAM, which was comparable to the omeprazole effect in the omeprazole control group. Oral administration of EEAM to rats caused a significant increase in the level of nitric oxide and antioxidant activities, including catalase, glutathione, and superoxide dismutase associated with attenuation in gastric acidity, and compensatory effect on the loss of gastric wall mucus. In addition, pretreatment of rats with EEAM caused significant reduction in the level of malondialdehyde, as a marker for oxidative stress, associated with an increase in prostaglandin E2 activity. Immunohistochemical staining also demonstrated that EEAM induced the downregulation of Bax and upregulation of Hsp70 proteins after pretreatment. Collectively, the present results suggest that EEAM has a promising antiulcer potential, which could be attributed to its suppressive effect against oxidative damage and preservative effect toward gastric wall mucus. PMID:25378912

  11. In Vivo Antioxidant and Antiulcer Activity of Parkia speciosa Ethanolic Leaf Extract against Ethanol-Induced Gastric Ulcer in Rats

    PubMed Central

    Al Batran, Rami; Al-Bayaty, Fouad; Jamil Al-Obaidi, Mazen M.; Abdualkader, Abdualrahman Mohammed; Hadi, Hamid A.; Ali, Hapipah Mohd; Abdulla, Mahmood Ameen

    2013-01-01

    Background The current study was carried out to examine the gastroprotective effects of Parkia speciosa against ethanol-induced gastric mucosa injury in rats. Methodology/Principal Findings Sprague Dawley rats were separated into 7 groups. Groups 1–2 were orally challenged with carboxymethylcellulose (CMC); group 3 received 20 mg/kg omeprazole and groups 4–7 received 50, 100, 200 and 400 mg/kg of ethanolic leaf extract, respectively. After 1 h, CMC or absolute ethanol was given orally to groups 2–7. The rats were sacrificed after 1 h. Then, the injuries to the gastric mucosa were estimated through assessment of the gastric wall mucus, the gross appearance of ulcer areas, histology, immunohistochemistry and enzymatic assays. Group 2 exhibited significant mucosal injuries, with reduced gastric wall mucus and severe damage to the gastric mucosa, whereas reductions in mucosal injury were observed for groups 4–7. Groups 3–7 demonstrated a reversal in the decrease in Periodic acid-Schiff (PAS) staining induced by ethanol. No symptoms of toxicity or death were observed during the acute toxicity tests. Conclusion Treatment with the extract led to the upregulation of heat-shock protein 70 (HSP70) and the downregulation of the pro-apoptotic protein BAX. Significant increases in the levels of the antioxidant defense enzymes glutathione (GSH) and superoxide dismutase (SOD) in the gastric mucosal homogenate were observed, whereas that of a lipid peroxidation marker (MDA) was significantly decreased. Significance was defined as p<0.05 compared to the ulcer control group (Group 2). PMID:23724090

  12. Gastric mucosal cell proliferation in ethanol-induced chronic mucosal injury is related to oxidative stress and lipid peroxidation in rats.

    PubMed

    Hernández-Muñoz, R; Montiel-Ruíz, C; Vázquez-Martínez, O

    2000-08-01

    The oxygen free radicals-induced lipid peroxidation (LP) has been implicated in the pathogenesis of acute ethanol-induced gastric mucosal lesions. However, the role of LP in the generation of chronic gastric mucosal injury is unknown. We have developed a model of chronic mucosal injury induced by continuous ethanol ingestion for 5 days and characterized by marked alterations in plasma membranes from gastric mucosa. Therefore, LP was evaluated in this experimental model. Indicators of peroxidative activity, mucosal glutathione content, thymidine kinase activity (an index of cell proliferation), and histamine H2-receptor (H2R) binding constants were quantified in animals undergoing gastric mucosal damage. The effect of famotidine, a H2R antagonist that readily ameliorates the chronic mucosal injury, was also tested. Increased free radicals and LP levels were detected during gastritis; however, a second, higher peak of LP was noted in mucosal plasma membranes after ethanol withdrawal (recovery period). This further increase of LP coincided with active cell proliferation, decreased mucosal glutathione levels, and diminished specific cimetidine binding by H2R. Administration of famotidine accelerated the mucosal proliferative process, inducing the second lipoperoxidative episode sooner, and preserved the content of glutathione. In addition, LP correlated directly with cell proliferation and inversely with mucosal membrane cimetidine binding. In conclusion, LP seems to be involved in chronic ethanol-induced gastric mucosal injury. However, a further enhancement of plasma membrane LP occurred, associated with increased DNA synthesis and diminished cimetidine binding by membrane H2R. Therefore, increased LP could also participate in the compensatory mucosal proliferation initiated after ethanol withdrawal. PMID:10950107

  13. PPARδ agonist attenuates alcohol-induced hepatic insulin resistance and improves liver injury and repair

    PubMed Central

    Pang, Maoyin; de la Monte, Suzanne M.; Longato, Lisa; Tong, Ming; He, Jiman; Chaudhry, Rajeeve; Duan, Kevin; Ouh, Jiyun; Wands, Jack R.

    2009-01-01

    Background/Aims Chronic ethanol exposure impairs liver regeneration due to inhibition of insulin signaling and oxidative injury. PPAR agonists function as insulin sensitizers and anti-inflammatory agents. We investigated whether treatment with a PPARδ agonist could restore hepatic insulin sensitivity, survival signaling, and regenerative responses vis-a-vis chronic ethanol feeding. Methods Adult rats were fed isocaloric liquid diets containing 0% or 37% ethanol, and administered a PPARδ agonist by i.p. injection. We used liver tissue to examine histopathology, gene expression, oxidative stress, insulin signaling, and regenerative responses to 2/3 hepatectomy. Results Chronic ethanol feeding caused insulin resistance, increased oxidative stress, lipid peroxidation, DNA damage, and hepatocellular injury in liver. These effects were associated with reduced insulin receptor binding and affinity, impaired survival signaling through PI3K/Akt/GSK3β, and reduced expression of insulin responsive genes mediating energy metabolism and tissue remodeling. PPARδ agonist treatment reduced ethanol-mediated hepatic injury, oxidative stress, lipid peroxidation, and insulin resistance, increased signaling through PI3K/Akt/GSK3β, and enhanced the regenerative response to partial hepatectomy. Conclusions PPARδ agonist administration may attenuate the severity of chronic ethanol-induced liver injury and ethanol’s adverse effects on the hepatic repair by restoring insulin responsiveness, even in the context of continued high-level ethanol consumption. PMID:19398227

  14. Protective Effect of Tyrosol and S-Adenosylmethionine against Ethanol-Induced Oxidative Stress of Hepg2 Cells Involves Sirtuin 1, P53 and Erk1/2 Signaling.

    PubMed

    Stiuso, Paola; Bagarolo, Maria Libera; Ilisso, Concetta Paola; Vanacore, Daniela; Martino, Elisa; Caraglia, Michele; Porcelli, Marina; Cacciapuoti, Giovanna

    2016-01-01

    Oxidative stress plays a major role in ethanol-induced liver damage, and agents with antioxidant properties are promising as therapeutic opportunities in alcoholic liver disease. In the present work, we investigated the effect of S-adenosylmethionine (AdoMet), Tyrosol (Tyr), and their combination on HepG2 cells exposed to ethanol exploring the potential molecular mechanisms. We exposed HepG2 cells to 1 M ethanol for 4 and 48 h; thereafter, we recorded a decreased cell viability, increase of intracellular reactive oxygen species (ROS) and lipid accumulation, and the release into culture medium of markers of liver disease such as triacylglycerol, cholesterol, transaminases, albumin, ferritin, and homocysteine. On the other hand, AdoMet and Tyrosol were able to attenuate or antagonize these adverse changes induced by acute exposure to ethanol. The protective effects were paralleled by increased Sirtuin 1 protein expression and nuclear translocation and increased ERK1/2 phosphorylation that were both responsible for the protection of cells from apoptosis. Moreover, AdoMet increased p53 and p21 expression, while Tyrosol reduced p21 expression and enhanced the expression of uncleaved caspase 3 and 9, suggesting that its protective effect may be related to the inhibition of the apoptotic machinery. Altogether, our data show that AdoMet and Tyrosol exert beneficial effects in ethanol-induced oxidative stress in HepG2 cells and provide a rationale for their potential use in combination in the prevention of ethanol-induced liver damage. PMID:27128904

  15. Protective Effect of Tyrosol and S-Adenosylmethionine against Ethanol-Induced Oxidative Stress of Hepg2 Cells Involves Sirtuin 1, P53 and Erk1/2 Signaling

    PubMed Central

    Stiuso, Paola; Bagarolo, Maria Libera; Ilisso, Concetta Paola; Vanacore, Daniela; Martino, Elisa; Caraglia, Michele; Porcelli, Marina; Cacciapuoti, Giovanna

    2016-01-01

    Oxidative stress plays a major role in ethanol-induced liver damage, and agents with antioxidant properties are promising as therapeutic opportunities in alcoholic liver disease. In the present work, we investigated the effect of S-adenosylmethionine (AdoMet), Tyrosol (Tyr), and their combination on HepG2 cells exposed to ethanol exploring the potential molecular mechanisms. We exposed HepG2 cells to 1 M ethanol for 4 and 48 h; thereafter, we recorded a decreased cell viability, increase of intracellular reactive oxygen species (ROS) and lipid accumulation, and the release into culture medium of markers of liver disease such as triacylglycerol, cholesterol, transaminases, albumin, ferritin, and homocysteine. On the other hand, AdoMet and Tyrosol were able to attenuate or antagonize these adverse changes induced by acute exposure to ethanol. The protective effects were paralleled by increased Sirtuin 1 protein expression and nuclear translocation and increased ERK1/2 phosphorylation that were both responsible for the protection of cells from apoptosis. Moreover, AdoMet increased p53 and p21 expression, while Tyrosol reduced p21 expression and enhanced the expression of uncleaved caspase 3 and 9, suggesting that its protective effect may be related to the inhibition of the apoptotic machinery. Altogether, our data show that AdoMet and Tyrosol exert beneficial effects in ethanol-induced oxidative stress in HepG2 cells and provide a rationale for their potential use in combination in the prevention of ethanol-induced liver damage. PMID:27128904

  16. Prenatal exposure of ethanol induces increased glutamatergic neuronal differentiation of neural progenitor cells

    PubMed Central

    2010-01-01

    Background Prenatal ethanol exposure during pregnancy induces a spectrum of mental and physical disorders called fetal alcohol spectrum disorder (FASD). The central nervous system is the main organ influenced by FASD, and neurological symptoms include mental retardation, learning abnormalities, hyperactivity and seizure susceptibility in childhood along with the microcephaly. In this study, we examined whether ethanol exposure adversely affects the proliferation of NPC and de-regulates the normal ratio between glutamatergic and GABAergic neuronal differentiation using primary neural progenitor culture (NPC) and in vivo FASD models. Methods Neural progenitor cells were cultured from E14 embryo brain of Sprague-Dawley rat. Pregnant mice and rats were treated with ethanol (2 or 4 g/kg/day) diluted with normal saline from E7 to E16 for in vivo FASD animal models. Expression level of proteins was investigated by western blot analysis and immunocytochemical assays. MTT was used for cell viability. Proliferative activity of NPCs was identified by BrdU incorporation, immunocytochemistry and FACS analysis. Results Reduced proliferation of NPCs by ethanol was demonstrated using BrdU incorporation, immunocytochemistry and FACS analysis. In addition, ethanol induced the imbalance between glutamatergic and GABAergic neuronal differentiation via transient increase in the expression of Pax6, Ngn2 and NeuroD with concomitant decrease in the expression of Mash1. Similar pattern of expression of those transcription factors was observed using an in vivo model of FASD as well as the increased expression of PSD-95 and decreased expression of GAD67. Conclusions These results suggest that ethanol induces hyper-differentiation of glutamatergic neuron through Pax6 pathway, which may underlie the hyper-excitability phenotype such as hyperactivity or seizure susceptibility in FASD patients. PMID:21073715

  17. Protective Effect of Tragopogon Graminifolius DC Against Ethanol Induced Gastric Ulcer

    PubMed Central

    Farzaei, Mohamad Hosein; Khazaei, Mozafar; Abbasabadei, Zahra; Feyzmahdavi, Maryam; Mohseni, Gholam Reza

    2013-01-01

    Background Gastric ulcer is a serious digestive system problem and affects 5% to 10% of people during their life. Chemical antigastric ulcer drugs have side effect, cannot prevent recurrence of ulcer and also show drug interaction with many other medicaments. Tragopogon graminifolius DC.(TG) is a herb which is widely used in the west of Iran and traditionally consumed for the treatment of gastrointestinal disorders. TG was introduced as one of the most beneficial plants for digestive ulcer in Iranian traditional medicine. Objectives The aim of the present study was to determine the acute toxicity and protective effect of hydroalcoholic extract of TG (HeTG) against ethanol induced gastric ulcer. Materials and Methods Male Wistar rats were divided into five groups (n = 7). HeTG at the doses of 50, 100, and 150 mg/kg were administered orally for 15 days and gastric ulcer was induced by pure ethanol (1 ml/200gr body weight). Ulcer index and protective rate were calculated and histological changes were determined. Results HeTG was nontoxic up to 2000 mg/Kg. Ulcer index decreased in extract groups significantly. Protective rates of HeTG were 48.94%, 46.39%, and 43.99% in 50, 100, and 150 mg/kg extract, respectively. 50 mg/kg HeTG group had higher protective effect. There was relatively normal cellular arrangement in HeTG groups. Conclusions TG showed protective effect against ethanol induced gastric ulcer. This study confirmed traditional medicine claims of TG. PMID:24616792

  18. Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis

    SciTech Connect

    Cui, Ruibing; Yan, Lihui; Luo, Zheng; Guo, Xiaolan; Yan, Ming

    2015-08-15

    Extracellular Ca{sup 2+} influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca{sup 2+} entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague–Dawley rats. Our data demonstrated that ethanol (0–400 mM) dose-dependently increased hepatocyte injury and 100 mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72 h in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca{sup 2+} overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. - Highlights: • Blockade of SOCE alleviated overload of Ca{sup 2+} and hepatotoxicity after ethanol application. • Blockade of SOCE inhibited mitochondrial apoptosis after ethanol application. • SOCE might be a useful therapeutic target in alcoholic liver diseases.

  19. Comparison of Cannabidiol, Antioxidants, and Diuretics in Reversing Binge Ethanol-Induced Neurotoxicity

    PubMed Central

    Hamelink, Carol; Hampson, Aidan; Wink, David A.; Eiden, Lee E.; Eskay, Robert L.

    2014-01-01

    Binge alcohol consumption in the rat induces substantial neurodegeneration in the hippocampus and entorhinal cortex. Oxidative stress and cytotoxic edema have both been shown to be involved in such neurotoxicity, whereas N-methyl-D-aspartate (NMDA) receptor activity has been implicated in alcohol withdrawal and excitoxic injury. Because the nonpsychoactive cannabinoid cannabidiol (CBD) was previously shown in vitro to prevent glutamate toxicity through its ability to reduce oxidative stress, we evaluated CBD as a neuroprotectant in a rat binge ethanol model. When administered concurrently with binge ethanol exposure, CBD protected against hippocampal and entorhinal cortical neurodegeneration in a dose-dependent manner. Similarly, the common antioxidants butylated hydroxytoluene and α-tocopherol also afforded significant protection. In contrast, the NMDA receptor antagonists dizocilpine (MK-801) and memantine did not prevent cell death. Of the diuretics tested, furosemide was protective, whereas the other two anion exchanger inhibitors, L-644,711 [(R)-(+)-(5,6-dichloro2,3,9,9a-tetrahydro 3-oxo-9a-propyl-1H-fluoren-7-yl)oxy acetic acid] and bumetanide, were ineffective. In vitro comparison of these diuretics indicated that furosemide is also a potent antioxidant, whereas the nonprotective diuretics are not. The lack of efficacy of L-644,711 and bumetanide suggests that the antioxidant rather than the diuretic properties of furosemide contribute most critically to its efficacy in reversing ethanol-induced neurotoxicity in vitro, in our model. This study provides the first demonstration of CBD as an in vivo neuroprotectant and shows the efficacy of lipophilic antioxidants in preventing binge ethanol-induced brain injury. PMID:15878999

  20. LIMB DEFECTS INDUCED BY RETINOIC ACID SIGNALING ANTAGONISM AND SYNTHESIS INHIBITION ARE CONSISTENT WITH ETHANOL-INDUCED LIMB DEFECTS

    EPA Science Inventory

    Limb defects induced by retinoic acid signaling antagonism and synthesis inhibition are consistent with ethanol-induced limb defects

    Johnson CS1, Sulik KK1,2, Hunter, ES III3
    1Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, NC....

  1. SELECTIVE VULNERABILITY OF EMBRYONIC CELL POPULATIONS TO ETHANOL-INDUCED APOPTOSIS: IMPLICATIONS FOR ALCOHOL RELATED BIRTH DEFECTS AND NEURODEVELOPMENTAL DISORDER

    EPA Science Inventory

    The locations of cell death and resulting malformations in embryos following teratogen exposure vary depending on the teratogen used, the genotype of the conceptus, and the developmental stage of the embryo at time of exposure. To date, ethanol-induced cell death has been charac...

  2. Apocynin protects against ethanol-induced gastric ulcer in rats by attenuating the upregulation of NADPH oxidases 1 and 4.

    PubMed

    El-Naga, Reem N

    2015-12-01

    Gastric ulcer is a common gastrointestinal disorder affecting many people all over the world. Absolute ethanol (5 ml/kg) was used to induce gastric ulceration in rats. Apocynin (50 mg/kg) was given orally one hour before the administration of absolute ethanol. Omeprazole (20 mg/kg) was used as a standard. Interestingly, apocynin pre-treatment provided 93.5% gastroprotection against ethanol-induced ulceration. Biochemically, gastric mucin content was significantly increased with apocynin pre-treatment. This finding was further supported by alcian blue staining of stomach sections obtained from the different treated groups. Also, gastric juice volume and acidity were significantly reduced. Apocynin significantly ameliorated ethanol-induced oxidative stress by replenishing reduced glutathione and superoxide dismutase levels as well as reducing elevated malondialdehyde levels in gastric tissues. Besides, ethanol-induced pro-inflammatory response was significantly decreased by apocynin pre-treatment via reducing elevated levels of pro-inflammatory markers; interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2 and inducible nitric oxide synthase. Additionally, caspase-3 tissue level was significantly reduced in apocynin pre-treated group. Interestingly, NADPH oxidase-1 (NOX-1) and NOX-4 up-regulation was shown to be partially involved in the pathogenesis of ethanol-induced gastric ulceration and was significantly reversed by apocynin pre-treatment. Gastroprotective properties of apocynin were confirmed by histopathological examination. It is worth mentioning that apocynin was superior in all aspects except gastric mucin content parameter where it was significantly increased by 13.5 folds in the omeprazole pre-treated group. This study was the first to show that apocynin is a promising gastroprotective agent against ethanol-induced gastric ulceration, partially via its anti-oxidant, anti-inflammatory, anti-apoptotic effects as well as down-regulating NOX-1 and NOX-4

  3. Protective effects of alginate–chitosan microspheres loaded with alkaloids from Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. (Zuojin Pill) against ethanol-induced acute gastric mucosal injury in rats

    PubMed Central

    Wang, Qiang-Song; Zhu, Xiao-Ning; Jiang, Heng-Li; Wang, Gui-Fang; Cui, Yuan-Lu

    2015-01-01

    Zuojin Pill (ZJP), a traditional Chinese medicine formula, consists of Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. in a ratio of 6:1 (w/w) and was first recorded in “Danxi’s experiential therapy” for treating gastrointestinal disorders in the 15th century. However, the poor solubility of alkaloids from ZJP restricted the protective effect in treating gastritis and gastric ulcer. The aim of the study was to investigate the protective mechanism of mucoadhesive microspheres loaded with alkaloids from C. chinensis Franch. and E. rutaecarpa (Juss.) Benth. on ethanol-induced acute gastric mucosal injury in rats. Surface morphology, particle size, drug loading, encapsulation efficiency, in vitro drug release, mucoadhesiveness, and fluorescent imaging of the microspheres in gastrointestinal tract were studied. The results showed that the mucoadhesive microspheres loaded with alkaloids could sustain the release of drugs beyond 12 hours and had gastric mucoadhesive property with 82.63% retention rate in vitro. The fluorescence tracer indicated high retention of mucoadhesive microspheres within 12 hours in vivo. The mucoadhesive microspheres loaded with alkaloids could reduce the gastric injury by decreasing the mucosal lesion index, increasing the percentage of inhibition and increasing the amount of mucus in the gastric mucosa in an ethanol-induced gastric mucosal injury rat model. Moreover, the mucoadhesive microspheres loaded with alkaloids reduce the inflammatory response by decreasing the levels of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), downregulating the mRNA expression of inducible nitric oxide synthase, TNF-α, and IL-1β in gastric mucosa. All the results indicate that mucoadhesive microspheres loaded with alkaloids could not only increase the residence time of alkaloids in rat stomach, but also exert gastroprotective effects through reducing the inflammatory response on ethanol-induced gastric mucosal damage. Thus

  4. Ischemia reperfusion of the hepatic artery induces the functional damage of large bile ducts by changes in the expression of angiogenic factors.

    PubMed

    Mancinelli, Romina; Glaser, Shannon; Francis, Heather; Carpino, Guido; Franchitto, Antonio; Vetuschi, Antonella; Sferra, Roberta; Pannarale, Luigi; Venter, Julie; Meng, Fanyin; Alpini, Gianfranco; Onori, Paolo; Gaudio, Eugenio

    2015-12-01

    Liver transplantation and cholangiocarcinoma induce biliary dysfunction following ischemia reperfusion (IR). The function of the intrahepatic biliary tree is regulated by both autocrine and paracrine factors. The aim of the study was to demonstrate that IR-induced damage of cholangiocytes is associated with altered expression of biliary angiogenic factors. Normal and bile duct ligation rats underwent 24-h sham or hepatic reperfusion after 30 min of transient occlusion of the hepatic artery (HAIR) or portal vein (PVIR) before collecting liver blocks and cholangiocyte RNA or protein. We evaluated liver histology, biliary apoptosis, proliferation and expression of VEGF-A/C, VEGFR-2/3, Ang-1/2, and Tie-1/2 in liver sections and isolated small and large cholangiocytes. Normal rat intrahepatic cholangiocyte cultures (NRICC) were maintained under standard conditions in normoxic or under a hypoxic atmosphere for 4 h and then transferred to normal conditions for selected times. Subsequently, we measured changes in biliary proliferation and apoptosis and the expression of VEGF-A/C and VEGFR-2/3. In vivo, HAIR (but not PVIR) induced damage of large bile ducts and decreased proliferation and secretin-stimulated cAMP levels. HAIR-induced damage of large bile ducts was associated with increased expression of VEGF-A/C, VEGFR-2/3, Ang-1/2, and Tie-1/2. In vitro, under hypoxic conditions, there was increased apoptosis and reduced proliferation of NRICC concomitant with enhanced expression of VEGF-A/C and VEGFR-2/3. The functional damage of large bile ducts by HAIR and hypoxia is associated with increased expression of angiogenic factors in small cholangiocytes, presumably due to a compensatory mechanism in response to biliary damage. PMID:26451003

  5. Dillenia suffruticosa L. Impedes Carbon Tetrachloride-Induced Hepatic Damage by Modulating Oxidative Stress and Inflammatory Markers in Rats.

    PubMed

    Shah, Muhammad Dawood; Gnanaraj, Charles; Khan, Mohammad Shaheen; Iqbal, Mohammad

    2015-01-01

    Dillenia suffruticosa L. (Dilleniaceae) is used in traditional medicine for protection against various diseases. The current study was designed to investigate the bioactive compounds and hepatoprotective potential of methanol leaves extract of D. suffruticosa against carbon tetrachloride (CCl4)-induced hepatic oxidative injury. Sprague Dawley rats were pretreated with methanol extract of D. suffruticosa leaves (200, 300, and 400 mg/kg body weight [bwt]) once daily for 14 days followed by two doses of CCl4 (1.0 mL/kg bwt). After 2 weeks the rats were sacrificed and hepatoprotective analysis was performed. The identified bioactive compounds include phenol (1.39%); benzyl alcohol (2.04%); 2H-pyran-2-one, 4,6-dimethyl (1.19%); phenol, 2,4-bis(1,1-dimethylethyl) (0.83%); dodecanoic acid (0.84%); hexadecanoic acid, methyl ester (2.66%); n-hexadecanoic acid (0.96%); and phytol (2.13%). The administration of D. suffruticosa significantly depleted the elevation of enzymatic levels of alanine transaminase and aspartate transaminase (4% to 59% recovery), reduced the extent of malondialdehyde production (13% to 79% recovery), elevated the level of reduced glutathione (5% to 21% recovery), and increased the activities of antioxidant enzymes (0.43% to 35% recovery). Histopathological analyses by light and electron microscopy revealed that the plant extract protects the liver from the toxic effects of CCl4 and cured lesions such as necrosis and fatty degeneration. It also decreased hepatocyte injuries such as irregular lamellar organization and dilations in endoplasmic reticulum. Immunohistochemical studies indicate the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxyl-2-nonenal (HNE)-modified protein adducts. In addition, the overexpression of the inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and prostaglandin E2 (PGE2) are reduced. Hence, we find D. suffruticosa to be a good source of bioactive compounds with hepatoprotective

  6. Evaluation of cell proliferation, apoptosis, and dna-repair genes as potential biomarkers for ethanol-induced cns alterations

    PubMed Central

    2012-01-01

    Background Alcohol use disorders (AUDs) lead to alterations in central nervous system (CNS) architecture along with impaired learning and memory. Previous work from our group and that of others suggests that one mechanism underlying these changes is alteration of cell proliferation, apoptosis, and DNA-repair in neural stem cells (NSCs) produced as a consequence of ethanol-induced effects on the expression of genes related to p53-signaling. This study tests the hypothesis that changes in the expression of p53-signaling genes represent biomarkers of ethanol abuse which can be identified in the peripheral blood of rat drinking models and human AUD subjects and posits that specific changes may be correlated with differences in neuropsychological measures and CNS structure. Results Remarkably, microarray analysis of 350 genes related to p53-signaling in peripheral blood leukocytes (PBLs) of binge-drinking rats revealed 190 genes that were significantly altered after correcting for multiple testing. Moreover, 40 of these genes overlapped with those that we had previously observed to be changed in ethanol-exposed mouse NSCs. Expression changes in nine of these genes were tested for independent confirmation by a custom QuantiGene Plex (QGP) assay for a subset of p53-signaling genes, where a consistent trend for decreased expression of mitosis-related genes was observed. One mitosis-related gene (Pttg1) was also changed in human lymphoblasts cultured with ethanol. In PBLs of human AUD subjects seven p53-signaling genes were changed compared with non-drinking controls. Correlation and principal components analysis were then used to identify significant relationships between the expression of these seven genes and a set of medical, demographic, neuropsychological and neuroimaging measures that distinguished AUD and control subjects. Two genes (Ercc1 and Mcm5) showed a highly significant correlation with AUD-induced decreases in the volume of the left parietal supramarginal

  7. Cytochrome P450-2E1 promotes aging-related hepatic steatosis, apoptosis and fibrosis through increased nitroxidative stress.

    PubMed

    Abdelmegeed, Mohamed A; Choi, Youngshim; Ha, Seung-Kwon; Song, Byoung-Joon

    2016-02-01

    The role of ethanol-inducible cytochrome P450-2E1 (CYP2E1) in promoting aging-dependent hepatic disease is unknown and thus was investigated in this study. Young (7 weeks) and aged female (16 months old) wild-type (WT) and Cyp2e1-null mice were used in this study to evaluate age-dependent changes in liver histology, steatosis, apoptosis, fibrosis and many nitroxidative stress parameters. Liver histology showed that aged WT mice exhibited markedly elevated hepatocyte vacuolation, ballooning degeneration, and inflammatory cell infiltration compared to all other groups. These changes were accompanied with significantly higher hepatic triglyceride and serum cholesterol in aged WT mice although serum ALT and insulin resistance were not significantly altered. Aged WT mice showed the highest rates of hepatocyte apoptosis and hepatic fibrosis. Further, the highest levels of hepatic hydrogen peroxide, lipid peroxidation, protein carbonylation, nitration, and oxidative DNA damage were observed in aged WT mice. These increases in the aged WT mice were accompanied by increased levels of mitochondrial nitroxidative stress and alteration of mitochondrial complex III and IV proteins in aged WT mice, although hepatic ATP levels seems to be unchanged. In contrast, the aging-related nitroxidative changes were very low in aged Cyp2e1-null mice. These results suggest that CYP2E1 is important in causing aging-dependent hepatic steatosis, apoptosis and fibrosis possibly through increasing nitroxidative stress and that CYP2E1 could be a potential target for translational research in preventing aging-related liver disease. PMID:26703967

  8. Effect of capsaicin and chilli on ethanol induced gastric mucosal injury in the rat.

    PubMed

    Kang, J Y; Teng, C H; Wee, A; Chen, F C

    1995-05-01

    Capsaicin, the pungent ingredient of chilli, is gastroprotective against experimental gastric injury when given intragastrically. Epidemiological and clinical data suggest that chilli ingestion may have a beneficial effect on human peptic ulcer disease. This study showed a gastroprotective effect of intragastric capsaicin, in doses of 2 and 5 mg, on ethanol induced gastric mucosal injury using macroscopic, histological, scanning electron microscopic, and biochemical indices. Subcutaneous administration of 2 mg of capsaicin had the same gastroprotective effect as intragastric administration. Acute intragastric administration and chronic ingestion of chilli powder in doses comparable with that consumed in humans (up to 200 mg in single doses or 200 mg daily for four weeks) likewise protected the gastric mucosa. Both the mucosa and gastric juice had higher mucus contents when capsaicin or chilli rather than saline or solvent was used before ethanol challenge. In control animals capsaicin also increased gastric juice mucus content although the mucosal content was unaffected. Increased gastric mucus production may therefore be one mechanism by which capsaicin and chilli exert their gastroprotective effect although an alternative explanation is that the reduction in mucosal mucus depletion is secondary to the protective effect of capsaicin and chilli. PMID:7541007

  9. Ethanol-Induced Activation of ATP-Dependent Proton Extrusion in Elodea densa Leaves 1

    PubMed Central

    Marrè, Maria T.; Venegoni, Alberto; Moroni, Anna

    1992-01-01

    In Elodea densa leaves, ethanol up to 0.17 m stimulates H+ extrusion activity. This effect is strictly dependent on the presence of K+ in the medium and is suppressed by the presence of the plasmalemma H+-ATPase inhibitor vanadate. Stimulation of H+ extrusion is associated with (a) a decrease in cellular ATP level, (b) a marked hyperpolarization of transmembrane electrical potential, and (c) an increase in net K+ influx. These results suggest that ethanol-induced H+ extrusion is mediated by an activation of the plasma membrane ATP-dependent, electrogenic proton pump. This stimulating effect is associated with an increase of cell sap pH and of the capacity to take up the weak acid 5,5-dimethyloxazolidine-2,4-dione, which is interpretable as due to an increase of cytosolic pH. This indicates that the stimulation of H+ extrusion by ethanol does not depend on a cytosolic acidification by products of ethanol metabolism. The similarity of the effects of ethanol and those of photosynthesis on proton pump activity in E. densa leaves suggests that a common metabolic situation is responsible for the activation of the ATP-dependent H+-extruding mechanism. PMID:16653093

  10. Effect of capsaicin and chilli on ethanol induced gastric mucosal injury in the rat.

    PubMed Central

    Kang, J Y; Teng, C H; Wee, A; Chen, F C

    1995-01-01

    Capsaicin, the pungent ingredient of chilli, is gastroprotective against experimental gastric injury when given intragastrically. Epidemiological and clinical data suggest that chilli ingestion may have a beneficial effect on human peptic ulcer disease. This study showed a gastroprotective effect of intragastric capsaicin, in doses of 2 and 5 mg, on ethanol induced gastric mucosal injury using macroscopic, histological, scanning electron microscopic, and biochemical indices. Subcutaneous administration of 2 mg of capsaicin had the same gastroprotective effect as intragastric administration. Acute intragastric administration and chronic ingestion of chilli powder in doses comparable with that consumed in humans (up to 200 mg in single doses or 200 mg daily for four weeks) likewise protected the gastric mucosa. Both the mucosa and gastric juice had higher mucus contents when capsaicin or chilli rather than saline or solvent was used before ethanol challenge. In control animals capsaicin also increased gastric juice mucus content although the mucosal content was unaffected. Increased gastric mucus production may therefore be one mechanism by which capsaicin and chilli exert their gastroprotective effect although an alternative explanation is that the reduction in mucosal mucus depletion is secondary to the protective effect of capsaicin and chilli. Images p665-a PMID:7541007

  11. Ethanol-induced activation of adenine nucleotide turnover. Evidence for a role of acetate

    SciTech Connect

    Puig, J.G.; Fox, I.H.

    1984-09-01

    Consumption of alcohol causes hyperuricemia by decreasing urate excretion and increasing its production. Our previous studies indicate that ethanol administration increases uric acid production by increasing ATP degradation to uric acid precursors. To test the hypothesis that ethanol-induced increased urate production results from acetate metabolism and enhanced adenosine triphosphate turnover, we gave intravenous sodium acetate, sodium chloride and ethanol (0.1 mmol/kg per min for 1 h) to five normal subjects. Acetate plasma levels increased from 0.04 +/- 0.01 mM (mean +/- SE) to peak values of 0.35 +/- 0.07 mM and to 0.08 +/- 0.01 mM during acetate and ethanol infusions, respectively. Urinary oxypurines increased to 223 +/- 13% and 316 +/- 44% of the base-line values during acetate and ethanol infusions, respectively. Urinary radioactivity from the adenine nucleotide pool labeled with (8-14C) adenine increased to 171 +/- 27% and to 128 +/- 8% of the base-line values after acetate and ethanol infusions. These data indicate that both ethanol and acetate increase purine nucleotide degradation by enhancing the turnover of the adenine nucleotide pool. They support the hypothesis that acetate metabolism contributes to the increased production of urate associated with ethanol intake.

  12. Ethanol induced astaxanthin accumulation and transcriptional expression of carotenogenic genes in Haematococcus pluvialis.

    PubMed

    Wen, Zewen; Liu, Zhiyong; Hou, Yuyong; Liu, Chenfeng; Gao, Feng; Zheng, Yubin; Chen, Fangjian

    2015-10-01

    Haematococcus pluvialis is one of the most promising natural sources of astaxanthin. However, inducing the accumulation process has become one of the primary obstacles in astaxanthin production. In this study, the effect of ethanol on astaxanthin accumulation was investigated. The results demonstrated that astaxanthin accumulation occurred with ethanol addition even under low-light conditions. The astaxanthin productivity could reach 11.26 mg L(-1) d(-1) at 3% (v/v) ethanol, which was 2.03 times of that of the control. The transcriptional expression patterns of eight carotenogenic genes were evaluated using real-time PCR. The results showed that ethanol greatly enhanced transcription of the isopentenyl diphosphate (IPP) isomerase genes (ipi-1 and ipi-2), which were responsible for isomerization reaction of IPP and dimethylallyl diphosphate (DMAPP). This finding suggests that ethanol induced astaxanthin biosynthesis was up-regulated mainly by ipi-1 and ipi-2 at transcriptional level, promoting isoprenoid synthesis and substrate supply to carotenoid formation. Thus ethanol has the potential to be used as an effective reagent to induce astaxanthin accumulation in H. pluvialis. PMID:26215339

  13. Ethanol-induced hypothermia and thermogenesis of brown adipose tissue in the rat.

    PubMed

    Huttunen, P; Sämpi, M; Myllylä, R

    1998-05-01

    The effects of two ethanol doses (2 and 3 g/kg) on colonic temperature and levels of norepinephrine (NE) and uncoupling protein (UCP) mRNA in the interscapular brown adipose tissue (IBAT) were examined in rats exposed to 20 degrees C or 4 degrees C for 2 h. The controls received 0.9% NaCl solution. Ethanol produced a significant hypothermic effect versus saline at both temperature conditions. The dose at 3 g/kg reduced colonic temperature more in the cold than at room temperature (p < 0.01), whereas the ambient temperature did not affect the decrease in rats that received ethanol 2 g/kg. At room temperature ethanol did not significantly change the levels of NE or UCP mRNA, whereas after cold exposure (4 degrees C) NE levels in the ethanol-treated rats were significantly lower than in the controls (p < 0.001). Ethanol did not prevent a cold-induced increase in the UCP mRNA levels, although it reduced an increase. The magnitude of the reduction in increase was dependent on the dose, being significant at the dose of 3 g/kg (p < 0.05). The results show that the ethanol-induced drop in body temperature is not necessarily related to IBAT thermogenesis, as indicated by the levels of NE and UCP mRNA. PMID:9590517

  14. The relationship between ethanol-induced hyperglycemia and hypothermia: evidence of genetic correlation.

    PubMed

    Risinger, F O; Cunningham, C L

    1991-08-01

    The hyperglycemic and hypothermic responses to acute ethanol exposure (0, 2, 4, 6 g/kg, intraperitoneally) were examined in non-fasted mice selectively bred for sensitivity (COLD line) or insensitivity (HOT line) to ethanol-induced hypothermia. Blood samples and rectal temperatures were obtained immediately before injection and hourly for 4 hr after injection. As expected, COLD mice demonstrated greater and more prolonged reductions in body temperature than HOT mice, especially at the 4 g/kg dose (HOT: -2.58 degrees C, COLD: -5.08 degrees C). Ethanol produced significant dose-dependent elevations in blood glucose levels over the 4-hr sampling period in both lines. The greatest elevations in blood glucose levels were seen at 4 g/kg, with COLD mice (mean = 225.1 mg/dl) showing significantly greater elevations in blood glucose levels compared to HOT mice (mean = 177.0 mg/dl). These results support the hypothesis that the thermic and glycemic effects produced by ethanol are due to related neural processes that share a common genetic component. PMID:1928651

  15. Effect of tannins from Quercus suber and Quercus coccifera leaves on ethanol-induced gastric lesions in mice.

    PubMed

    Khennouf, Seddik; Benabdallah, Hassiba; Gharzouli, Kamel; Amira, Smain; Ito, Hideyuki; Kim, Tae-Hoon; Yoshida, Takashi; Gharzouli, Akila

    2003-02-26

    The gastroprotective effects of 70% acetone extracts of Quercus suber and Quercus coccifera leaves and of tannins (pedunculagin, castalagin, phillyraeoidin A, and acutissimin B) purified from these extracts were examined in the mouse using the ethanol-induced gastric ulcer model. Both extracts (25, 50, and 100 mg/kg), given orally, prevented the formation of ethanol-induced lesions in the stomach. The percent protection varied between 68 and 91%. Purified tannins (50 mg/kg) were also effective in protecting the stomach against ethanol, and the percent protection varied from 66 to 83%. Castalagin was the most potent. Both extracts and all of the tannins tested (10, 25, and 50 microg/mL) strongly inhibited (55-65%) the lipid peroxidation of rabbit brain homogenate. These results suggest that the gastroprotective effects of extracts of Q. suber and Q. coccifera leaves and the purified tannins in this experimental model are related to their anti-lipoperoxidant properties. PMID:12590500

  16. The Zebrafish, a Novel Model Organism for Screening Compounds Affecting Acute and Chronic Ethanol-Induced Effects.

    PubMed

    Tran, S; Facciol, A; Gerlai, R

    2016-01-01

    Alcohol addiction is a major unmet medical and economic issue for which very few efficacious pharmacological treatment options are currently available. The development and identification of new compounds and drugs to treat alcohol addiction is hampered by the high costs and low amenability of traditional laboratory rodents to high-throughput behavioral screens. The zebrafish represents an excellent compromise between systems complexity and practical simplicity by overcoming many limitations inherent in these rodent models. In this chapter, we review current advances in the behavioral and neurochemical characterization of ethanol-induced changes in zebrafish. We also discuss the basic principles and methods of and the most recent advances in using paradigms with which one can screen for compounds altering acute and chronic ethanol-induced effects in zebrafish. PMID:27055623

  17. Rg1 Attenuates alcoholic hepatic damage through regulating AMP-activated protein kinase and nuclear factor erythroid 2-related factor 2 signal pathways.

    PubMed

    Gao, Yan; Chu, Shi-Feng; Xia, Cong-Yuan; Zhang, Zhao; Zhang, Shuai; Chen, Nai-Hong

    2016-08-01

    Rg1 has shown multiple pharmacological activities and been considered to be evaluated for hepatic protective activity, as Rg1 could modulate different pathways in various diseases. Herein we assessed its effect and potential mechanism in a newly modified ethanol model. C57BL/6 mice were fed with Lieber-DeCarli liquid diet containing ethanol or isocaloric maltose dextrin as control diet with or without Rg1. Meanwhile, bicyclol was treated as positive drug to compare the efficacy of Rg1 against alcoholic hepatotoxicity. According to our data, Rg1 indeed improved the survival rate and lowered the abnormal high levels of serum parameters. H&E and Oil Red O staining indicated that the condition of liver damage was mitigated by Rg1 administration. Furthermore, AMPK and Nrf2 pathways were all modulated at both RNA and protein levels. In accordance with these findings, Rg1 effectively protected against alcoholic liver injury, possibly by modulating metabolism, suppressing oxidative stress, and enhancing oxidant defense systems of Nrf2 pathway. In vitro, Rg1 has no cell toxicity and promotes Nrf2 translocate into nuclear. In summary, we demonstrate that Rg1 is a potent activator of Nrf2 pathway, and could therefore be applied for prevention of hepatic damage. PMID:27229011

  18. Antioxidant and antiulcer potential of aqueous leaf extract of Kigelia africana against ethanol-induced ulcer in rats

    PubMed Central

    dos Santos, Matheus M; Olaleye, Mary T; Ineu, Rafael P; Boligon, Aline A; Athayde, Margareth L; Barbosa, Nilda BV; Rocha, João Batista Teixeira

    2014-01-01

    Ethnobotanical claims regarding Kigelia africana reported antiulcer properties as part of its medicinal application. In this work, aqueous leaf extract from K. africana was investigated for its phytochemical constituents and antiulcer potential against ethanol-induced ulcer in rats. The participation of oxidative stress on ethanol-induced ulcer and the potential protective antioxidant activity of K. africana extracts were investigated by determining vitamin C and thiobarbituric acid reactive species (TBARS) contents in the gastric mucosa of rats. The HPLC analysis showed the presence of gallic acid, chlorogenic acid, caffeic acid and also the flavonoids rutin, quercetin and kaempferol in the aqueous plant extract. Oral treatment with K. africana extract (1.75; 3.5; 7 and 14 mg/kg) one hour after ulcer induction with ethanol decreased in a dose dependent manner the ulcer index. Ethanol increased significantly stomachal TBARS levels and decreased vitamin C content when compared to the control animals. K. africana blunted the ethanol-induced oxidative stress and restored vitamin C content to the control levels. The present results indicate that the aqueous leaf extract from K. africana possesses antiulcer potential. The presence of flavonoids in plant extract suggests that its antiulcerogenic potential is associated with antioxidant activity. Of particular therapeutic potential, K. africana was effective against ethanol even after the induction of ulcer, indicating that it can have protective and curative effects against gastric lesion. PMID:26417263

  19. Increased oxidative DNA damage and hepatocyte overexpression of specific cytochrome P450 isoforms in hepatitis of mice infected with Helicobacter hepaticus.

    PubMed Central

    Sipowicz, M. A.; Chomarat, P.; Diwan, B. A.; Anver, M. A.; Awasthi, Y. C.; Ward, J. M.; Rice, J. M.; Kasprzak, K. S.; Wild, C. P.; Anderson, L. M.

    1997-01-01

    A recently discovered bacterium, Helicobacter hepaticus, infects the intrahepatic bile canaliculi of mice, causing a severe chronic hepatitis culminating in liver cancer. Thus, it affords an animal model for study of bacteria-associated tumorigenesis including H. pylori-related gastric cancer. Reactive oxygen species are often postulated to contribute to this process. We now report that hepatitis of male mice infected with H. hepaticus show significant increases in the oxidatively damaged DNA deoxynucleoside 8-hydroxydeoxyguanosine, with the degree of damage increasing with progression of the disease. Perfusion of infected livers with nitro blue tetrazolium revealed that superoxide was produced in the cytoplasm of hepatocytes, especially in association with plasmacytic infiltrates near portal triads. Contrary to expectations, Kupffer cells, macrophages, and neutrophils were rarely involved. However, levels of cytochrome P450 (CYP) isoforms 1A2 and 2A5 in hepatocytes appeared to be greatly increased, as indicated by the number of cells positive in immunohistochemistry and the intensity of staining in many cells, concomitant with severe hepatitis. The CYP2A5 immunohistochemical staining co-localized with formazan deposits resulting from nitro blue tetrazolium reduction and occurred in nuclei as well as cytoplasm. These findings suggest that CYP2A5 contributes to the superoxide production and 8-hydroxydeoxyguanosine formation, although reactive oxygen species from an unknown source in the hepatocytes leading to CYP2A5 induction or coincidental occurrence of these events are also possibilities. Three glutathione S-transferase isoforms, mGSTP1-1 (pi), mGSTA1-1 (YaYa), and mGSTA4-4, also showed striking increases evidencing major oxidative stress in these livers. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:9327726

  20. Amelioration of ethanol-induced liver injury in rats by nanogold flakes.

    PubMed

    Chen, Ya-Ling; Peng, Hsiang-Chi; Tan, Shan-Wen; Tsai, Cheng-Yuh; Huang, Yi-Huei; Wu, Hao-Yu; Yang, Suh-Ching

    2013-09-01

    The purpose of this study was to investigate the protective effects of nanogold flakes against alcoholic liver disease. Six-week-old male Wistar rats were divided into 6 groups: C (control liquid diet), CLF (control liquid diet with gold flakes at 1.03 mg/kg body weight [BW]/day), CHF (control liquid diet with gold flakes at 5.15 mg/kg BW/day), E (ethanol liquid diet), ELF (ethanol liquid diet with gold flakes at 1.03 mg/kg BW/day), and EHF (ethanol liquid diet with gold flakes at 5.15 mg/kg BW/day). The liquid diets were prepared daily. Gold flakes were added to the ethanol 1 h before preparing the ethanol liquid diets, as an aging process. After 10 weeks, rats in group E showed significantly higher plasma aspartate transaminase (AST) and alanine transaminase (ALT) activities than those in group C. A significantly increased concentration of hepatic triglyceride (TG) was found in group E. Furthermore, higher hepatic glutathione reductase (GRD), superoxide dismutase (SOD), and catalase (CAT) activities together with higher tumor necrosis factor (TNF)-α concentration and higher hepatic cytochrome (CYP2E1) protein expression were also observed in group E. In contrast, the hepatic TG concentration in group EHF was significantly lower than that of group E. In addition, hepatic glutathione peroxidase (GPX), SOD, and CAT activities together with TNF-α concentration and hepatic CYP2E1 protein expression in group EHF were significantly lower than those in group E. We concluded that nanogold flakes might ameliorate alcohol-induced liver injury by maintaining the hepatic antioxidative status. In addition, nanogold flakes may reduce fat accumulation caused by chronic ethanol feeding via decreasing hepatic TNF-α. PMID:23830375

  1. Oxidative stress mediated toxicity exerted by ethanol-inducible CYP2E1

    SciTech Connect

    Wu Defeng; Cederbaum, Arthur I. . E-mail: arthur.cederbaum@mssm.edu

    2005-09-01

    Induction of CYP2E1 by ethanol is one of the central pathways by which ethanol generates a state of oxidative stress in hepatocytes. To study the biochemical and toxicological actions of CYP2E1, our laboratory established HepG2 cell lines which constitutively overexpress CYP2E1 and characterized these cells with respect to ethanol toxicity. Addition of ethanol or an unsaturated fatty acid such as arachidonic acid or iron was toxic to the CYP2E1-expressing cells but not control cells. This toxicity was associated with elevated lipid peroxidation and could be prevented by antioxidants and inhibitors of CYP2E1. Apoptosis occurred in the CYP2E1-expressing cells exposed to ethanol, arachidonic acid, or iron. Removal of GSH caused a loss of viability in the CYP2E1-expressing cells even in the absence of added toxin or pro-oxidant. This was associated with mitochondrial damage and decreased mitochondrial membrane potential. Low concentrations of iron and arachidonic acid synergistically interacted with CYP2E1 to produce cell toxicity, suggesting these nutrients may act as priming or sensitizing agents to alcohol-induced liver injury. Surprisingly, CYP2E1-expressing cells had elevated GSH levels, due to transcriptional activation of glutamate cysteine ligase. Similarly, levels of catalase, alpha-, and microsomal glutathione transferase were also increased, suggesting that upregulation of these antioxidant genes may reflect an adaptive mechanism to remove CYP2E1-derived oxidants. Using co-cultures, interaction between CYP2E1-derived diffusible mediators to activate collagen production in hepatic stellate cells was found. While it is likely that several mechanisms contribute to alcohol-induced liver injury, the linkage between CYP2E1-dependent oxidative stress, mitochondrial injury, stellate cell activation, and GSH homeostasis may contribute to the toxic action of ethanol on the liver. HepG2 cell lines overexpressing CYP2E1 may be a valuable model to characterize the

  2. Acute Toxicity and Gastroprotection Studies of a New Schiff Base Derived Manganese (II) Complex against HCl/Ethanol-Induced Gastric Ulcerations in Rats.

    PubMed

    Ibrahim, Mohamed Yousif; Hashim, Najihah Mohd; Dhiyaaldeen, Summaya M; Al-Obaidi, Mazen M Jamil; El-Ferjani, Rashd M; Adam, Hoyam; Alkotaini, Bassam; Batran, Rami Al; Ali, Hapipah Mohd

    2016-01-01

    Manganese is a crucial element for health. In this study, the gastroprotective efficacy of Mn (II) complex (MDLA) against acidified ethanol (HCl/Ethanol)-induced gastric ulceration in rats was evaluated. The animals were distributed into 5 groups. Groups 1 and 2 received carboxymethylcellulose (CMC), group 3 was pretreated with omeprazole, and groups 4 and 5 were given 10 and 20 mg/kg of MDLA, respectively. After one hour, CMC and HCl/Ethanol were given to groups 2-5 whilst the animals in group 1 were ingested with CMC. After sacrifice, gastric lesions were evaluated by wall mucus, gross appearance, histology, antioxidant enzymes and immunohistochemistry. Group 2 displayed severe gastric damage with a significant reduction in wall mucus. Conversely, gastric lesions were reduced in groups 3-5 by 85.72%, 56.51% and 65.93%, respectively. The rats in groups 3-5 showed up-regulation of heat shock protein 70 (Hsp70) with down-regulation of Bcl-2-associated protein x (Bax). Pretreatment with omeprazole or MDLA led to an increase in the uptake of Periodic Acid Schiff (PAS) stain in the glandular part of the gastric tissue, raised levels of prostaglandin E2 (PGE2) and superoxide dismutase (SOD), and a reduction in malondialdehyde (MDA) concentrations. These results suggested the gastroprotective action of Mn (II) complex. PMID:27229938

  3. Acute Toxicity and Gastroprotection Studies of a New Schiff Base Derived Manganese (II) Complex against HCl/Ethanol-Induced Gastric Ulcerations in Rats

    PubMed Central

    Ibrahim, Mohamed Yousif; Hashim, Najihah Mohd; Dhiyaaldeen, Summaya M.; Al-Obaidi, Mazen M.Jamil; El-Ferjani, Rashd M.; Adam, Hoyam; Alkotaini, Bassam; Batran, Rami Al; Ali, Hapipah Mohd

    2016-01-01

    Manganese is a crucial element for health. In this study, the gastroprotective efficacy of Mn (II) complex (MDLA) against acidified ethanol (HCl/Ethanol)-induced gastric ulceration in rats was evaluated. The animals were distributed into 5 groups. Groups 1 and 2 received carboxymethylcellulose (CMC), group 3 was pretreated with omeprazole, and groups 4 and 5 were given 10 and 20 mg/kg of MDLA, respectively. After one hour, CMC and HCl/Ethanol were given to groups 2–5 whilst the animals in group 1 were ingested with CMC. After sacrifice, gastric lesions were evaluated by wall mucus, gross appearance, histology, antioxidant enzymes and immunohistochemistry. Group 2 displayed severe gastric damage with a significant reduction in wall mucus. Conversely, gastric lesions were reduced in groups 3–5 by 85.72%, 56.51% and 65.93%, respectively. The rats in groups 3–5 showed up-regulation of heat shock protein 70 (Hsp70) with down-regulation of Bcl-2-associated protein x (Bax). Pretreatment with omeprazole or MDLA led to an increase in the uptake of Periodic Acid Schiff (PAS) stain in the glandular part of the gastric tissue, raised levels of prostaglandin E2 (PGE2) and superoxide dismutase (SOD), and a reduction in malondialdehyde (MDA) concentrations. These results suggested the gastroprotective action of Mn (II) complex. PMID:27229938

  4. Molecular Mechanisms of Ethanol-Induced Pathogenesis Revealed by RNA-Sequencing

    PubMed Central

    Camarena, Laura; Bruno, Vincent; Euskirchen, Ghia; Poggio, Sebastian; Snyder, Michael

    2010-01-01

    Acinetobacter baumannii is a common pathogen whose recent resistance to drugs has emerged as a major health problem. Ethanol has been found to increase the virulence of A. baumannii in Dictyostelium discoideum and Caenorhabditis elegans models of infection. To better understand the causes of this effect, we examined the transcriptional profile of A. baumannii grown in the presence or absence of ethanol using RNA-Seq. Using the Illumina/Solexa platform, a total of 43,453,960 reads (35 nt) were obtained, of which 3,596,474 mapped uniquely to the genome. Our analysis revealed that ethanol induces the expression of 49 genes that belong to different functional categories. A strong induction was observed for genes encoding metabolic enzymes, indicating that ethanol is efficiently assimilated. In addition, we detected the induction of genes encoding stress proteins, including upsA, hsp90, groEL and lon as well as permeases, efflux pumps and a secreted phospholipase C. In stationary phase, ethanol strongly induced several genes involved with iron assimilation and a high-affinity phosphate transport system, indicating that A. baumannii makes a better use of the iron and phosphate resources in the medium when ethanol is used as a carbon source. To evaluate the role of phospholipase C (Plc1) in virulence, we generated and analyzed a deletion mutant for plc1. This strain exhibits a modest, but reproducible, reduction in the cytotoxic effect caused by A. baumannii on epithelial cells, suggesting that phospholipase C is important for virulence. Overall, our results indicate the power of applying RNA-Seq to identify key modulators of bacterial pathogenesis. We suggest that the effect of ethanol on the virulence of A. baumannii is multifactorial and includes a general stress response and other specific components such as phospholipase C. PMID:20368969

  5. Pdgfra protects against ethanol-induced craniofacial defects in a zebrafish model of FASD.

    PubMed

    McCarthy, Neil; Wetherill, Leah; Lovely, C Ben; Swartz, Mary E; Foroud, Tatiana M; Eberhart, Johann K

    2013-08-01

    Human birth defects are highly variable and this phenotypic variability can be influenced by both the environment and genetics. However, the synergistic interactions between these two variables are not well understood. Fetal alcohol spectrum disorders (FASD) is the umbrella term used to describe the wide range of deleterious outcomes following prenatal alcohol exposure. Although FASD are caused by prenatal ethanol exposure, FASD are thought to be genetically modulated, although the genes regulating sensitivity to ethanol teratogenesis are largely unknown. To identify potential ethanol-sensitive genes, we tested five known craniofacial mutants for ethanol sensitivity: cyp26b1, gata3, pdgfra, smad5 and smoothened. We found that only platelet-derived growth factor receptor alpha (pdgfra) interacted with ethanol during zebrafish craniofacial development. Analysis of the PDGF family in a human FASD genome-wide dataset links PDGFRA to craniofacial phenotypes in FASD, prompting a mechanistic understanding of this interaction. In zebrafish, untreated pdgfra mutants have cleft palate due to defective neural crest cell migration, whereas pdgfra heterozygotes develop normally. Ethanol-exposed pdgfra mutants have profound craniofacial defects that include the loss of the palatal skeleton and hypoplasia of the pharyngeal skeleton. Furthermore, ethanol treatment revealed latent haploinsufficiency, causing palatal defects in ∼62% of pdgfra heterozygotes. Neural crest apoptosis partially underlies these ethanol-induced defects in pdgfra mutants, demonstrating a protective role for Pdgfra. This protective role is mediated by the PI3K/mTOR pathway. Collectively, our results suggest a model where combined genetic and environmental inhibition of PI3K/mTOR signaling leads to variability within FASD. PMID:23861062

  6. Pdgfra protects against ethanol-induced craniofacial defects in a zebrafish model of FASD

    PubMed Central

    McCarthy, Neil; Wetherill, Leah; Lovely, C. Ben; Swartz, Mary E.; Foroud, Tatiana M.; Eberhart, Johann K.

    2013-01-01

    Human birth defects are highly variable and this phenotypic variability can be influenced by both the environment and genetics. However, the synergistic interactions between these two variables are not well understood. Fetal alcohol spectrum disorders (FASD) is the umbrella term used to describe the wide range of deleterious outcomes following prenatal alcohol exposure. Although FASD are caused by prenatal ethanol exposure, FASD are thought to be genetically modulated, although the genes regulating sensitivity to ethanol teratogenesis are largely unknown. To identify potential ethanol-sensitive genes, we tested five known craniofacial mutants for ethanol sensitivity: cyp26b1, gata3, pdgfra, smad5 and smoothened. We found that only platelet-derived growth factor receptor alpha (pdgfra) interacted with ethanol during zebrafish craniofacial development. Analysis of the PDGF family in a human FASD genome-wide dataset links PDGFRA to craniofacial phenotypes in FASD, prompting a mechanistic understanding of this interaction. In zebrafish, untreated pdgfra mutants have cleft palate due to defective neural crest cell migration, whereas pdgfra heterozygotes develop normally. Ethanol-exposed pdgfra mutants have profound craniofacial defects that include the loss of the palatal skeleton and hypoplasia of the pharyngeal skeleton. Furthermore, ethanol treatment revealed latent haploinsufficiency, causing palatal defects in ∼62% of pdgfra heterozygotes. Neural crest apoptosis partially underlies these ethanol-induced defects in pdgfra mutants, demonstrating a protective role for Pdgfra. This protective role is mediated by the PI3K/mTOR pathway. Collectively, our results suggest a model where combined genetic and environmental inhibition of PI3K/mTOR signaling leads to variability within FASD. PMID:23861062

  7. Neuroprotection by taurine in ethanol-induced apoptosis in the developing cerebellum

    PubMed Central

    2010-01-01

    Background Acute ethanol administration leads to massive apoptotic neurodegeneration in the developing central nervous system. We studied whether taurine is neuroprotective in ethanol-induced apoptosis in the mouse cerebellum during the postnatal period. Methods The mice were divided into three groups: ethanol-treated, ethanol+taurine-treated and controls. Ethanol (20% solution) was administered subcutaneously at a total dose of 5 g/kg (2.5 g/kg at time 1 h and 2.5 g/kg at 3 h) to the ethanol and ethanol+taurine groups. The ethanol+taurine group also received two injections of taurine (1 g/kg each, at time zero and at 4 h). To estimate apoptosis, immunostaining for activated caspase-3 and TUNEL staining were made in the mid-sagittal sections containing lobules I-X of the cerebellar vermis at 12 or 8 hours after the first taurine injection. Changes in the blood taurine level were monitored at each hour by reverse-phase high-performance liquid chromatography (HPLC). Results Ethanol administration induced apoptosis of Purkinje cells on P4 in all cerebellar lobules, most extensively in lobules IX and X, and on P7 increased the number of activated caspase-3-immunoreactive and TUNEL-positive cells in the internal layer of the cerebellum. Administration of taurine significantly decreased the number of activated caspase-3-immunoreactive and TUNEL-positive cells in the internal layer of the cerebellum on P7, but had no effect on Purkinje cells in P4 mice. The high initial taurine concentration in blood of the ethanol+taurine group diminished dramatically during the experiment, not being different at 13 h from that in the controls. Conclusions We conclude that the neuroprotective action of taurine is not straightforward and seems to be different in different types of neurons and/or requires prolonged maintenance of the high taurine concentration in blood plasma. PMID:20804586

  8. Prophylactic effects of Clausena excavata Burum. f. leaf extract in ethanol-induced gastric ulcers

    PubMed Central

    Albaayit, Shaymaa Fadhel Abbas; Abba, Yusuf; Abdullah, Rasedee; Abdullah, Noorlidah

    2016-01-01

    Clausena excavata is a natural herb with both antioxidant and anti-inflammatory properties. It has been used for decades in folkloric practice for the amelioration of various ailments. In this study, the gastroprotective activity of methanolic extract of C. excavata leaves (MECE) was determined in the Sprague Dawley rat ethanol-induced gastric ulcer model. Rats were pretreated with a single dose of vehicle (5% Tween 20), 20 mg/mL omeprazole, 400 and 200 mg/mL of MECE dissolved in 5% Tween 20. Ulcer was induced with 5 mL/kg of ethanol and stomach tissue was obtained after 1 hour. Histological examination was done on hematoxylin and eosin, periodic acid-Schiff, and immunochemically stained gastric mucosal tissues. Prostaglandin E2, superoxide dismutase, catalase, glutathione peroxidase, and lipid peroxidation levels of the gastric tissue homogenates were also determined. Significantly (P<0.05) smaller ulcer areas, less intense edema, and fewer leukocytes’ infiltration were observed in MECE- and omeprazole-treated than in untreated gastric mucosa with ulcer. The gastric pH, mucus production, superoxide dismutase, catalase, and glutathione peroxidase contents increased, while the lipid peroxidation content decreased as a result of MECE treatment. Bcl-2-associated X protein was underexpressed, while heat shock protein 70 and transforming growth factor-beta protein were overexpressed in the ulcerated gastric mucosa tissues treated with omeprazole and MECE. Similarly, there was a reduction in the levels of tumor necrotic factor-alpha and interleukin-6, while the level of interleukin-10 was increased. This study showed that the gastroprotective effect of MECE is achieved through inhibition of gastric juice secretion and ulcer lesion development, stimulation of mucus secretion, elevation of gastric pH, reduction of reactive oxygen species production, inhibition of apoptosis in the gastric mucosa, and modulation of inflammatory cytokines. PMID:27366052

  9. Ethanol-induced hyperactivity is associated with hypodopaminergia in the 22-TNJ ENU-mutated mouse

    PubMed Central

    Mathews, Tiffany A.; Brookshire, Bethany R.; Budygin, Evgeny A.; Hamre, Kristen; Goldowitz, Daniel; Jones, Sara R.

    2009-01-01

    Characterization of neurochemical and behavioral responses to ethanol in phenotypically distinct mouse strains can provide insight into the mechanisms of ethanol stimulant actions. Increases in striatal dopamine (DA) levels have often been linked to ethanol-induced hyperactivity. We examined the functional status of the DA system and behavioral responsiveness to ethanol, cocaine and a DA receptor agonist in an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain, 22-TNJ, generated by the Integrative Neuroscience Initiative on Alcoholism Consortium. The 22-TNJ mouse strain exhibited greater locomotor responses to 2.25 g/kg ethanol and 10 mg/kg cocaine, compared to control mice. In vivo microdialysis showed low baseline DA levels and a larger DA increase with both 2.25 g/kg ethanol and 10 mg/kg cocaine. In in vitro voltammetry studies, the 22-TNJ mice displayed increased Vmax rates for DA uptake, possibly contributing to the low baseline DA levels found with microdialysis. Finally, 22-TNJ mice showed enhanced in vitro autoreceptor sensitivity to the D2/D3 agonist, quinpirole, and greater locomotor responses to both autoreceptor-selective and postsynaptic receptor-selective doses of apomorphine, compared to controls. Taken together, these results indicate that the dopaminergic system of the 22-TNJ mouse is low-functioning compared to control, with consequent receptor supersensitivity, such that mutant animals exhibit enhanced behavioral responses to DA-activating drugs such as ethanol. Thus, the 22-TNJ mouse represents a model for a relatively hypodopaminergic system, and could provide important insights into the mechanisms of hyperresponsiveness to ethanol’s stimulant actions. PMID:19801272

  10. Shuidouchi (Fermented Soybean) Fermented in Different Vessels Attenuates HCl/Ethanol-Induced Gastric Mucosal Injury.

    PubMed

    Suo, Huayi; Feng, Xia; Zhu, Kai; Wang, Cun; Zhao, Xin; Kan, Jianquan

    2015-01-01

    Shuidouchi (Natto) is a fermented soy product showing in vivo gastric injury preventive effects. The treatment effects of Shuidouchi fermented in different vessels on HCl/ethanol-induced gastric mucosal injury mice through their antioxidant effect was determined. Shuidouchi contained isoflavones (daidzein and genistein), and GVFS (glass vessel fermented Shuidouchi) had the highest isoflavone levels among Shuidouchi samples fermented in different vessels. After treatment with GVFS, the gastric mucosal injury was reduced as compared to the control mice. The gastric secretion volume (0.47 mL) and pH of gastric juice (3.1) of GVFS treated gastric mucosal injury mice were close to those of ranitidine-treated mice and normal mice. Shuidouchi could decrease serum motilin (MTL), gastrin (Gas) level and increase somatostatin (SS), vasoactive intestinal peptide (VIP) level, and GVFS showed the strongest effects. GVFS showed lower IL-6, IL-12, TNF-α and IFN-γ cytokine levels than other vessel fermented Shuidouchi samples, and these levels were higher than those of ranitidine-treated mice and normal mice. GVFS also had higher superoxide dismutase (SOD), nitric oxide (NO) and malonaldehyde (MDA) contents in gastric tissues than other Shuidouchi samples. Shuidouchi could raise IκB-α, EGF, EGFR, nNOS, eNOS, Mn-SOD, Gu/Zn-SOD, CAT mRNA expressions and reduce NF-κB, COX-2, iNOS expressions as compared to the control mice. GVFS showed the best treatment effects for gastric mucosal injuries, suggesting that glass vessels could be used for Shuidouchi fermentation in functional food manufacturing. PMID:26540032

  11. Ethanol and liver: recent insights into the mechanisms of ethanol-induced fatty liver.

    PubMed

    Liu, Jinyao

    2014-10-28

    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

  12. Autoradiographic and histopathological studies of boric acid-mediated BNCT in hepatic VX2 tumor-bearing rabbits: Specific boron retention and damage in tumor and tumor vessels.

    PubMed

    Yang, C H; Lin, Y T; Hung, Y H; Liao, J W; Peir, J J; Liu, H M; Lin, Y L; Liu, Y M; Chen, Y W; Chuang, K S; Chou, F I

    2015-12-01

    Hepatoma is a malignant tumor that responds poorly to conventional therapies. Boron neutron capture therapy (BNCT) may provide a better way for hepatoma therapy. In this research, (10)B-enriched boric acid (BA, 99% (10)B) was used as the boron drug. A multifocal hepatic VX2 tumor-bearing rabbit model was used to study the mechanisms of BA-mediated BNCT. Autoradiography demonstrated that BA was selectively targeted to tumors and tumor vessels. Histopathological examination revealed the radiation damage to tumor-bearing liver was concentrated in the tumor regions during BNCT treatment. The selective killing of tumor cells and the destruction of the blood vessels in tumor masses may be responsible for the success of BA-mediated BNCT for liver tumors. PMID:26372198

  13. Lactobacillus fermentum Suo Attenuates HCl/Ethanol Induced Gastric Injury in Mice through Its Antioxidant Effects

    PubMed Central

    Suo, Huayi; Zhao, Xin; Qian, Yu; Sun, Peng; Zhu, Kai; Li, Jian; Sun, Baozhong

    2016-01-01

    The purpose of the study was to determine the inhibitory effects of Lactobacillus fermentum Suo (LF-Suo) on HCl/ethanol induced gastric injury in ICR (Institute for Cancer Research) mice and explain the mechanism of these effects through the molecular biology activities of LF-Suo. The studied mice were divided into four groups: healthy, injured, LF-Suo-L and LF-Suo-H group. After the LF-Suo intragastric administration, the gastric injury area was reduced compared to the injured group. The serum MOT (motilin), SP (substance P), ET (endothelin) levels of LF-Suo treated mice were lower, and SS (somatostatin), VIP (vasoactive intestinal peptide) levels were higher than the injured group mice. The cytokine IL-6 (interleukin 6), IL-12 (interleukin 12), TNF-α (tumor necrosis factor-α) and IFN-γ (interferon-γ) serum levels were decreased after the LF-Suo treatment. The gastric tissues SOD (superoxide dismutase), GSH-Px (glutathione peroxidase), NO (nitric oxide) and activities of LF-Suo treated mice were increased and MDA (malondialdehyde) activity was decreased compared to the injured group mice. By the RT-PCR assay, LF-Suo raised the occludin, EGF (epidermal growth factor), EGFR (epidermal growth factor receptor), VEGF (vascular endothelial growth factor), Fit-1 (fms-like tyrosine kinase-1), IκB-α (inhibitor kappaB-α), nNOS (neuronal nitric oxide synthase), eNOS (endothelial nitric oxide synthase), Mn-SOD, Cu/Zn-SOD, CAT (catalase) mRNA or protein expressions and reduced the COX-2, NF-κB (nuclear factor kappaB), and iNOS (inducible nitric oxide synthase) expressions in gastric tissues compared to the gastric injured group mice. A high concentration (1.0 × 109 CFU/kg b.w.) of LF-Suo treatment showed stronger anti-gastric injury effects compared to a low concentration of (0.5 × 109 CFU/kg b.w.) of LF-Suo treatment. LF-Suo also showed strong survival in pH 3.0 man-made gastric juice and hydrophobic properties. These results indicate that LF-Suo has potential use

  14. Ethanol-Induced Alterations in Fatty Acid-Related Lipids in Serum and Tissues in Mice

    PubMed Central

    Zhao, Zhenwen; Yu, Menggang; Crabb, David; Xu, Yan; Liangpunsakul, Suthat

    2010-01-01

    Background Chronic alcohol consumption is a major factor for several human diseases and alcoholism is associated with a host of societal problems. One of the major alcohol- induced metabolic changes is the increased NADH levels, which reduces glucose synthesis and increases fatty acid (FA) synthesis. Probably more important is the induction of FA synthesizing enzymes under the control of sterol regulatory element binding proteins (SREBP), plus increased malonyl-CoA which blocks FA entry to the mitochondria for oxidation. The changes in FA-related lipids, particularly lysophospholipids (LPLs) and ceramides (Cers), in different tissues in ethanol-fed have not been reported. Methods We systematically determined the levels of FA-related lipids, including FAs, phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), lysophosphatidylinositol (LPI), sphingomyelins (SMs), and ceramides (Cers) in the serum and different tissues by high-performance-liquid-chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). The study was performed in C57BL/6J mice fed with Lieber DeCarli diet; in which ethanol was added to account for 27.5% of total calories. The serum and tissues were collected at the time of sacrifice in these mice and the results were compared to pair-fed controls. Results The important observation was that ethanol induced tissue-specific changes, which were related to different FA chains. Several 22:6 FA, 18:0 FA, 18:0 to 18:3 FA-containing lipids were significantly increased in the serum, liver, and skeletal muscle, respectively. In the kidney, all 22:6 FA-containing lipids detected were increased. In addition, alterations of other lipids in tissues, except adipose tissue, were also observed. Conclusions We found tissue-specific alterations in the levels of FA-related lipids after ethanol administration. The implications of these findings

  15. [The effect of altan on the functional activity of the liver mitochondria and microsomes from rats with toxic hepatitis].

    PubMed

    Gordienko, A D; Iakovleva, L V

    1999-01-01

    In in vitro experiments althan had no effect on the respiration of intact mitochondria in state 4 according to Chance and produced a high antioxidant effect in fermentative and ascorbate-dependent lipid peroxidation in intact microsomes isolated from the rat liver. In ethanol-induced toxic hepatitis althan restored the functional activity of mitochondria to the level of that in intact animals and increased microsome hydroxylase activity in CCl4-hepatitis. PMID:10513340

  16. Enhanced intracellular calcium promotes metabolic and secretory disturbances in rat gastric mucosa during ethanol-induced gastritis.

    PubMed

    Hernández-Rincón, Ileana; Olguín-Martínez, Marisela; Hernández-Muñoz, Rolando

    2003-03-01

    Changes in the Ca(2+) homeostasis have been implicated in cell injury and death. However, Ca(2+) participation in ethanol-induced chronic gastric mucosal injury has not been elucidated. We have developed a model of ethanol-induced chronic gastric injury in rats, characterized by marked alterations in plasma membranes from gastric mucosa and a compensatory cell proliferation, which follows ethanol withdrawal. Therefore, the present study explored the possible role of intracellular Ca(2+) in the oxidative metabolism and in acid secretion in this experimental model. Glucose oxidation was greatly enhanced in the injured mucosa, as evaluated by CO(2) production by isolated mucosal preparations incubated with (14)C-radiolabeled glucose in different carbons. Oxygen consumption and acid secretion (aminopyrine accumulation) were also stimulated. A predominating secretory status was morphologically identified by electron microscopy in oxyntic cells of gastric mucosa from ethanol-treated rats. A coupling between secretory and metabolic effects induced by ethanol (demonstrated by an inhibitory effect of omeprazole in both parameters) was found. These ethanol-induced effects were also inhibited by addition of Ca(2+) chelators to isolated gastric mucosa samples. Lanthanum, a Ca(2+) channel blocker, inhibited ethanol-promoted increase of oxidative metabolism. In addition, a stimulated Ca(2+) uptake by mucosal minces and increased in vivo Ca(2+) levels in cytosolic and mitochondrial fractions, were also noticed. Enhanced glucose and oxygen consumptions were associated with higher ATP and NADP+ availability, whereas cytosolic NAD/NADH ratio (assessed by mucosal levels of lactate and pyruvate) was not significantly modified by the chronic ethanol administration. In conclusion, changes in Ca(2+) homeostasis, probably mainly due to increased extracellular Ca(2+) uptake, could mediate secretory and metabolic alterations found in the gastric mucosa from rats chronically treated with

  17. NT69L blocks ethanol-induced increase of dopamine and glutamate levels in striatum of mouse.

    PubMed

    Li, Zhimin; Boules, Mona; Richelson, Elliott

    2011-01-10

    Recent study shows that NT69L, an analog of neurotensin (NT) (8-13), reduces ethanol consumption and preference in mice through modulation of neurotensin receptor subtype one. The current study showed that NT69L significantly decreased ethanol-induced increase of dopamine and glutamate levels in striatum of mouse. These data suggest that NT69L prevents ethanol consumption through the modulation of both dopaminergic and glutamatergic systems implicated in ethanol addiction. NT agonists may provide novel treatment for alcohol addiction. PMID:20974215

  18. Atorvastatin induced hepatic oxidative stress and apoptotic damage via MAPKs, mitochondria, calpain and caspase12 dependent pathways.

    PubMed

    Pal, Sankhadeep; Ghosh, Manoranjan; Ghosh, Shatadal; Bhattacharyya, Sudip; Sil, Parames C

    2015-09-01

    Atorvastatin (ATO), a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, is used widely for the treatment of hypercholesterolemia and hypertriglyceridemia. Application of this drug has now been made somehow limited because of ATO associated several acute and chronic side effects. The present study has been carried out to investigate the dose-dependent hepatic tissue toxicity in ATO induced oxidative impairment and cell death in mice. Administration of ATO enhanced ALT, ALP level, increased reactive oxygen species (ROS) production and altered the pro oxidant-antioxidant status of liver by reducing intracellular GSH level, anti-oxidant enzymes activities and increasing intracellular lipid peroxidation. Our experimental evidence suggests that ATO markedly decreased mitochondrial membrane potential, disturbed the Bcl-2 family protein balance, enhanced cytochrome c release in the cytosol, increased the levels of Apaf1, caspase-9, -3, cleaved PARP protein and ultimately led to apoptotic cell death. Besides, ATO distinctly increased the phosphorylation of p38, JNK, and ERK MAPKs, enhanced Caspase12 and calpain level. Histological studies also support the dose-dependent toxic effect of ATO in these organs pathophysiology. These results reveal that ATO induces hepatic tissue toxicity via MAPKs, mitochondria and ER dependent signaling pathway, in which calcium ions and ROS act as the pivotal mediators of the apoptotic signaling. PMID:26051349

  19. Correlations of Gut Microbial Community Shift with Hepatic Damage and Growth Inhibition of Carassius auratus Induced by Pentachlorophenol Exposure.

    PubMed

    Kan, Haifeng; Zhao, Fuzheng; Zhang, Xu-Xiang; Ren, Hongqiang; Gao, Shixiang

    2015-10-01

    Goldfish (Carassius auratus) were exposed to 0-100 μg/L pentachlorophenol (PCP) for 28 days to investigate the correlations of fish gut microbial community shift with the induced toxicological effects. PCP exposure caused accumulation of PCP in the fish intestinal tract in a time- and dose-dependent manner, while hepatic PCP reached the maximal level after a 21 day exposure. Under the relatively higher PCP stress, the fish body weight and liver weight were reduced and hepatic CAT and SOD activities were inhibited, demonstrating negative correlations with the PCP levels in liver and gut content (R < -0.5 and P < 0.05 each). Pyrosequencing of the 16S rRNA gene indicated that PCP exposure increased the abundance of Bacteroidetes in the fish gut. Within the Bacteroidetes phylum, the Bacteroides genus had the highest abundance, which was significantly correlated with PCP exposure dosage and duration (R > 0.5 and P < 0.05 each). Bioinformatic analysis revealed that Bacteroides showed quantitatively negative correlations with Chryseobacterium, Microbacterium, Arthrobacter, and Legionella in the fish gut, and the Bacteroidetes abundance, Bacteroides abundance, and Firmicutes/Bacteroidetes ratio played crucial roles in the reduction of body weight and liver weight under PCP stress. The results may extend our knowledge regarding the roles of gut microbiota in ecotoxicology. PMID:26378342

  20. Antioxidative Role of Hatikana (Leea macrophylla Roxb.) Partially Improves the Hepatic Damage Induced by CCl4 in Wistar Albino Rats

    PubMed Central

    Akhter, Samina; Rahman, Md. Atiar; Aklima, Jannatul; Hasan, Md. Rakibul; Hasan Chowdhury, J. M. Kamirul

    2015-01-01

    This research investigated the protective role of Leea macrophylla extract on CCl4-induced acute liver injury in rats. Different fractions of Leea macrophylla (Roxb.) crude extract were subjected to analysis for antioxidative effects. Rats were randomly divided into four groups as normal control, hepatic control, and reference control (silymarin) group and treatment group. Evaluations were made for the effects of the fractions on serum enzymes and biochemical parameters of CCl4-induced albino rat. Histopathological screening was also performed to evaluate the changes of liver tissue before and after treatment. Different fractions of Leea macrophylla showed very potent 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging effect, FeCl3 reducing effect, superoxide scavenging effect, and iron chelating effect. Carbon tetrachloride induction increased the level of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) and other biochemical parameters such as lipid profiles, total protein, and CK-MB. In contrast, treatment of Leea macrophylla reduced the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) activities as well as biochemical parameters activities. L. macrophylla partially restored the lipid profiles, total protein, and CK-MB. Histopathology showed the treated liver towards restoration. Results evidenced that L. macrophylla can be prospective source of hepatic management in liver injury. PMID:26221590

  1. Protective effect of 1,25-dihydroxyvitamin D3 on ethanol-induced intestinal barrier injury both in vitro and in vivo.

    PubMed

    Chen, Shan-Wen; Ma, Yuan-Yuan; Zhu, Jing; Zuo, Shuai; Zhang, Jun-Ling; Chen, Zi-Yi; Chen, Guo-Wei; Wang, Xin; Pan, Yi-Sheng; Liu, Yu-Cun; Wang, Peng-Yuan

    2015-09-01

    Studies have suggested the role of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in protecting intestinal barrier function from injuries induced by multiple reagents. Vitamin D deficiency was reported to be associated with poor prognosis in patients with alcoholic liver disease (ALD). This study is designed to investigate the effect of 1,25(OH)2D3 on ethanol-induced intestinal barrier dysfunction and the underlying mechanisms utilizing Caco-2 cell monolayers and a mouse model with acute ethanol injury. In Caco-2 monolayers, ethanol significantly increased monolayer permeability, disrupted TJ distribution, increased phosphorylation level of MLC, and induced generation of ROS compared with controls. However, pre-treatment with 1,25(OH)2D3 greatly ameliorated the ethanol-induced barrier dysfunction, TJ disruption, phosphorylation level of MLC, and generation of ROS compared with ethanol-exposed monolayers. Mice fed with vitamin d-sufficient diet had a higher plasma level of 25(OH)D3 and were more resistant to ethanol-induced acute intestinal barrier injury compared with the vitamin d-deficient group. These results suggest that the suppression of generation of ROS and increased phosphorylation level of MLC might be one of the mechanisms underlying the protective effect of 1,25(OH)2D3 on ethanol-induced intestinal barrier injury and provide evidence for the application of vitamin D as therapeutic factors against ethanol-induced gut leakiness. PMID:26068064

  2. Hepatoprotective effect of the aqueous extract of Simarouba amara Aublet (Simaroubaceae) stem bark against carbon tetrachloride (CCl4)-induced hepatic damage in rats.

    PubMed

    Maranhão, Hélida M L; Vasconcelos, Carlos F B; Rolim, Larissa A; Neto, Pedro J Rolim; Neto, Jacinto da C Silva; Filho, Reginaldo C da Silva; Fernandes, Mariana P; Costa-Silva, João H; Araújo, Alice V; Wanderley, Almir G

    2014-01-01

    Simarouba amara stem bark decoction has been traditionally used in Brazil to treat malaria, inflammation, fever, abdominal pain, diarrhea, wounds and as a tonic. In this study, we investigate the hepatoprotective effects of the aqueous extract of S. amara stem bark (SAAE) on CCl4-induced hepatic damage in rats. SAAE was evaluated by high performance liquid chromatography. The animals were divided into six groups (n = 6/group). Groups I (vehicle-corn oil), II (control-CCl4), III, IV, V and VI were pretreated during 10 consecutive days, once a day p.o, with Legalon® 50 mg/kg b.w, SAAE at doses 100, 250 and 500 mg/kg b.w, respectively. The hepatotoxicity was induced on 11th day with 2 mL/kg of 20% CCl4 solution. 24 h after injury, the blood samples were collected and their livers were removed to biochemical and immunohistochemical analyzes. The SAAE decreased the levels of liver markers and lipid peroxidation in all doses and increased the catalase levels at doses 250 and 500 mg/kg. Immunohistochemical results suggested hepatocyte proliferation in all doses. These results may be related to catechins present in SAAE. Thus, SAAE prevented the oxidative damage at the same time that increased regenerative and reparative capacities of the liver. PMID:25365298

  3. The damage-associated molecular pattern HMGB1 is elevated in human alcoholic hepatitis, but does not seem to be a primary driver of inflammation.

    PubMed

    Laursen, Tea Lund; Støy, Sidsel; Deleuran, Bent; Vilstrup, Hendrik; Grønbaek, Henning; Sandahl, Thomas Damgaard

    2016-09-01

    The role of sterile inflammation caused by release of damage-associated molecular patterns (DAMP) remains unclear in human alcoholic hepatitis (AH). The DAMP, high mobility group box-1 protein (HMGB1) is released by tissue damage and inflammation. We aimed to investigate whether HMGB1 is a primary inflammatory driver in AH by determining HMGB1 serum levels and effects on inflammatory cells from AH patients. We measured serum HMGB1 in 34 AH patients and 10 healthy controls using ELISA. Toll-like receptor 4 (TLR4) and CD14 expressions were assessed by flow cytometry on HMGB1-stimulated peripheral blood mononuclear cells (PBMC) and ELISA was used to measure TNF-α and IL-1β in the supernatants. We observed 5-fold higher serum levels of HMGB1 in AH patients at the day of diagnosis and day 30, but no associations to clinical outcome. HMGB1 stimulation increased the expression of TLR4 on CD14+-monocytes compared with unstimulated cells in the AH patients. The TNF-α and IL-1β production in response to HMGB1 was diminished in AH patients. In conclusion, AH patients have increased levels of HMGB1 in their blood. This combined with an increased TLR4 expression, but an unaffected cytokine response to HMGB1 suggest that HMGB1 is not the primary driver of inflammation in AH. PMID:27357188

  4. The influence of chronic or acute nicotine pretreatment on ethanol-induced gastric ulceration in the rat.

    PubMed

    Wong, S H; Ogle, C W; Cho, C H

    1986-07-01

    The effects in rats of chronic or acute nicotine pretreatment were studied on three gastric parameters: ethanol-induced ulceration, gastric wall mucus content and gastric acid secretion, under basal or histamine-stimulated conditions. Oral administration of ethanol (40%, 10 ml kg-1) depleted gastric wall mucus and produced ulceration in the gastric glandular mucosa. Ten-day nicotine pretreatment (15 or 25 micrograms ml-1 drinking water) worsened the adverse effects of ethanol on mucosal ulceration and mucus content, potentiated the gastric secretory action of histamine, but did not affect basal acid secretion. Single oral doses of nicotine (2 or 4 mg kg-1, given 1 h beforehand) prevented ulceration and mucus depletion in ethanol-treated animals; however, they did not influence either basal or histamine-stimulated gastric acid output. It is concluded that chronic nicotine administration aggravates ethanol ulceration, possibly by decreasing gastric wall mucus content and sensitizing the stomach to the acid secretory action of histamine. On the other hand, an acute oral dose of nicotine preserves the mucus content and prevents ethanol-induced ulcer formation. PMID:2427681

  5. Phytochemical, antioxidant and protective effect of Rhus tripartitum root bark extract against ethanol-induced ulcer in rats.

    PubMed

    Alimi, Hichem; Mbarki, Sakhria; Barka, Zeineb B; Feriani, Anwer; Bouoni, Zouhour; Hfaeidh, Najla; Sakly, Mohsen; Tebourbi, Olfa; Rhouma, Khémais B

    2013-03-01

    Rhus tripartitum (sumac) is an Anacardiaceae tree with a wide phytotherapeutic application including the use of its roots in the management of gastric ulcer. In the present study the Rhus tripartitum root barks extract (RTE) was phytochemical studied, in vitro tested for their potential antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and reducing power assay and in vivo evaluated for its ability to prevent ethanol-induced gastric ulcer in rats. The RTE was rich in phenolics, flavonoids, tannins and polysaccharide contents and exhibited a low but not weak in vitro antioxidant activity when compared with (+)-catechin. Pre-treatment with RTE at oral doses 50, 200 and 400 mg/kg body weight was found to provide a dose-dependent protection against ethanol-induced ulcer by averting the deep ulcer lesions of the gastric epithelium, by reducing gastric juice and acid output, by enhancing gastric mucus production by preserving normal antioxidant enzymes activities, and inhibiting the lipid peroxidation. The antiulcerogenic activity of RTE might be due to a possible synergistic antioxidant and antisecretory effects. PMID:23531841

  6. Tiao He Yi Wei Granule, a Traditional Chinese Medicine, against Ethanol-Induced Gastric Ulcer in Mice

    PubMed Central

    Yao, Jinfu

    2015-01-01

    Tiao He Yi Wei granule (DHYW), a traditional Chinese medicine, has been used for the treatment of gastric ulcer in clinical setting. The purpose of the present study was to investigate the possible effect of DHYW and explore the underlying mechanism against ethanol-induced gastric ulcer in mice. The model of ethanol-induced gastric ulcer in mice was induced by ethanol (0.2 mL/kg). Administration of DHYW at the doses of 250, 500 mg/kg body weight prior to the ethanol ingestion could effectively protect the stomach from ulceration. The gastric lesions were significantly ameliorated in the DHYW group compared with that in the model group. Treatment with DHYW markedly decreased the levels of interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α). In addition, DHYW treatment elevated myeloperoxidase (MPO) level in stomach, increased superoxide dismutase (SOD) activity, and decreased malonaldehyde (MDA) content in serum and stomach compared with those in the model group. DHYW significantly inhibited NF-κB pathway expressions in the gastric mucosa ulcer group. Taken together, DHYW exerted a gastroprotective effect against gastric ulceration and the underlying mechanism might be associated with NF-κB pathway. PMID:26779276

  7. Autonomous system for cross-organ investigation of ethanol-induced acute response in behaving larval zebrafish.

    PubMed

    Lin, Xudong; Li, Vincent W T; Chen, Siya; Chan, Chung-Yuen; Cheng, Shuk-Han; Shi, Peng

    2016-03-01

    Ethanol is widely consumed and has been associated with various diseases in different organs. It is therefore important to study ethanol-induced responses in living organisms with the capability to address specific organs in an integrative manner. Here, we developed an autonomous system based on a series of microfluidic chips for cross-organ investigation of ethanol-induced acute response in behaving larval zebrafish. This system enabled high-throughput, gel-free, and anesthetic-free manipulation of larvae, and thus allowed real-time observation of behavioral responses, and associated physiological changes at cellular resolution within specific organs in response to acute ethanol stimuli, which would otherwise be impossible by using traditional methods for larva immobilization and orientation. Specifically, three types of chips ("motion," "lateral," and "dorsal"), based on a simple hydrodynamic design, were used to perform analysis in animal behavior, cardiac, and brain physiology, respectively. We found that ethanol affected larval zebrafish in a dose-dependent manner. The motor function of different body parts was significantly modulated by ethanol treatment, especially at a high dose of 3%. These behavioral changes were temporally associated with a slow-down of heart-beating and a stereotyped activation of certain brain regions. As we demonstrated in this proof-of-concept study, this versatile Fish-on-Chip platform could potentially be adopted for systematic cross-organ investigations involving chemical or genetic manipulations in zebrafish model. PMID:27158291

  8. Estrogen blocks the protective action of melatonin in a behavioral model of ethanol-induced hangover in mice.

    PubMed

    Karadayian, A G; Mac Laughlin, M A; Cutrera, R A

    2012-09-10

    Melatonin has antioxidant and neuroprotective properties in human beings and experimental models, as well as 'anti-estrogenic' effects. Ethanol (EtOH) affects various behavioral parameters during a period known as ethanol-induced hangover. Our study evaluated the neuroprotective effect of melatonin on motor performance during ethanol hangover in male and female Swiss mice. The females were subjected to specific hormonal states: ovariectomized (OVX) and OVX estrogenized (OVX-E(2)). Mice received melatonin (25 μg/ml) or vehicle in their drinking water for seven days and were given intraperitoneal (i.p.) injections of EtOH (3.8 g/kg) or saline on the morning of the eighth day. Motor performance was evaluated by the tightrope test 6h after EtOH exposure (hangover onset). During ethanol hangover, males exhibited lower motor performance than controls (p<0.01) but pretreatment with melatonin significantly improved performance during hangover (p<0.05). In females, melatonin treatment before ethanol-induced hangover led to a better motor performance in OVX compared with intact females (p<0.01) and a lower performance in OVX-E(2) compared with not-estrogenized OVX (p<0.05). Consequently, estrogen reversed the motor performance enhancement afforded by melatonin. We conclude that estrogen interferes with the protective action of melatonin on motor performance during ethanol hangover. PMID:22819771

  9. Ecklonia cava Polyphenol Has a Protective Effect against Ethanol-Induced Liver Injury in a Cyclic AMP-Dependent Manner

    PubMed Central

    Yamashita, Haruka; Goto, Mayu; Matsui-Yuasa, Isao; Kojima-Yuasa, Akiko

    2015-01-01

    Previously, we showed that Ecklonia cava polyphenol (ECP) treatment suppressed ethanol-induced increases in hepatocyte death by scavenging intracellular reactive oxygen species (ROS) and maintaining intracellular glutathione levels. Here, we examined the effects of ECP on the activities of alcohol-metabolizing enzymes and their regulating mechanisms in ethanol-treated hepatocytes. Isolated hepatocytes were incubated with or without 100 mM ethanol. ECP was dissolved in dimethylsulfoxide. ECP was added to cultured cells that had been incubated with or without ethanol. The cells were incubated for 0–24 h. In cultured hepatocytes, the ECP treatment with ethanol inhibited cytochrome P450 2E1 (CYP2E1) expression and activity, which is related to the production of ROS when large quantities of ethanol are oxidized. On the other hand, ECP treatment with ethanol increased the activity of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase. These changes in activities of CYP2E1 and ADH were suppressed by treatment with H89, an inhibitor of protein kinase A. ECP treatment with ethanol enhanced cyclic AMP concentrations compared with those of control cells. ECP may be a candidate for preventing ethanol-induced liver injury via regulating alcohol metabolic enzymes in a cyclic AMP-dependent manner. PMID:26096275

  10. Ecklonia cava Polyphenol Has a Protective Effect against Ethanol-Induced Liver Injury in a Cyclic AMP-Dependent Manner.

    PubMed

    Yamashita, Haruka; Goto, Mayu; Matsui-Yuasa, Isao; Kojima-Yuasa, Akiko

    2015-06-01

    Previously, we showed that Ecklonia cava polyphenol (ECP) treatment suppressed ethanol-induced increases in hepatocyte death by scavenging intracellular reactive oxygen species (ROS) and maintaining intracellular glutathione levels. Here, we examined the effects of ECP on the activities of alcohol-metabolizing enzymes and their regulating mechanisms in ethanol-treated hepatocytes. Isolated hepatocytes were incubated with or without 100 mM ethanol. ECP was dissolved in dimethylsulfoxide. ECP was added to cultured cells that had been incubated with or without ethanol. The cells were incubated for 0-24 h. In cultured hepatocytes, the ECP treatment with ethanol inhibited cytochrome P450 2E1 (CYP2E1) expression and activity, which is related to the production of ROS when large quantities of ethanol are oxidized. On the other hand, ECP treatment with ethanol increased the activity of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase. These changes in activities of CYP2E1 and ADH were suppressed by treatment with H89, an inhibitor of protein kinase A. ECP treatment with ethanol enhanced cyclic AMP concentrations compared with those of control cells. ECP may be a candidate for preventing ethanol-induced liver injury via regulating alcohol metabolic enzymes in a cyclic AMP-dependent manner. PMID:26096275