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Antioxidant and hepatoprotective effect of Garcinia indica fruit rind in ethanol-induced hepatic damage in rodents  

PubMed Central

The protective effects of aqueous extracts of the fruit rind of Garcinia indica (GIE) on ethanol-induced hepatotoxicity and the probable mechanisms involved in this protection were investigated in rats. Liver damage was induced in rats by administering ethanol (5 g/kg, 20% w/v p.o.) once daily for 21 days. GIE at 400 mg/kg and 800 mg/kg and the reference drug silymarin (200 mg/kg) were administered orally for 28 days to ethanol treated rats, this treatment beginning 7 days prior to the commencement of ethanol administration. Levels of marker enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP)), triglyceride (sTG), albumin (Alb) and total protein (TP) were evaluated in serum. Antioxidant parameters (reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR)), hepatic triglycerides (hTG) and the lipid peroxidation marker malondialdehyde (MDA) were determined in liver. GIE and silymarin elicited significant hepatoprotective activity by attenuating the ethanol–elevated levels of AST, ALT, ALP, sTG, hTG and MDA and restored the ethanol-depleted levels of GSH, SOD, CAT, GPx, GR, Alb and TP. GIE 800 mg/kg demonstrated greater hepatoprotection than GIE 400 mg/kg. The present findings indicate that hepatoprotective effects of GIE in ethanol-induced oxidative damage may be due to an augmentation of the endogenous antioxidants and inhibition of lipid peroxidation in liver.

Ashar, Hardik; Srinath, Sudhamani



Antioxidant and hepatoprotective effect of Garcinia indica fruit rind in ethanol-induced hepatic damage in rodents.  


The protective effects of aqueous extracts of the fruit rind of Garcinia indica (GIE) on ethanol-induced hepatotoxicity and the probable mechanisms involved in this protection were investigated in rats. Liver damage was induced in rats by administering ethanol (5 g/kg, 20% w/v p.o.) once daily for 21 days. GIE at 400 mg/kg and 800 mg/kg and the reference drug silymarin (200 mg/kg) were administered orally for 28 days to ethanol treated rats, this treatment beginning 7 days prior to the commencement of ethanol administration. Levels of marker enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP)), triglyceride (sTG), albumin (Alb) and total protein (TP) were evaluated in serum. Antioxidant parameters (reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR)), hepatic triglycerides (hTG) and the lipid peroxidation marker malondialdehyde (MDA) were determined in liver. GIE and silymarin elicited significant hepatoprotective activity by attenuating the ethanol-elevated levels of AST, ALT, ALP, sTG, hTG and MDA and restored the ethanol-depleted levels of GSH, SOD, CAT, GPx, GR, Alb and TP. GIE 800 mg/kg demonstrated greater hepatoprotection than GIE 400 mg/kg. The present findings indicate that hepatoprotective effects of GIE in ethanol-induced oxidative damage may be due to an augmentation of the endogenous antioxidants and inhibition of lipid peroxidation in liver. PMID:23554565

Panda, Vandana; Ashar, Hardik; Srinath, Sudhamani



Pharmacological evaluation of mangiferin herbosomes for antioxidant and hepatoprotection potential against ethanol induced hepatic damage.  


Context: Fatty liver is the first stage of alcoholic damage which is reversible with abstinence from alcohol. Mangiferin (MF) showed potent scavenging activity on diphenyl-1-picrylhydrazyl radicals which stimulate liver regeneration in various liver injuries. Objective: Although, MF shows hepatoprotection against various liver disorders but due to rapid clearance and limited solubility in lipoid environment, there is problem of its poor absorption from intestine hence poor bioavailability. Owing to which there is a need to develop MF herbosomes to resolve the problem of poor bioavailability to enhance the therapeutic potential. Methods: Successfully prepared MF herbosomes through complexation with phospholipids were characterized by physicochemical, chromatography, spectroscopy (differential scanning calorimetry (DSC), infrared (IR), and nuclear magnetic resonance (NMR)), ex vivo absorption using everted small intestine sac technique and in vivo studies using ethanol inducing hepatotoxicity in albino rats and comparing the results against plain MF. Results: Ex vivo study showed significant increased absorption of MF from prepared MF herbosomes as compared to plain MF. The hepatoprotective potential of MF herbosomes evaluated by in vivo study revealed significantly decreased levels of serum glutamate oxaloacetate transminase (SGOT), serum glutamate pyruvate transminase (SGPT), total bilirubin, and alkaline phosphatase (ALP) in MF herbosomes as compared to plain MF. MF herbosomes also showed significantly decreased level of malonyl dehydrogenase along with increased levels of reduced glutathione, superoxide dismutase (SOD) and catalase as compared to plain MF which was also comparable to the standard drug, silymarin (SL). Conclusion: The above mentioned results showed that hepatoprotective and antioxidant potency of MF enhanced due to the preparation of its herbosomes. PMID:23167243

Jain, Pushpendra Kumar; Kharya, Murlidhar; Gajbhiye, Asmita



Copper deficiency potentiates ethanol induced liver damage  

SciTech Connect

Copper sufficient (+Cu) and deficient ({minus}Cu) rats were fed liquid diets with EtOH or dextrose at 36% of kcals for 2 mo. Consumption of either the {minus}Cu diet or EtOH resulted in lower liver CuZn superoxide dismutase (CuZnSOD) and glutathione peroxidase (GPx) activities were lowest in EtOH/{minus}Cu rats; being 20% and 50% of control values, respectively. Ethanol resulted in higher MnSOD activity in +Cu and {minus}Cu rats. Low Cu intake as well as EtOH resulted in lower mitochondrial (Mit) TBARS relative to controls. TBARS were lowest in Mit from EtOH/{minus}Cu rats. Microsomal (Micro) TBARS were lower in {minus}Cu and EtOH-fed rats than in controls. The peroxidizability index (PI) was calculated as an index of substrate availability for lipid peroxidation. Ethanol feeding resulted in lower PI's in Mit and Micro than measured in non-EtOH rats. There was a positive correlation between Micro PI's and TBARS. These results show that despite reductions in components of antioxidant defense, compensatory mechanism arise resulting in reduction in peroxidation targets and/or an increase in alternate free radical quenching factors. Histological examination demonstrated increased portal and intralobular connective tissue and cell necrosis in EtOH/{minus}Cu rats, suggesting that Cu may be a critical modulator of EtOH induced tissue damage.

Zidenberg-Cherr, S.; Han, B.; Graham, T.W.; Keen, C.L. (Univ. of California, Davis (United States))



Genetic determinants of ethanol-induced liver damage.  

PubMed Central

BACKGROUND: Although a clear correlation exists between cumulative alcohol intake and liver disease, only some of the alcohol abusers develop signs of ethanol-induced liver damage. To identify some of the genetic variations predisposing persons to alcoholic liver disease (ALD), a genetic study was performed in heavy drinkers from the cohort of the Dionysis study, a survey aimed at evaluating liver disease in the open population of two towns in Northern Italy (6917 individuals). MATERIALS AND METHODS: 158 heavy drinkers (approximately 85% of all heavy drinkers in the population; daily alcohol intake > 120 g in males and >60 g in females) were investigated by the analysis of nine polymorphic regions, mapping in exons III and IX of the alcohol-dehydrogenase (ADH)-2 gene, in exon VIII of the ADH3 gene, in intron VI, in the promoter region of the cytochrome P4502E1 (CYP2E1) gene, and in the promoter region of the tumor necrosis factor-alpha gene. RESULTS: Heavy drinkers with or without ALD significantly differed for the distribution of alleles of the cytochrome P4502E1 (CYP2E1) and alcohol-dehydrogenase-3 (ADH-3) genes. In one town, allele C2 in the promoter region of the CYP2E1 gene had a frequency of 0.06 in healthy heavy drinkers, of 0.19 in heavy drinkers with ALD (p = 0.012), and of 0.33 in heavy drinkers with cirrhosis (p = 0.033). In the other town, whose inhabitants have different genetic derivation, a prominent association between ALD and homozygosity for allele ADH3*2 of ADH3 was found, with a prevalence of 0.31 in heavy drinkers with ALD and of 0.07 in healthy heavy drinkers controls (p = 0.004). CONCLUSIONS. Both heterozygosity for allele C2 of CYP2E1 and homozygosity for allele ADH3*2 of ADH3 are independent risk factors for ALD in alcohol abusers. The relative contribution of these genotypes to ALD is dependent on their frequency in the population. Overall, heavy drinkers lacking either of these two genotypes are 3.2 and 4.3 times more protected from developing ALD and cirrhosis respectively.

Monzoni, A.; Masutti, F.; Saccoccio, G.; Bellentani, S.; Tiribelli, C.; Giacca, M.



Gastroprotective Effect of Selenium on Ethanol-Induced Gastric Damage in Rats  

PubMed Central

In the present study, we examined the gastroprotective effect of selenium against ethanol-induced gastric mucosal lesions in rats. The gastric mucosal lesions were produced by oral administration with various concentrations of ethanol for three days, and 80% ethanol treatment was determined to be the optimal condition for induction of gastric damage. To identify the protective effect of selenium on ethanol-induced gastric damage, various doses of selenium were given as pretreatment for three days, and then gastric damage was induced by 80% ethanol treatment. Selenium showed a protective effect against ethanol-induced gastric mucosal lesions in a dose dependent manner. Specifically, 100 ?g/kg selenium showed the highest level of gastroprotection. In addition, selenium markedly attenuated ethanol-induced lipid peroxidation in gastric mucosa and increased activities of radical scavenging enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase in a dose-dependent manner. Histological data showed that 100 ?g/kg selenium distinctly reduced the depth and severity of the ethanol induced gastric lesion. These results clearly demonstrate that selenium inhibits the formation of ethanol-induced gastric mucosal lesions through prevention of lipid peroxidation and activation of enzymatic radical scavenging.

Kim, Jeong-Hwan; Park, Shin-Hyung; Nam, Soo-Wan; Choi, Yung-Hyun



Effect of exercise training on ethanol-induced oxidative damage in aged rats.  


It is well known that lipid peroxidation increases with age, and alcohol drinking further exacerbates this damage. The present study determined the effect of regular exercise training on alcohol-induced oxidative damage and antioxidant status in the liver of aged animals. The age-matched Wistar albino rats (3 months young, n=24; 18 months old, n=24) were evenly divided into four groups: control (C), exercise trained (Ex), ethanol drinking (Et), and exercise plus ethanol drinking (Ex+Et). With ethanol drinking, hepatic malondialdehyde (MDA) level was significantly elevated above control (P<.001), whereas glutathione (GSH) and ascorbic acid (vitamin C) contents were significantly decreased below control. These changes were found to be greater in the aged rats than those of the young rats. For both age groups, exercise training significantly reversed the increase in MDA and decreases in GSH and ascorbic acid induced by ethanol drinking. The present study showed that ethanol-induced deterioration in lipid peroxidation and reduction in antioxidant status in the liver were exacerbated with age. Here, we found that exercise training significantly reversed the adverse conditions that were caused by ethanol in aged rats. PMID:19185211

Mallikarjuna, K; Nishanth, K; Hou, Chien-Wen; Kuo, Chia-Hua; Sathyavelu Reddy, K



Propranolol reduces ethanol-induced gastric mucosal damage in portal hypertensive rats.  


In a standardized rat model of portal hypertension, we investigated the effects of propranolol on alcohol-induced gastric mucosal damage. Portal hypertensive rats pretreated with 2 mg propranolol, compared with those receiving saline, had significantly reduced portal pressures (24 +/- 1 vs 32 +/- 1 cm saline), macroscopic mucosal damage (24 +/- 1 vs 39 +/- 4% of mucosa), and histologic deep necrosis (36 +/- 2 vs 61 +/- 4% of mucosal length). Increased dosage of propranolol to 4 mg did not produce any further reduction of portal pressure or mucosal damage. Central venous and systemic arterial pressures were not significantly altered by propranolol. The extent of mucosal damage correlated with levels of portal pressure (P less than 0.01) in portal hypertensive rats. Sham-operated normotensive rats had less macroscopic mucosal damage (26 +/- 4%) than portal hypertensive rats, and propranolol did not affect the extent of ethanol-induced damage or portal pressures in these animals. We conclude: (1) Propranolol is effective in reducing extent of ethanol-induced gastric mucosal damage in portal hypertensive rats, but not in sham-operated controls; (2) this effect correlates with reduction of portal pressure; and (3) our study supports the clinical impression that reducing portal pressure may be one approach for the prevention and therapy of gastric mucosal damage in portal hypertension. PMID:3943443

Sankary, H; Sarfeh, I J; Tarnawski, A; Maeda, R; Ivey, K J; Mason, G R



PPAR?/? modulates ethanol-induced hepatic effects by decreasing pyridoxal kinase activity.  


Because of the significant morbidity and lethality caused by alcoholic liver disease (ALD), there remains a need to elucidate the regulatory mechanisms that can be targeted to prevent and treat ALD. Toward this goal, minimally invasive biomarker discovery represents an outstanding approach for these purposes. The mechanisms underlying ALD include hepatic lipid accumulation. As the peroxisome proliferator-activated receptor-?/? (PPAR?/?) has been shown to inhibit steatosis, the present study examined the role of PPAR?/? in ALD coupling metabolomic, biochemical and molecular biological analyses. Wild-type and Ppar?/?-null mice were fed either a control or 4% ethanol diet and examined after 4-7 months of treatment. Ethanol fed Ppar?/?-null mice exhibited steatosis after short-term treatment compared to controls, the latter effect appeared to be due to increased activity of sterol regulatory element binding protein 1c (SREBP1c). The wild-type and Ppar?/?-null mice fed the control diet showed clear differences in their urinary metabolomic profiles. In particular, metabolites associated with arginine and proline metabolism, and glycerolipid metabolism, were markedly different between genotypes suggesting a constitutive role for PPAR?/? in the metabolism of these amino acids. Interestingly, urinary excretion of taurine was present in ethanol-fed wild-type mice but markedly lower in similarly treated Ppar?/?-null mice. Evidence suggests that PPAR?/? modulates pyridoxal kinase activity by altering Km, consistent with the observed decreased in urinary taurine excretion. These data collectively suggest that PPAR?/? prevents ethanol-induced hepatic effects by inhibiting hepatic lipogenesis, modulation of amino acid metabolism, and altering pyridoxal kinase activity. PMID:23851158

Goudarzi, Maryam; Koga, Takayuki; Khozoie, Combiz; Mak, Tytus D; Kang, Boo-Hyon; Jr, Albert J Fornace; Peters, Jeffrey M



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

Microsoft Academic Search

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

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



Sulfated-polysaccharide fraction from red algae Gracilaria caudata protects mice gut against ethanol-induced damage.  


The aim of the present study was to investigate the gastroprotective activity of a sulfated-polysaccharide (PLS) fraction extracted from the marine red algae Gracilaria caudata and the mechanism underlying the gastroprotective activity. Male Swiss mice were treated with PLS (3, 10, 30 and 90 mg·kg(-1), p.o.), and after 30 min, they were administered 50% ethanol (0.5 mL/25 g(-1), p.o.). One hour later, gastric damage was measured using a planimeter. Samples of the stomach tissue were also obtained for histopathological assessment and for assays of glutathione (GSH) and malondialdehyde (MDA). Other groups were pretreated with l-NAME (10 mg·kg(-1), i.p.), dl-propargylglycine (PAG, 50 mg·kg(-1), p.o.) or glibenclamide (5 mg·kg(-1), i.p.). After 1 h, PLS (30 mg·kg(-1), p.o.) was administered. After 30 min, ethanol 50% was administered (0.5 mL/25 g(-1), p.o.), followed by sacrifice after 60 min. PLS prevented-ethanol-induced macroscopic and microscopic gastric injury in a dose-dependent manner. However, treatment with l-NAME or glibenclamide reversed this gastroprotective effect. Administration of propargylglycine did not influence the effect of PLS. Our results suggest that PLS has a protective effect against ethanol-induced gastric damage in mice via activation of the NO/K(ATP) pathway. PMID:22163181

Silva, Renan Oliveira; dos Santos, Geice Maria Pereira; Nicolau, Lucas Antonio Duarte; Lucetti, Larisse Tavares; Santana, Ana Paula Macedo; Chaves, Luciano de Souza; Barros, Francisco Clark Nogueira; Freitas, Ana Lúcia Ponte; Souza, Marcellus Henrique Loiola Ponte; Medeiros, Jand-Venes Rolim



Sulfated-Polysaccharide Fraction from Red Algae Gracilaria caudata Protects Mice Gut Against Ethanol-Induced Damage  

PubMed Central

The aim of the present study was to investigate the gastroprotective activity of a sulfated-polysaccharide (PLS) fraction extracted from the marine red algae Gracilaria caudata and the mechanism underlying the gastroprotective activity. Male Swiss mice were treated with PLS (3, 10, 30 and 90 mg·kg?1, p.o.), and after 30 min, they were administered 50% ethanol (0.5 mL/25 g?1, p.o.). One hour later, gastric damage was measured using a planimeter. Samples of the stomach tissue were also obtained for histopathological assessment and for assays of glutathione (GSH) and malondialdehyde (MDA). Other groups were pretreated with l-NAME (10 mg·kg?1, i.p.), dl-propargylglycine (PAG, 50 mg·kg?1, p.o.) or glibenclamide (5 mg·kg?1, i.p.). After 1 h, PLS (30 mg·kg?1, p.o.) was administered. After 30 min, ethanol 50% was administered (0.5 mL/25g?1, p.o.), followed by sacrifice after 60 min. PLS prevented-ethanol-induced macroscopic and microscopic gastric injury in a dose-dependent manner. However, treatment with l-NAME or glibenclamide reversed this gastroprotective effect. Administration of propargylglycine did not influence the effect of PLS. Our results suggest that PLS has a protective effect against ethanol-induced gastric damage in mice via activation of the NO/KATP pathway.

Silva, Renan Oliveira; dos Santos, Geice Maria Pereira; Nicolau, Lucas Antonio Duarte; Lucetti, Larisse Tavares; Santana, Ana Paula Macedo; de Souza Chaves, Luciano; Barros, Francisco Clark Nogueira; Freitas, Ana Lucia Ponte; Souza, Marcellus Henrique Loiola Ponte; Medeiros, Jand-Venes Rolim



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


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, stimulation of endogenous prostaglandins and nitric oxide, and opening of K(+)(ATP) channels. These combined effects are likely to be accompanied by an increase in gastric microcirculation. PMID:19853593

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



Ginseng, the root of Panax ginseng C.A. Meyer, protects ethanol-induced gastric damages in rat through the induction of cytoprotective heat-shock protein 27.  


Ginseng, the root of Panax ginseng C.A. Meyer, has been reported to exert preventive effects on gastropathy via anti-oxidative and anti-inflammatory actions. In this study, we investigated the protective effects of ginseng against ethanol-induced gastric damages in rat. To examine the preventive effect of ginseng, rats received two different ginseng extracts, A and B, 1 h prior to the administration of ethanol. Pretreatment of rats with ginseng extract A and B attenuated the ethanol-induced gastric lesions by 111 +/- 48 and 142 +/- 47 mm(2) compared to control group (164 +/- 54 mm(2)). Significant induction of cytoprotective heat-shock proteins HSP27 and HSP70 was found in the ginseng-administrated rats, suggesting that the restoration of the proteins might contribute to prevention of ethanol-induced gastric injuries. It is, therefore, suggested that ginseng has a protective effect against ethanol-induced gastric damages by induction of heat-shock proteins 70 and 27. PMID:17763949

Yeo, Marie; Kim, Dong-Kyu; Cho, Sung Won; Hong, Hee Do



Betaine Treatment Attenuates Chronic Ethanol-Induced Hepatic Steatosis and Alterations to the Mitochondrial Respiratory Chain Proteome  

PubMed Central

Introduction. Mitochondrial damage and disruption in oxidative phosphorylation contributes to the pathogenesis of alcoholic liver injury. Herein, we tested the hypothesis that the hepatoprotective actions of betaine against alcoholic liver injury occur at the level of the mitochondrial proteome. Methods. Male Wister rats were pair-fed control or ethanol-containing liquid diets supplemented with or without betaine (10?mg/mL) for 4-5 wks. Liver was examined for triglyceride accumulation, levels of methionine cycle metabolites, and alterations in mitochondrial proteins. Results. Chronic ethanol ingestion resulted in triglyceride accumulation which was attenuated in the ethanol plus betaine group. Blue native gel electrophoresis (BN-PAGE) revealed significant decreases in the content of the intact oxidative phosphorylation complexes in mitochondria from ethanol-fed animals. The alcohol-dependent loss in many of the low molecular weight oxidative phosphorylation proteins was prevented by betaine supplementation. This protection by betaine was associated with normalization of SAM?:?S-adenosylhomocysteine (SAH) ratios and the attenuation of the ethanol-induced increase in inducible nitric oxide synthase and nitric oxide generation in the liver. Discussion/Conclusion. In summary, betaine attenuates alcoholic steatosis and alterations to the oxidative phosphorylation system. Therefore, preservation of mitochondrial function may be another key molecular mechanism responsible for betaine hepatoprotection.

Kharbanda, Kusum K.; Todero, Sandra L.; King, Adrienne L.; Osna, Natalia A.; McVicker, Benita L.; Tuma, Dean J.; Wisecarver, James L.; Bailey, Shannon M.



Propranolol reduces ethanol-induced gastric mucosal damage in portal hypertensive rats  

Microsoft Academic Search

In a standardized rat model of portal hypertension, we investigated the effects of propranolol on alcohol-induced gastric\\u000a mucosal damage. Portal hypertensive rats pretreated with 2 mg propranolol, compared with those receiving saline, had significantly\\u000a reduced portal pressures (24±1 vs 32±1 cm saline), macroscopic mucosal damage (24 ±1 vs 39±4% of mucosa), and histologic deep\\u000a necrosis (36±2 vs 61±4% of mucosal

H. Sankary; I. J. Sarfeh; A. Tarnawski; R. Maeda; K. J. Ivey; G. R. Mason



Mechanisms for cytoprotection by vitamin U from ethanol-induced gastric mucosal damage in rats.  


A comparison was made of the effects of a nonsulfhydryl compound, vitamin U (methylmethioninesulfonium chloride, MMSC), and a sulfhydryl compound, cysteine (Cys), with regard to the inducement of acute gastric mucosal damage in the presence and absence of N-ethylmaleimide (NEM), a sulfhydryl-blocking reagent. The effects of MMSC, Cys, or NEM on gastric mucin content were examined using a newly developed biochemical method. MMSC and Cys inhibited mucosal damage due to 50% ethanol. The preinjection of NEM had no effect on cytoprotection of prostaglandins, but prevented the effects of Cys and MMSC. MMSC and Cys increased surface mucin content but lessened that of deep mucin. NEM decreased surface mucin and increased deep mucin. It thus follows that sulfhydryl compounds accelerate the secretion of deep mucin and accumulate surface mucin. The cytoprotective mechanism of MMSC may thus be mediated by sulfhydryl compounds, and the increase in surface mucosal mucin may possibly be related to cytoprotection. PMID:8565766

Watanabe, T; Ohara, S; Ichikawa, T; Saigenji, K; Hotta, K



Proteasome Activation by Hepatitis C Core Protein is Reversed by Ethanol-Induced Oxidative Stress  

PubMed Central

Background and Aims The proteasome is a major cellular proteinase. Its activity is modulated by cellular oxidants. Hepatitis C core protein and ethanol exposure both cause enhanced oxidant generation. The aim was to investigate whether core protein, by its ability to generate oxidants, alters proteasome activity and whether these alterations are further affected byethanol exposure. Methods These interactions were examined in Huh-7 cell lines that expressed inducible HCV core protein and/or constitutive cytochrome P450 2E1 (CYP2E1) and as purified components in a cell free system. Chymotrypsin-like proteasome activity was measured fluorometrically. Results Proteasome activity in core-positive 191-20 cells was 20% higher than that in core-negative cells and was enhanced three-fold in CYP2E1-expressing L14 cells. Exposure of core-positive cells to glutathione ethyl ester, catalase, or the CYP2E1 inhibitor, DAS, partially reversed the elevation of proteasome activity in core-positive cells, while ethanol exposure suppressed proteasome activity. The results indicate that proteasome activity was up-regulated by low levels of core-induced oxidative stress and down-regulated by high levels of ethanol-elicited stress. These findings were partially mimicked in cell free system. Addition of core protein enhanced the peptidase activity of purified 20S proteasome containing the proteasome activator, PA28 and was further potentiated by addition of liver mitochondrial and/or microsome fractions. However, proteasome activation was significantly attenuated when fractions were obtained from ethanol-fed animals. Conclusions HCV core protein interacts with PA28, mitochondrial and ER proteins to cause low levels of oxidant stress and proteasome activation, which is dampened during ethanol metabolism when oxidant generation is higher.

Osna, Natalia A.; White, Ronda L.; Krutik, Viatcheslav M.; Wang, Ting; Weinman, Steven A.; Donohue, Terrence M.



Ginseng, the Root of Panax ginseng C.A. Meyer, Protects Ethanol-Induced Gastric Damages in Rat through the Induction of Cytoprotective Heat-Shock Protein 27  

Microsoft Academic Search

Ginseng, the root of Panax ginseng C.A. Meyer, has been reported to exert preventive effects on gastropathy via anti-oxidative and anti-inflammatory actions.\\u000a In this study, we investigated the protective effects of ginseng against ethanol-induced gastric damages in rat. To examine\\u000a the preventive effect of ginseng, rats received two different ginseng extracts, A and B, 1 h prior to the administration of

Marie Yeo; Dong-Kyu Kim; Sung Won Cho; Hee Do Hong



Prophylactic effects of sucralfate and geraniin on ethanol-induced gastric mucosal damage in rats.  


The aim is to study the protective effects of topical sucralfate and geraniin on acidified ethanol (EtOH dissolved in 100 mM HCI plus 54 mM NaCl)-induced gastric acid back-diffusion, mucus production and mucosal ulcerations in the rat. After irrigation the stomach with acidified EtOH (10-40% v/v) for 3 hrs, a concentration-dependent increase in acid back-diffusion and in mucosal lesions, and -dependent reduction in mucus production was found. These ulcerogenic effects of EtOH were dose-relatedly inhibited by pretreatment of intragastric sucralfate (10-200 mg/kg). A high correlation (r = -0.9572) between sucralfate-induced inhibition in acid back-diffusion and -induced reduction in mucosal ulceration provoked by 30% EtOH was observed. Geraniin (10-100 mg/kg), given 30 min prior to EtOH perfusion, produced potent inhibitory effects on those ulcerogenic parameters provoked by EtOH in a dose-dependent manner. The correlation (r = -0.8638) between geraniin-induced inhibitions in acid back-diffusion and in mucosal ulceration produced by EtOH was achieved. These cytoprotective effects of sucralfate and geraniin were further confirmed by morphological and histological studies. The results suggested that the protective effects of sucralfate and geraniin on gastric mucosa against acidified EtOH-induced damage are at least partly through the inhibition in acid back-diffusion and the elevation of gastric mucus production. PMID:8925673

Hung, C R; Cheng, J T; Neu, S L



Dietary zinc deficiency exaggerates ethanol-induced liver injury in mice: involvement of intrahepatic and extrahepatic factors.  


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

Zhong, Wei; Zhao, Yantao; Sun, Xinguo; Song, Zhenyuan; McClain, Craig J; Zhou, Zhanxiang



Dietary Zinc Deficiency Exaggerates Ethanol-Induced Liver Injury in Mice: Involvement of Intrahepatic and Extrahepatic Factors  

PubMed Central

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.

Sun, Xinguo; Song, Zhenyuan; McClain, Craig J.; Zhou, Zhanxiang



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


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)-?, ? interferon (IFN-?), vascular endothelial growth factor (VEGF)-A, and transforming growth factor (TGF)-?1, as well as decreased IL-4 activity in mice blood. These results were comparable with the activity of ascorbic acid. PMID:22409310

Das, Subir Kumar; Mukherjee, Sukhes



Endogenous A1 adenosine receptor protects mice from acute ethanol-induced hepatotoxicity.  


Previous studies have indicated a critical role of adenosine and its receptors in the pathogenesis of liver diseases. The aim of this study was to determine the contribution of A1 adenosine receptor (A1AR) to acute ethanol-induced hepatotoxicity. Wild-type (WT) and A1AR(-/-) mice were intragastrically administered with ethanol (5 g/kg), and hepatic injury was evaluated 6h thereafter. Mice lacking A1AR were more susceptible to ethanol-induced liver damage than WT mice, as evidenced by higher serum transaminase levels and increased extent of histopathological changes. Ethanol induced triglycerides accumulation in the serum and liver, and this accumulation was augmented in A1AR(-/-) mice. Analysis of gene expression in the liver revealed up-regulated mRNA levels of genes related to lipogenesis (including: FAS, SCD1, ACC1, DGAT2, and PPAR?) in A1AR(-/-) mice after ethanol treatment. In addition, lack of A1AR aggravated lipid peroxidation and superoxide dismutase depletion caused by acute ethanol exposure. A subsequent study revealed that, pretreatment with A1AR antagonist DPCPX increases the sensitivity of mice to ethanol-induced liver injury. In conclusion, these results indicated that endogenous A1AR activation protects mice against acute ethanol-induced liver injury by reducing oxidative stress and decreasing lipid accumulation. PMID:23692951

Yang, Ping; Wang, Zhongqiu; Zhan, Yibei; Wang, Tao; Zhou, Mengyi; Xia, Lin; Yang, Xiao; Zhang, Jianfa



Tacrolimus (FK506) prevents early stages of ethanol induced hepatic fibrosis by targeting LARP6 dependent mechanism of collagen synthesis.  


Tacrolimus (FK506) is a widely used immunosuppressive drug. Its effects on hepatic fibrosis have been controversial and attributed to immunosuppression. We show that in vitro FK506, inhibited synthesis of type I collagen polypeptides, without affecting expression of collagen mRNAs. In vivo, administration of FK506 at a dose of 4 mg/kg completely prevented development of alcohol/carbon tetrachloride induced liver fibrosis in rats. Activation of hepatic stellate cells (HSCs) was absent in the FK506 treated livers and expression of collagen ?2(I) mRNA was at normal levels. Collagen ?1(I) mRNA was increased in the FK506 treated livers, but this mRNA was not translated into ?1(I) polypeptide. No significant inflammation was associated with the fibrosis model used. FK506 binding protein 3 (FKBP3) is one of cellular proteins which binds FK506 with high affinity. We discovered that FKBP3 interacts with LARP6 and LARP6 is the major regulator of translation and stability of collagen mRNAs. In the presence of FK506 the interaction between FKBP3 and LARP6 is weakened and so is the pull down of collagen mRNAs with FKBP3. We postulate that FK506 inactivates FKBP3 and that lack of interaction of LARP6 and FKBP3 results in aberrant translation of collagen mRNAs and prevention of fibrosis. This is the first report of such activity of FK506 and may renew the interest in using this drug to alleviate hepatic fibrosis. PMID:23755290

Manojlovic, Zarko; Blackmon, John; Stefanovic, Branko



Effect of ebrotidine on ethanol-induced gastric mucosal damage in the rat. Comparative study with other H2-receptor antagonists.  


Ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl ] amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) is a novel H2-receptor antagonist with additional gastroprotective effect. The gastroprotective effect of oral doses of ebrotidine against ethanol-induced mucosal damage in female rats was compared with the effect of cimetidine, ranitidine and famotidine. Macroscopically, ebrotidine showed dose-dependent inhibition of the lesion, with significant differences from that of controls at doses of > or = 12.50 mg/kg (ED50 was 26.54 mg/kg). None of the other drugs tested showed gastroprotective effect under the same conditions. The histopathological study revealed significant reduction in the number of deep and superficial ulcers in ebrotidine-treated animals. The gastroprotective effect of ebrotidine is patent even in the presence of indometacin suggesting that prostaglandins play a rather negligible role in gastroprotective action. These results suggest that ebrotidine may be more useful than the classically known H2-antagonists in the treatment of peptic ulcers. PMID:9205742

Palop, D; Romero, A; Villamayor, F; Conejo, L; Sacristán, A; Ortiz, J A



Dietary Supplementation of Grape Polyphenols to Rats Ameliorates Chronic Ethanol-Induced Changes in Hepatic Morphology without Altering Changes in Hepatic Lipids1  

Microsoft Academic Search

Increase in oxidative stress after chronic ethanol consumption can result in hepatic injury. Because polyphenolic compounds can offer antioxidant protection to the cardiovascular system, this study was designed to investigate whether dietary supplementation of polyphenols from grapes may ameliorate hepatic injury resulting from chronic ethanol consumption. Male Sprague-Dawley rats were administered the following diets for 2 mo: 1) Lieber-DeCarli (L-D)

Grace Y. Sun; Jinming Xia; Jianfeng Xu; Brian Allenbrand; Agnes Simonyi; P. Kevin Rudeen; Albert Y. Sun


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

PubMed Central

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 ?g/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 generation of ceramide in response to ethanol feeding may underlie several effects of ethanol. ASMase inhibitors may be considered as a therapeutic target for alcohol-induced hepatic steatosis and activation of stress kinases.

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



Ethanol-induced acute gastric injury in mast cell-deficient and congenic normal mice. Evidence that mast cells can augment the area of damage.  

PubMed Central

The authors used stereomicroscopy and planimetry to measure the area of glandular stomach mucosa acutely injured by oral ethanol in mast cell-deficient and congenic normal (+/+) mice, and examined the damaged areas in 1-mu sections. Ethanol caused degranulation and/or disruption of gastric mucosal mast cells, and, at certain concentrations of ethanol, mast cell-deficient WBB6F1-W/Wv or WCB6F1-Sl/Sld mice developed significantly less (43-90% less) acute gastric injury than either congenic +/+ mice or WBB6F1-W/Wv mice whose mast cells were restored by bone marrow transplantation from WBB6F1-+/+ mice. Nevertheless, ethanol produced detectable, and in some cases substantial, gastric injury even in the complete absence of mast cells. Thus, ethanol can produce some damage to the gastric mucosa independently of mast cells. But these data suggest that under certain circumstances mast cells can augment the area of acute gastric injury induced by ethanol. Images Figure 3

Galli, S. J.; Wershil, B. K.; Bose, R.; Walker, P. A.; Szabo, S.



Hepatoprotective effect of aqueous extract of Aframomum melegueta on ethanol-induced toxicity in rats.  


In recent years there have been remarkable developments in the prevention of diseases, especially with regards to the role of free radicals and antioxidants. Ethanol-induced oxidative stress appears to be one mechanism by which ethanol causes liver injury. The protective effect of aqueous plant extract of Aframomum melegueta on ethanol-induced toxicity was investigated in male Wistar rats. The rats were treated with 45 % ethanol (4.8 g/kg b.w.t.) for 16 days to induce alcoholic diseases in the liver. The activities of alanine aminotransferase, aspartate aminotransferase and triglyceride were monitored and the histological changes in liver examined in order to evaluate the protective effects of the plant extract. Hepatic malondialdehyde and reduced glutathione, as well as superoxide dismutase and glutathione-S-transferase activities were determined for the antioxidant status. Chronic ethanol administration resulted in a statistically significant elevation of serum alanine aminotransferases and triglyceride levels, as well as a decrease in reduced glutathione and superoxide dismutase which was dramatically attenuated by the co-administration of the plant extract. Histological changes were related to these indices. Co-administration of the plant extract suppressed the elevation of lipid peroxidation, restored the reduced glutathion, and enhanced the superoxide dismutase activity. These results highlight the ability of Aframomum melegueta to ameliorate oxidative damage in the liver and the observed effects are associated with its antioxidant activities. PMID:21887409

Nwozo, Sarah O; Oyinloye, Babatunji E



Antioxidant activity and hepatoprotective potential of Hammada scoparia against ethanol-induced liver injury in rats.  


The present work was aimed at studying the antioxidative activity and hepatoprotective effects of methanolic extract (ME) of Hammada scoparia leaves against ethanol-induced liver injury in male rats. The animals were treated daily with 35 % ethanol solution (4 g kg(-1) day(-1)) during 4 weeks. This treatment led to an increase in the lipid peroxidation, a decrease in antioxidative enzymes (catalase, superoxide dismutase, and glutathione peroxidase) in liver, and a considerable increase in the serum levels of aspartate and alanine aminotransferase and alkaline phospahatase. However, treatment with ME protects efficiently the hepatic function of alcoholic rats by the considerable decrease in aminotransferase contents in serum of ethanol-treated rats. The glycogen synthase kinase-3 ? was inhibited after ME administration, which leads to an enhancement of glutathione peroxidase activity in the liver and a decrease in lipid peroxidation rate by 76 %. These biochemical changes were consistent with histopathological observations, suggesting marked hepatoprotective effect of ME. These results strongly suggest that treatment with methanolic extract normalizes various biochemical parameters and protects the liver against ethanol induced oxidative damage in rats. PMID:22893526

Bourogaa, Ezzeddine; Nciri, Riadh; Mezghani-Jarraya, Raoudha; Racaud-Sultan, Claire; Damak, Mohamed; El Feki, Abdelfattah



Hepatoprotective effects of aqueous leaf extract and crude isolates of Murraya koenigii against in vitro ethanol-induced hepatotoxicity model.  


Medicinal plants constitute a principal health care resource corroborating their gradual acceptance by the global population. The ethno medicinal plant, Murraya koeniggi (Curry-leaf tree) as is native to India exhibits diverse biological activities. Unpublished data from our laboratory revealed hepatoprotective activity of its crude aqueous extract against ethanol-induced hepatotoxicity in experimental animals. Chronic ethanol consumption diminishes the cellular antioxidant levels through free radical induced injury causing hepatitis and cirrhosis with mortality in severe cases. This provided a rationale for studying its mechanistic approaches in terms of modulation of antioxidant defenses for probable hepatoprotective activity against ethanol-induced hepatotoxicity in vitro. Based on the inhibitory concentration (IC(50)) obtained from the cell viability assay, graded concentrations of 100 ?g/ml and 500 ?g/ml of aqueous extract (WE), isolated carbazole alkaloids (CA) and tannin (T) fraction were chosen to study the hepatoprotective activity against ethanol-induced hepatotoxicity using liver carcinoma cell lines (Hep G(2)). Their antioxidant activity with anti-lipid peroxidation potential (LPO), effects on protein content, liver metabolizing enzymes viz., glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and the morphology of the cells were studied as parameters of hepatoprotection. The tannins and the carbazole alkaloids from the aqueous extract exhibited excellent hepatoprotective activity with respect to the different parameters studied and maintained normal morphology even after ethanolic challenge to the cells as comparable to the protection offered by the standard drug L-ornithine L-aspartate (LOLA). The modulating effect of the aqueous extract and isolates on liver metabolizing enzymes, reduction in lipid peroxidation and decreased cellular damage were found to contribute to the hepatoprotective activity. PMID:20488686

Sathaye, Sadhana; Bagul, Yogita; Gupta, Sanjay; Kaur, Harpreet; Redkar, Roopali



Genetic factors influence ethanol-induced uroporphyria in Hfe(-/-) mice.  


Two major risk factors for porphyria cutanea tarda (PCT) are alcohol consumption and homozygosity for the C282Y mutation in the hereditary hemochromatosis gene (HFE). We recently described an animal model for alcohol-induced uroporphyria, using Hfe(-/-) mice. In the present study we show that this effect is dependent on genetic background and ethanol dose. In the 129S6/SvEvTac (129) strain, treatment with 15% ethanol in the drinking water for 6.5 months produced an accumulation of hepatic uroporphyrin (URO) 4-fold higher than that observed with 10% ethanol, a 90% decrease in uroporphyrinogen decarboxylase activity (UROD), and further increased the activities of hepatic 5-aminolevulinate synthase (ALAS) and CYP1A2. Hepatic nonheme iron (NHFe) and hepatocyte iron staining were not further increased by 15% compared to 10% ethanol. Treatment of C57BL/6 Hfe(-/-) mice with 15% ethanol for 6.5 months did not increase hepatic URO. Although NHFe was increased by ethanol, the resulting level was only half that of ethanol-treated 129 Hfe(-/-) mice. ALAS induction was similar in both Hfe(-/-) strains. In wild-type 129 mice treated with ethanol for 6 to 7 months, administration of iron dextran increased hepatic URO accumulation and decreased UROD activity. In conclusion, this study demonstrates a strong effect of genetic background on ethanol-induced uroporphyria, which is probably due to a greater effect of ethanol on iron metabolism in the susceptible strain. PMID:15382179

Gorman, Nadia; Trask, Heidi W; Bement, William J; Szakacs, Juliana G; Elder, George H; Balestra, Dominic; Jacobs, Nicholas J; Jacobs, Judith M; Sinclair, Jacqueline F; Gerhard, Glenn S; Sinclair, Peter R



Ethanol-induced water stress in yeast  

Microsoft Academic Search

This review considers the effect of ethanol-induced water stress on yeast metabolism and integrity. Ethanol causes water stress by lowering water activity (aw) and thereby interferes with hydrogen bonding within and between hydrated cell components, ultimately disrupting enzyme and membrane structure and function. The impact of ethanol on the energetic status of water is considered in relation to cell metabolism.

John E. Hallsworth



Perillyl alcohol protects against ethanol induced acute liver injury in Wistar rats by inhibiting oxidative stress, NF?-B activation and proinflammatory cytokine production.  


Oxidative stress and inflammation are two major etiological factors that are suggested to play key roles in the development of ethanol induced liver injury. Release of proinflammatory cytokine like tumor necrosis factor alpha (TNF-?) and activation of nuclear factor kappa-B (NF?-B) may strongly intensify inflammation and cell damage. Additionally, reactive oxygen species (ROS) also exerts significant effect in this whole cell signaling machinery. The present study was designed to investigate the protective effects of perillyl alcohol (POH) on ethanol-induced acute liver injury in Wistar rats and its probable mechanism. We have successfully demonstrated that pre-treatment with POH, besides exerting antioxidant activity might be able to modulate TNF-? release and NF?-B activation. Rats were divided into five groups and treated with ethanol or POH via an intragastric tube for one week. Control group was treated with vehicle, and ethanol treated group was given ethanol (5 g/kg body wt). Animal of treatment groups were pretreated with POH (50 & 100 mg/kg body wt) and have been given ethanol. Serum aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase and hepatic malondialdehyde were increased significantly by ethanol treatment. Ethanol administration decreased hepatic reduced glutathione content and various antioxidant enzymes activity. TNF-? production and NF?-B activation was also found to be increased after ethanol administration. POH pre-treatment significantly ameliorates ethanol induced acute liver injury possibly by inhibition of lipid peroxidation, replenishment of endogenous enzymatic and non-enzymatic defense system, downregulation of TNF-? as well as NF?-B. PMID:20923693

Khan, Abdul Quaiyoom; Nafees, Sana; Sultana, Sarwat



Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis.  


Macrophage migration inhibitory factor (MIF), a multipotent protein that exhibits both cytokine and chemotactic properties, is expressed by many cell types, including hepatocytes and nonparenchymal cells. We hypothesized that MIF is a key contributor to liver injury after ethanol exposure. Female C57BL/6 or MIF-/- mice were fed an ethanol-containing liquid diet or pair-fed control diet for 4 (11% total kcal;early response) or 25 (32% kcal; chronic response) days. Expression of MIF messenger RNA (mRNA) was induced at both 4 days and 25 days of ethanol feeding. After chronic ethanol, hepatic triglycerides and plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were increased in wildtype, but not MIF-/-, mice. In order to understand the role of MIF in chronic ethanol-induced liver injury, we investigated the early response of wildtype and MIF-/- to ethanol. Ethanol feeding for 4 days increased apoptosis of hepatic macrophages and activated complement in both wildtype and MIF-/- mice. However, tumor necrosis factor alpha (TNF-?) expression was increased only in wildtype mice. This attenuation of TNF-? expression was associated with fewer F4/80+ macrophages in liver of MIF-/- mice. After 25 days of ethanol feeding, chemokine expression was increased in wildtype mice, but not MIF-/- mice. Again, this protection was associated with decreased F4/80+ cells in MIF-/- mice after ethanol feeding. Chronic ethanol feeding also sensitized wildtype, but not MIF-/-, mice to lipopolysaccharide, increasing chemokine expression and monocyte recruitment into the liver. Conclusion: Taken together, these data indicate that MIF is an important mediator in the regulation of chemokine production and immune cell infiltration in the liver during ethanol feeding and promotes ethanol-induced steatosis and hepatocyte damage. PMID:23174952

Barnes, Mark A; McMullen, Megan R; Roychowdhury, Sanjoy; Pisano, Sorana G; Liu, Xiuli; Stavitsky, Abram B; Bucala, Richard; Nagy, Laura E



Hepatoprotective and antioxidant activities of grapeseeds against ethanol-induced oxidative stress in rats.  


The present study was carried out to evaluate the hepatoprotective effect and antioxidant role of grape (Vitis vinifera L.) seeds (GS) against ethanol-induced oxidative stress. The hepatoprotective and antioxidant roles of the GS supplementation feed against ethanol-induced oxidative stress were evaluated by measuring liver damage serum marker enzymes, aspartate aminotransferase, alanine aminotransferase, ?-glutamyl transpeptidase and lactate dehydrogenase, antioxidant defence system such as GSH, glutathione reductase, superoxide dismutase, glutathione S-transferase and glutathione peroxidase and malondialdehyde (MDA) content in various tissues of rats. Rats were divided into four experimental groups: I (control), II (20 % ethanol), III (15 % GS) and IV (20 % ethanol+15 % GS). According to the results, the level of serum marker enzymes was significantly increased in group II as compared to that of group I, but decreased in group IV as compared to that of group II. Also, administration of GS-supplemented food restored the ethanol-induced MDA, which was increased near the control level. The results indicated that GS could be as important as diet-derived antioxidants in preventing oxidative damage in the tissues by reducing the lipid oxidation or inhibiting the production of ethanol-induced free radicals in rats. PMID:21733325

Dogan, Abdulahad; Celik, Ismail



PKC? plays a causal role in acute ethanol-induced steatosis  

PubMed Central

Steatosis is a critical stage in the pathology of alcoholic liver disease (ALD), and preventing steatosis could protect against later stages of ALD. PKC? has been shown to contribute to hepatic steatosis in experimental non-alcoholic fatty liver disease (NAFLD); however, the role of PKC? in ethanol-induced steatosis has not been determined. The purpose of this study was to therefore test the hypothesis that PKC? contributes to ethanol-induced steatosis. Accordingly, the effect of acute ethanol on indices of hepatic steatosis and insulin signaling were determined in PKC? knockout mice and in wild-type mice that received an antisense oligonucleotide (ASO) to knockdown PKC? 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 PKC?. 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 PKC??/? 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 PKC?, which then exacerbates hepatic lipid accumulation by inducing insulin resistance. These data also suggest that PKC? plays a causal role in at least the early phases of ethanol-induced liver injury.

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.



Ethanol-induced oxidative stress: basic knowledge  

PubMed Central

After a general introduction, the main pathways of ethanol metabolism (alcohol dehydrogenase, catalase, coupling of catalase with NADPH oxidase and microsomal ethanol-oxidizing system) are shortly reviewed. The cytochrome P450 isoform (CYP2E1) specifically involved in ethanol oxidation is discussed. The acetaldehyde metabolism and the shift of the NAD/NADH ratio in the cellular environment (reductive stress) are stressed. The toxic effects of acetaldehyde are mentioned. The ethanol-induced oxidative stress: the increased MDA formation by incubated liver preparations, the absorption of conjugated dienes in mitochondrial and microsomal lipids and the decrease in the most unsaturated fatty acids in liver cell membranes are discussed. The formation of carbon-centered (1-hydroxyethyl) and oxygen-centered (hydroxyl) radicals during the metabolism of ethanol is considered: the generation of hydroxyethyl radicals, which occurs likely during the process of univalent reduction of dioxygen, is highlighted and is carried out by ferric cytochrome P450 oxy-complex (P450–Fe3+O2·?) formed during the reduction of heme-oxygen. The ethanol-induced lipid peroxidation has been evaluated, and it has been shown that plasma F2-isoprostanes are increased in ethanol toxicity.

Signorini, Cinzia; Leoncini, Silvia; Gardi, Concetta; Ciccoli, Lucia; Giardini, Anna; Vecchio, Daniela; Arezzini, Beatrice



The Role of NOX Enzymes in Ethanol-induced Oxidative Stress and Apoptosis in Mouse Embryos  

PubMed Central

Reactive oxygen species (ROS) play an important role in ethanol-induced apoptosis and teratogenesis. However, the major sources of ROS in ethanol-exposed embryos have remained undefined. This study was conducted to determine the role of NADPH oxidase (NOX) in ethanol-induced oxidative stress and apoptosis in mouse embryos. Analyses of mRNA expression indicated that ethanol treatment resulted in a significant increase in mRNA expression of NOX catalytic subunit Duox-1 in gestational day 9 (GD 9:0) mouse embryos. Ethanol exposure also resulted in significant increases in mRNA expression of NOX regulatory subunits, p22phox, p67phox, NOXA1 and NOXO1. In addition, a significant increase in NOX enzyme activity was found in the ethanol-exposed embryos as compared to controls. Co-treatment with the NOX inhibitor, diphenyleneiodonium (DPI), significantly prevented ethanol-induced increases in NOX enzyme activity, ROS generation and oxidative DNA damage in ethanol-exposed embryos. DPI treatment also resulted in a reduction in caspase-3 activation, decreased caspase-3 activity and diminished prevalence of apoptosis in ethanol-exposed embryos. These results support the hypothesis that NOX is a critical source of ROS in ethanol-exposed embryos and that it plays an important role in ethanol-induced oxidative stress and pathogenesis.

Dong, Jian; Sulik, Kathleen K; Chen, Shao-yu



Hibiscus protocatechuic acid inhibits lipopolysaccharide-induced rat hepatic damage.  


Hibiscus protocatechuic acid (PCA), a phenolic compound found in the dried flowers of Hibiscus sabdariffa L. (Malvaceae), was demonstrated to have an antioxidant effect in vitro and in vivo, and an antitumor property in our previous study. In the present study, we used lipopolysaccharide (LPS, an endotoxin) to induce rat liver inducible nitric oxide synthase (iNOS), and found that pretreatment with PCA decreased the liver iNOS and the serum total nitrite induced by LPS. Our investigation showed that pretreatment of rats with PCA (0.2 and 0.5 mmol/kg dosed by gavage) for 5 days significantly decreased the serum levels of the hepatic enzyme markers alanine- and aspartate aminotransferase (ALT, alanine aminotransferase; AST, aspartate aminotransferase) induced by the 6-h treatment with LPS (i.p.; 5 mg/kg). Histopathological evaluation of the rat livers revealed that PCA reduced the incidence of liver lesions induced by LPS, including neutrophil infiltration, congestion, and liver cell swelling induced by LPS in rats. We conclude that PCA, an antioxidant, presents an inhibitory potential on iNOS and hepatic damage induced by LPS. PMID:12491040

Lin, W-L; Hsieh, Y-J; Chou, F-P; Wang, C-J; Cheng, M-T; Tseng, T-H



Ethanol-Induced Conditioned Taste Avoidance  

PubMed Central

Background Rats avoid intake of a palatable taste cue when paired with all drugs of abuse tested. Evidence suggests that, at least for morphine and cocaine, rats avoid the taste cue because they are anticipating the rewarding properties of the drug. Thus, the suppressive effects of a rewarding sucrose solution and cocaine, but not those of the putatively aversive agent, LiCl, are exaggerated in drug sensitive Lewis rats. Likewise, the suppressive effects of sucrose and morphine, but not those of LiCl, are eliminated by bilateral lesions of the gustatory thalamus. Unlike morphine and cocaine, it is less clear whether rewarding or aversive drug properties are responsible for ethanol-induced suppression of intake of a taste cue. The present set of studies tests whether, like cocaine, ethanol-induced suppression of intake of a taste cue also is greater in the drug-sensitive Lewis rats and whether the suppressive effects of the drug are prevented by bilateral lesions of the taste thalamus. Methods In Experiment 1, fluid deprived Lewis and Fischer rats were given 5 min access to 0.15% saccharin and then injected with saline or a range of doses of ethanol (0.5, 0.75, 1.0, or 1.5 g/kg). There was a total of 6 such pairings. In Experiments 2 and 3, Sprague-Dawley rats received bilateral electrophysiologically-guided lesions of the gustatory thalamus. After recovery, suppression of intake of the saccharin cue was evaluated following repeated daily pairings with either a high (1.5 g/kg) or a low (0.75 g/kg) dose of ethanol. Results Ethanol-induced suppression of intake of the saccharin conditioned stimulus (CS) did not differ between the drug-sensitive Lewis rats relative to the less-sensitive Fischer rats. Lesions of the taste thalamus, however, prevented the suppressive effect of the 0.75 g/kg dose of the drug, but had no impact on the suppressive effect of the 1.5 g/kg dose of ethanol. Conclusion The results suggest that the suppressive effects of ethanol on CS intake are mediated by both rewarding and aversive consequences, varying as a function of dose.

Liu, Chuang; Showalter, John; Grigson, Patricia Sue



Protective effect of a polysaccharide from Hizikia fusiformis against ethanol-induced cytotoxicity in IEC-6 cells.  


In the present study, we examined the signaling pathways related to the ethanol-protective effect of Hf-PS-1 in IEC-6 cells. Ethanol induced the death of IEC-6 cells in a dose-dependent manner, and pretreatment with Hf-PS-1 abrogated the ethanol toxicity. When we examined whether the effect of Hf-PS-1 on ethanol cytotoxicity was associated with insulin growth factor-I receptor signaling pathways, involving mitogen-activated protein kinase (MAPK), we found that ethanol treatment decreased the phosphorylation of Shc and the binding of Grb2 to Shc, and Hf-PS-1 pretreatment increased them. Ethanol treatment also induced the phosphorylation of JNK and ERK, whereas Hf-PS-1 pretreatment decreased JNK activation but not ERK activation. Using a JNK inhibitor (SP600125), we examined GSH levels to determine whether Hf-PS-1 pretreatment mi20 ght protect against ethanol-induced gastric intestinal damage by down-regulating JNK. Co-treatment with SP600125 and ethanol decreased GSH levels, indicating that JNK phosphorylation is a critical factor during ethanol-induced injury and that the effect of Hf-PS-1 occurs via JNK down-regulation. We have thus demonstrated the protective effect of Hf-PS-1 against ethanol-induced cellular damage. Therefore, Hf-PS-1 may be useful as a bio-functional food source to protect against ethanol-induced gastrointestinal injury. PMID:19735724

Choi, Eun-Young; Hwang, Hye-Jung; Nam, Taek-Jeong



Antioxidant Effect of Alpha-Lipoic Acid against Ethanol-Induced Gastric Mucosal Erosion in Rats  

Microsoft Academic Search

Background\\/Aims: This investigation elucidates the role of free radicals in ethanol-induced gastric mucosal erosion and the protective effect of lipoic acid. Methods: After overnight fasting, Wistar albino rats were orally treated with 1 ml of absolute ethanol to induce gastric erosion. Lipoic acid (100 mg\\/kg) was given orally for 3 days before ethanol administration. Mucosal damage was evaluated 1 h

Meral Yüksel; Can Erzik; Sule Çetinel



Protective Effect of a Novel Rice Extract Against Ethanol-Induced Gastric Mucosal Injury in Rat  

Microsoft Academic Search

The aim of this study was to investigate the protective action of rice extract on ethanol-induced mucosal damage in vivo and\\u000a wound healing of epithelial cells in vitro. Also, the effect of rice extract on gastric mucosal prostaglandin E2 level, HSP72 expression, gastric acid secretion, and contribution of vanilloid receptor-mediated action was studied. In addition,\\u000a using cultured gastric mucosal cells

Tamotsu Matsuhashi; Michiro Otaka; Masaru Odashima; Mario Jin; Koga Komatsu; Isao Wada; Youhei Horikawa; Reina Ohba; Jinko Oyake; Natsumi Hatakeyama; Sumio Watanabe



Mesenchymal stem cells inhibition of chronic ethanol-induced oxidative damage via upregulation of phosphatidylinositol-3-kinase\\/Akt and modulation of extracellular signal-regulated kinase 1\\/2 activation in PC12 cells and neurons  

Microsoft Academic Search

It is well known that chronic ethanol consumption damages CNS through oxidative stress which results in many dysfunctions. Recently, it has been demonstrated that as a promising strategy to treat several neurological diseases, transplanted bone marrow-derived mesenchymal stem cells (MSCs) can secrete lots of protective factors that in turn promote function recovery. In the present study, we assessed the potential

L. Liu; J.-X. Cao; B. Sun; H.-L. Li; Y. Xia; Z. Wu; C.-L. Tang; J. Hu



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

NASA Astrophysics Data System (ADS)

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.

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



Mechanisms of ethanol-induced death of cerebellar granule cells.  


Maternal ethanol exposure during pregnancy may cause fetal alcohol spectrum disorders (FASD). FASD is the leading cause of mental retardation. The most deleterious effect of fetal alcohol exposure is inducing neuroapoptosis in the developing brain. Ethanol-induced loss of neurons in the central nervous system underlies many of the behavioral deficits observed in FASD. The cerebellum is one of the brain areas that are most susceptible to ethanol during development. Ethanol exposure causes a loss of both cerebellar Purkinje cells and granule cells. This review focuses on the toxic effect of ethanol on cerebellar granule cells (CGC) and the underlying mechanisms. Both in vitro and in vivo studies indicate that ethanol induces apoptotic death of CGC. The vulnerability of CGC to ethanol-induced death diminishes over time as neurons mature. Several mechanisms for ethanol-induced apoptosis of CGC have been suggested. These include inhibition of N-methyl-D-aspartate receptors, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, disturbance of potassium channel currents, thiamine deficiency, and disruption of translational regulation. Cultures of CGC provide an excellent system to investigate cellular/molecular mechanisms of ethanol-induced neurodegeneration and to evaluate interventional strategies. This review will also discuss the approaches leading to neuroprotection against ethanol-induced neuroapoptosis. PMID:20927663

Luo, Jia



Mechanisms of Ethanol-induced Death of Cerebellar Granule Cells  

PubMed Central

Maternal ethanol exposure during pregnancy may cause fetal alcohol spectrum disorders (FASD). FASD is the leading cause of mental retardation. The most deleterious effect of fetal alcohol exposure is inducing neuroapoptosis in the developing brain. Ethanol-induced loss of neurons in the central nervous system (CNS) underlies many of the behavioral deficits observed in FASD. The cerebellum is one of the brain areas that is most susceptible to ethanol during development. Ethanol exposure causes a loss of both cerebellar Purkinje cells and granule cells. This review focuses on the toxic effect of ethanol on cerebellar granule cells (CGC) and the underlying mechanisms. Both in vitro and in vivo studies indicate that ethanol induces apoptotic death of CGC. The vulnerability of CGC to ethanol-induced death diminishes over time as neurons mature. Several mechanisms for ethanol-induced apoptosis of CGC have been suggested. These include inhibition of NMDA receptors, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, disturbance of potassium channel currents, thiamine deficiency, and disruption of translational regulation. Cultures of CGC provide an excellent system to investigate cellular/molecular mechanisms of ethanol-induced neurodegeneration and to evaluate interventional strategies. This review will also discuss the approaches leading to neuroprotection against ethanol-induced neuroapoptosis.

Luo, Jia



Geraniin and amariin, ellagitannins from Phyllanthus amarus, protect liver cells against ethanol induced cytotoxicity.  


Ethanol mediated free radical generation plays an important role in the pathogenesis of liver injuries and alcoholic liver diseases. In the present study two ellagitannins namely geraniin and amariin isolated from Phyllanthus amarus were examined for their ability to protect mouse liver slices against ethanol induced toxicity and possible mechanism of its protection. Oxidative stress markers such as, lipid peroxidation, protein carbonyl formation, amount of 8-hydroxy-2-deoxyguanosine and antioxidant enzymes levels were measured using specific biochemical assays. Poly (ADP-ribose) polymerase (PARP), Bax and Bcl2 were checked to assess the induction of apoptosis using western blots. The results showed that geraniin and amariin protected mouse liver slices against ethanol induced cytotoxicity. Both compounds inhibited oxidation of lipid, protein and formation of 8-hydroxy-2-deoxyguanosine, all of which were found to be elevated on exposure to ethanol. These compounds restored the antioxidant enzymes altered on ethanol exposure. Compounds also inhibited the cleavage of PARP and bax and restored Bcl2, induced on exposure to ethanol. In summary, both ellagitannins effectively protected mouse liver slices against ethanol induced cytotoxicity and apoptosis by reducing oxidative damage to biological molecules and modulating Bax/Bcl-2 ratio respectively, thus minimizing liver injury. PMID:22982332

Londhe, Jayant S; Devasagayam, Thomas P A; Foo, L Yeap; Shastry, Padma; Ghaskadbi, Saroj S



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

SciTech Connect

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.

Shaw, S.; Jayatilleke, E. (V.A. Medical Center, Bronx, NY (United States) Mount Sinai School of Medicine, New York, NY (United States))



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

PubMed Central

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.

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



Role of TNF-? in renal damage in mice showing hepatic steatosis induced by high fat diet.  


The present study was designed to investigate the role of TNF-? in renal damage observed in mice with hepatic steatosis. We induced hepatic steatosis in mice using high fat diet and treated mice with ectanercept at the dose sufficient to block TNF-? receptors or vehicle for 1 month. Plasma TNF-?, total cholesterol (TC), triglyceride (TG), LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C) were determined at the end of this treatment. Renal damage was identified by histologic observation and the higher of serum blood urea nitrogen (BUN) and creatinine. Also, changes of PPAR-? in kidney and renal mesangial cell (RMC) were analyzed using Western blot. Plasma TNF-? was markedly raised in mice showing hepatic steatosis. However, the levels of blood lipids (TC, TG, HDL-C, and LDL-C) and TNF-? were not modified by the treatment of etanercept although the hepatic steatosis has been improved. Etanercept shows renal protection from histological identification and recovery of serum BUN and creatinine levels. Moreover, restoration of PPAR-? expression by etanercept was observed in mice kidney. Direct effect of TNF-? on PPAR-? expression was also characterized in RMC cell. We suggest that renal damage in mice with hepatic steatosis is mainly induced by increase of TNF-? through the decrease of renal PPAR-?. Etanercept could block TNF-? receptors to restore PPAR-? and improve renal function in mice with hepatic steatosis. PMID:22956307

Lai, Y H; Chen, L J; Cheng, J T



[Hemorheological effects of thiophane on tetrachloromethane induced hepatic damage].  


Carbon tetrachloride-induced hepatitis in rats is accompanied by blood hyperviscosity syndrome development. A course intragastric administration of thiophane under these conditions prevents the increase in whole blood viscosity by normalizing the microrheological indices (deformability and aggregation of erythrocytes), which is manifested by increasing oxygen availability for tissues. PMID:20919556

Smol'iakova, V I; Plotnikov, M B; Chernysheva, G A; Ivanov, I S; Prosenko, A E; Kandalintseva, N V



Ethanol induces cell cycle arrest and triggers apoptosis via Sp1-dependent p75NTR expression in human neuroblastoma cells.  


Ethanol exposure has deleterious effects on the central nervous system. Although several mechanisms for ethanol-induced damage have been suggested, the precise mechanism underlying ethanol-induced neuronal cell death remains unclear. Recent studies indicate that the p75 neurotrophin receptor (p75NTR) has a critical role in the regulation of neuronal survival. This study was designed to examine the role of p75NTR in ethanol-induced apoptotic signaling in neuroblastoma cells. Ethanol caused highly increased level of p75NTR expression. The use of small interfering RNA to inhibit p75NTR expression markedly attenuated ethanol-induced cell cycle arrest and apoptosis. DNA binding activity of Sp1 was increased by ethanol, whereas inhibition of Sp1 activity by mithramycin, a Sp1 inhibitor, or short hairpin RNA suppressed ethanol-induced p75NTR expression. In addition, inhibitors of casein kinase 2 (CK2) and extracellular signal-regulated kinase (ERK) augmented ethanol-induced p75NTR expression. Our results also demonstrate that inhibition of ERK and CK2 caused a further increase in the activation of the p75NTR proximal promoter induced by ethanol. This increased activation was partially suppressed by the deletion of the Sp1 binding sites. These results suggest that Sp1-mediated p75NTR expression is regulated at least in part by ERK and CK2 pathways. The present study also showed that treatment with ethanol resulted in significant increases in the expression of p21, but not the levels of p53 and p53 target genes such as Bax, Puma, and Bcl-2. Furthermore, the inhibition of p75NTR expression or Sp1 activity suppressed ethanol-induced p21 expression, cell cycle arrest, and apoptosis. These data suggest that ethanol increases p75NTR expression, and CK2 and ERK signaling inversely regulate Sp1-mediated p75NTR expression in ethanol-treated neuroblastoma cells. Thus, our study provides more insight into the mechanisms underlying ethanol actions. PMID:24026251

Do, Hang; Park, Hey-Jin; Sohn, Eun-Hwa; Kim, Byung-Oh; Um, Sung Hee; Kwak, Jong-Hwan; Moon, Eun-Yi; Rhee, Dong-Kwon; Pyo, Suhkneung



Evaluation of hepatoprotective effect of Amalkadi Ghrita against carbon tetrachloride-induced hepatic damage in rats  

Microsoft Academic Search

Amalkadi Ghrita (AG), a polyherbal formulation, was evaluated for its hepatoprotective activity against carbon tetrachloride (CCl4)-induced hepatic damage in rats. The hepatoprotective activity of AG was evaluated by measuring levels of serum marker enzymes like serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), and acid phosphatase (ACP). The serum levels of total proteins and bilirubin

Girish S Achliya; Sudhir G Wadodkar; Avinash K Dorle



Pharmacokinetics of norfloxacin in healthy volunteers and patients with renal and hepatic damage  

Microsoft Academic Search

The pharmacokinetics of norfloxacin were studied in six healthy volunteers, and three patients each with moderate renal and hepatic damage. A new specific and sensitive high performance liquid chromatography method was set up to measure plasma and urine concentrations of norfloxacin. The mean urinary concentrations after a single oral dose of 400 mg norfloxacin exceeded many times the MIC and

M. Eandi; I. Viano; F. Di Nola; L. Leone; E. Genazzani



Preventive effects of geranylgeranylacetone on rat ethanol-induced gastritis  

PubMed Central

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 control group were significantly lower than that in the normal control group (all P < 0.01) and the 2 model therapy groups (all P < 0.05). Scanning and transmission electron microscopy observation showed that in the model control group, the epithelial junctions were vague, the intercellular joints disappeared and damage of the intracellular organelles were significantly worse than those in the normal control group. However, in the 2 model therapy groups, damage to the intercellular joints and organelles was ameliorate relative to the model control group. CONCLUSION: Administration of geranylgeranylacetone was correlated with a more favorable pattern of gastric mucosa damage after ethanol perfusion. The mechanism could be related to regulation of ET-1, NO and PGE2.

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



Carvedilol improves ethanol-induced liver injury via modifying the interaction between oxidative stress and sympathetic hyperactivity in rats.  


AIM: Oxidative stress is a major pathway mediating ethanol hepatotoxicity and liver injury. We previously found that carvedilol, which can block the sympathetic nervous system via ?1-, ?2- and ?1-adrenoreceptors, modifies ethanol-induced production of lipogenesis- and fibrogenesis-related mediators from hepatic stellate cells (HSC). In the present study, we assessed the effects of carvedilol on ethanol-induced liver injury, hepatic insulin resistance, and the interaction between oxidative stress and sympathetic hyperactivity in rats with alcoholic fatty liver disease (AFLD). METHODS: Male Wistar rats were pair-fed for 49 days and divided into four groups: control and ethanol liquid-diet-fed rats with and without 7-day carvedilol treatment. Rats' sympathetic activity, hepatic oxidative stress, hepatic insulin resistance and liver injury were evaluated based on biochemical analysis, enzyme-linked immunosorbent assay, fluorescence immunohistochemistry, western blot and reverse transcriptase polymerase chain reaction. RESULTS: Forty-nine days of ethanol consumption induced the increases in circulating noradrenaline metabolite (3-methoxy-4-hydroxyphenylglycol), hepatic noradrenaline and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, the downregulation of hepatic insulin receptor substrate-1 gene expression, and the accumulation of fatty droplets within hepatocytes with the increased hepatic triglyceride and blood alanine aminotransferase levels. All of these changes were modified by carvedilol treatment. 8-OHdG was detected in activated HSC and suppressed by carvedilol treatment based on fluorescence immunohistochemical double-staining analysis. CONCLUSION: Carvedilol may modify the interaction between the oxidative stress and the sympathetic hyperactivity, and then contribute to attenuating the development of AFLD in rats. Additionally, oxidative stress may be responsible for the activation of HSC during the early stage of alcoholic liver disease. PMID:23607506

Hakucho, Ayako; Liu, Jinyao; Liu, Xu; Fujimiya, Tatsuya



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


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-? and IL-6) levels and myeloperoxidase (MPO) activity, as well as the expression of nuclear factor-?B (NF-?B) 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-?B expression. PMID:23769714

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



Timing of reinfection and mechanisms of hepatocellular damage in transplanted hepatitis C virus-reinfected liver.  


Pathogenic mechanisms and dynamics of hepatitis C virus (HCV) reinfection in orthotopic liver transplantation (OLT) are poorly defined. This study focuses on these aspects by studying 55 frozen biopsy specimens from transplant recipients with various histological diagnoses obtained from 4 days to 4 years post-OLT and 10 patients with HCV-related chronic hepatitis. The percentage of HCV-infected hepatocytes, number and distribution of CD8 and natural killer cells, and rates of hepatocellular apoptosis and proliferation were quantified by immunohistochemistry. HCV antigens were detected in 37% of biopsy specimens obtained within 20 days and 90% of biopsy specimens obtained from 21 days to 6 months after OLT. The number of HCV-infected hepatocytes was never less than 40% in acute hepatitis specimens and never greater than 30% in the other cases. Hepatocellular apoptosis was high in biopsy specimens of acute hepatitis and moderate in those from transplant recipients with normal histological characteristics, but still greater than in specimens of chronic active hepatitis. Proliferation correlated significantly with apoptosis. Lymphocyte infiltration was high and similar among cases of acute hepatitis, chronic hepatitis, and rejection. These data: (1) show that the detection of liver HCV antigens is sensitive enough to be used in clinical practice as a diagnostic tool to detect infection of the transplanted liver and might be useful, combined with conventional histological evaluation to detect hepatitic damage, for therapeutic decision making; (2) suggest direct cytotoxicity of HCV, as well as immunologic mechanisms possibly prevalent in chronic hepatitis and rejection, at least in the phase of acute massive liver infection; and (3) show that hepatocellular apoptosis and regeneration might be active enough to lead to replacement of the entire transplanted liver in 2 weeks. PMID:11799480

Ballardini, Giorgio; De Raffele, Emilio; Groff, Paolo; Bioulac-Sage, Paulette; Grassi, Alberto; Ghetti, Sabrina; Susca, Micaela; Strazzabosco, Mario; Bellusci, Roberto; Iemmolo, Rosa Maria; Grazi, Gianluca; Zauli, Daniela; Cavallari, Antonino; Bianchi, Francesco Bianco



AMPA Receptor Potentiation can Prevent Ethanol-Induced Intoxication  

Microsoft Academic Search

We present a substantial series of behavioral and imaging experiments, which demonstrate, for the first time, that increasing AMPA receptor-mediated neurotransmission via administration of potent and selective biarylsulfonamide AMPA potentiators LY404187 and LY451395 reverses the central effects of an acutely intoxicating dose of ethanol in the rat. Using pharmacological magnetic resonance imaging (phMRI), we observed that LY404187 attenuated ethanol-induced reductions

Nicholas Jones; Marcus J Messenger; Michael J O'Neill; Anna Oldershaw; Gary Gilmour; Rosa M A Simmons; Smriti Iyengar; Vincenzo Libri; Mark Tricklebank; Steve C R Williams



Recovery of Saccharomyces cerevisiae from ethanol - induced growth inhibition  

SciTech Connect

Ethanol caused altered mobility of the lipophilic probe 1,6-diphenyl-1,3,5-hexatriene in plasma membrane preparations of Saccharomyces cerevisiae. Because lipids had been shown to protect yeast cells against ethanol toxicity, sterols, fatty acids, proteins, and combinations of these were tested; however, protection from growth inhibition was not seen. Ethanol-induced, prolonged lag periods and diminished growth rates in S. cerevisiae were reduced by an autoconditioning of the medium by the inoculum.

Walker-Caprioglio, H.M.; Rodriguez, R.J.; Parks, L.W.



Recovery of Saccharomyces cerevisiae from ethanol - induced growth inhibition  

Microsoft Academic Search

Ethanol caused altered mobility of the lipophilic probe 1,6-diphenyl-1,3,5-hexatriene in plasma membrane preparations of Saccharomyces cerevisiae. Because lipids had been shown to protect yeast cells against ethanol toxicity, sterols, fatty acids, proteins, and combinations of these were tested; however, protection from growth inhibition was not seen. Ethanol-induced, prolonged lag periods and diminished growth rates in S. cerevisiae were reduced by

H. M. Walker-Caprioglio; R. J. Rodriguez; L. W. Parks



Recovery of Saccharomyces cerevisiae from ethanol-induced growth inhibition.  

PubMed Central

Ethanol caused altered mobility of the lipophilic probe 1,6-diphenyl-1,3,5-hexatriene in plasma membrane preparations of Saccharomyces cerevisiae. Because lipids had been shown to protect yeast cells against ethanol toxicity, sterols, fatty acids, proteins, and combinations of these were tested; however, protection from growth inhibition was not seen. Ethanol-induced, prolonged lag periods and diminished growth rates in S. cerevisiae were reduced by an autoconditioning of the medium by the inoculum.

Walker-Caprioglio, H M; Rodriguez, R J; Parks, L W



Effect of dried fruits of Solanum nigrum LINN against CCl4-induced hepatic damage in rats.  


Ethanol extract of Solanum nigrum LINN was investigated for its hepatoprotective activity against CCl4-induced hepatic damage in rats. The ethanol extract showed remarkable hepatoprotective activity. The activity was evaluated using biochemical parameters such as serum aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP) and total bilirubin. The histopathological changes of liver sample in treated animals were compared with respect to control. PMID:14600413

Raju, Kuppuswamy; Anbuganapathi, Govindaraju; Gokulakrishnan, Velusamy; Rajkapoor, Balasubramanian; Jayakar, Balasundarm; Manian, Sellamuthu



Bamboo salt attenuates CCl4-induced hepatic damage in Sprague-Dawley rats.  


Bamboo salt, a Korean folk medicine, is prepared with solar salt (sea salt) and baked several times at high temperatures in a bamboo case. In this study, we compared the preventive effects of bamboo salt and purified and solar salts on hepatic damage induced by carbon tetrachloride in Sprague-Dawley rats. Compared with purified and solar salts, bamboo salts prevented hepatic damage in rats, as evidenced by significantly reduced serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase (P < 0.05). Bamboo salt (baked 9×) triggered the greatest reduction in these enzyme levels. In addition, it also reduced the levels of the proinflammatory cytokines interleukin (IL)-6, interferon (IFN)-?, and tumor necrosis factor (TNF)-?. Histopathological sections of liver tissue demonstrated the protective effect of bamboo salt, whereas sections from animals treated with the other salt groups showed a greater degree of necrosis. We also performed reverse transcription-polymerase chain reaction and western blot analyses of the inflammation-related genes iNOS, COX-2, TNF-?, and IL-1? in rat liver tissues. Bamboo salt induced a significant decrease (~80%) in mRNA and protein expression levels of COX-2, iNOS, TNF-?, and IL-1?, compared with the other salts. Thus, we found that baked bamboo salt preparations could prevent CCl4-induced hepatic damage in vivo. PMID:23964314

Zhao, Xin; Song, Jia-Le; Kil, Jeung-Ha; Park, Kun-Young



Protective Effects of Emodin and Chrysophanol Isolated from Marine Fungus Aspergillus sp. on Ethanol-Induced Toxicity in HepG2/CYP2E1 Cells  

PubMed Central

Alcohol-induced liver injury progresses from fatty infiltration followed by a harmful cause of inflammation leading to an irreversible damage. In this study, two compounds (emodin and chrysophanol) isolated from marine fungus Aspergillus sp. were examined for their protective effects against ethanol-induced toxicity in vitro. Ethanol-induced HepG2/CYP2E1 cells were treated with the compounds at various concentrations, and the results showed that there was a dose-dependent decrease of gamma-glutamyl transpeptidase (GGT) activity and increase of glutathione (GSH) in the culture media with an increase in cell viability. Furthermore, the protective effects of the compounds were evaluated by protein expression levels of GGT, GSH, and CYP2E1 using Western blot. Among the compounds, emodin addressed to the ethanol-induced cytotoxicity more effectively compared to the chrysophanol. It could be suggested that emodin isolated from this genus would be a potential candidate for attenuating ethanol induced liver damage for further industrial applications such as functional food and pharmaceutical developments.

Qian, Zhong-Ji; Zhang, Chen; Li, Yong-Xin; Je, Jae-Young; Kim, Se-Kwon; Jung, Won-Kyo



Ulcerative colitis-induced hepatic damage in mice: studies on inflammation, fibrosis, oxidative DNA damage and GST-P expression.  


There exists a close relationship between ulcerative colitis and various hepatic disorders. The present study was aimed to evaluate the hepatocellular damage in experimental colitis model. Ulcerative colitis was induced in Swiss mice by cyclic treatment with 3% w/v dextran sulfate sodium in drinking water. The severity of colitis was assessed on the basis of disease activity index and colon histology. The effect of ulcerative colitis on the liver was assessed using various biochemical parameters, histological evaluation, sirius red staining, immunohistochemical staining with peroxisome proliferator-activated receptor ?, 8-oxo-7,8-dihydro-2'-deoxyguanosine and placental glutathione S-transferase, comet assay (alkaline and modified), Terminal Deoxynucleotidyl Transferase-mediated dUTP Nick End Labeling assay and western blot analysis to detect the protein expression of nuclear factor kappa B, cyclooxygenase-2, nuclear erythroid 2-related factor 2 and NADPH: quinone oxidoreductase-1. Dextran sulfate sodium induced severe colitis in mice as evident from an elevated disease activity index and histological abnormalities. Ulcerative colitis increased the permeability of colon as apparent from a significant reduction in the expression of tight junction protein, occludin. Further, the bacterial translocation assay as well as the analysis of lipopolysaccharide level revealed the existence of various bacterial species in the liver of ulcerative colitis-induced mice. There was a significant increase in the plasma alanine and aspartate transaminases and liver triglyceride levels, expression of peroxisome proliferator-activated receptor ?, inflammatory markers, oxidative stress, fibrosis, oxidative DNA damage and apoptosis in the liver of mice. Moreover, there was an increase in the expression of nuclear factor kappa B and cyclooxygenase-2 and a reduction in the expression of nuclear erythroid 2-related factor 2 and NADPH: quinone oxidoreductase-1 in the liver of severe ulcerative colitis-induced mice. The results of the present study provide evidence that ulcerative colitis is accompanied with hepatic damage in mice. PMID:23261717

Trivedi, P P; Jena, G B



Influence of aging on ethanol-induced oxidative stress in digestive tract of rats.  


Aging and ethanol induce oxidative stress due to increased prooxidant production and decreased antioxidative capacity. The aim was to investigate the influence of aging on oxidative stress in liver, stomach and pancreas in acute ethanol intoxication. Adult (3 months) and old (18 months) male Wistar rats were divided into the following groups: control (control group rats aged 3 months (C3) and control group rats aged 18 months (C18)) and ethanol-treated groups (ethanol-treated 3-month-old rats (E3) and ethanol-treated 18-month-old rats (E18)). Ethanol was administered in five doses of 2 g/kg at 12-h intervals by orogastric tube. Tissue samples were collected for the determination of oxidative stress parameters. Malondialdehyde (MDA) concentration was increased in all the experimental groups and investigated organs versus C3 group (?p?Hepatic, gastric and pancreatic NO x level was significantly increased in E18 group when compared with E3 group (?p?ethanol-induced oxidative stress in liver, stomach and pancreas due to increased lipid peroxidation and nitrosative stress and decreased antioxidative tissue capacity. PMID:23821589

Vucevi?, D; Mladenovi?, D; Ninkovi?, M; Stankovi?, Mn; Jorgacevi?, B; Stankovi?, Ms; de Luka, S; Radosavljevi?, T



Ethanol induces rotational behavior in 6-hydroxydopamine lesioned mice  

SciTech Connect

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.

Silverman, P.B.



Ischemic and non-ischemic acute kidney injury cause hepatic damage.  


Recent studies have documented that remote organs are affected by ischemic injury to the kidney. Here we studied whether the liver also suffers damage during induction of renal ischemia-reperfusion in rats and compared this to bilateral nephrectomy. Hepatic levels of tumor necrosis factor-alpha increased significantly after 6 and 24 h of renal ischemia or nephrectomy. Malondialdehyde, an index of lipid peroxidation, increased while total glutathione was decreased in the liver in both the renal ischemia and nephrectomy groups, suggesting activation of oxidative stress. Expression of liver spermine-spermidine acetyl transferase, an enzyme upregulated in early phases of hepatic injury was significantly increased 6 h after either kidney ischemia or nephrectomy. Apoptosis was increased in hepatocytes 24 h after nephrectomy. We also found histological evidence of hepatocyte injury following both ischemia and bilateral nephrectomy. Infusion of reduced glutathione, before the induction of renal ischemia, significantly improved liver architecture and was associated with a reduction in hepatic malondialdehyde and serum alanine transaminase levels. Our study shows that acute kidney ischemia or renal failure activates oxidative stress and promotes inflammation, apoptosis, and tissue damage in hepatocytes. PMID:19177157

Golab, Fereshteh; Kadkhodaee, Mehri; Zahmatkesh, Maryam; Hedayati, Mehdi; Arab, Hossein; Schuster, Rebecca; Zahedi, Kamyar; Lentsch, Alex B; Soleimani, Manoocher



Dietary high vanadium causes oxidative damage-induced renal and hepatic toxicity in broilers.  


The purpose of this study was to investigate the renal and hepatic oxidative damage and toxicity caused by dietary high vanadium in broilers. A total of 420 one-day-old avian broilers were divided into six groups and fed on a corn-soybean basal diet as control diet (vanadium 0.073 mg/kg), and five high vanadium diets (vanadium 5 mg/kg, high vanadium group I; 15 mg/kg, high vanadium group II; 30 mg/kg, high vanadium group III; 45 mg/kg, high vanadium group IV; and 60 mg/kg, high vanadium group V) throughout the experimental period of 42 days. The results showed that the renal and hepatic superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, ability to inhibit hydroxy radical, and malondialdehyde (MDA), glutathione, and vanadium contents were not significantly changed in high vanadium group I and II when compared with those of the control groups. However, the SOD and GSH-Px activities, ability to inhibit hydroxy radical, and GSH content were significantly decreased, and the MDA and vanadium contents were markedly increased in high vanadium groups III, IV, and V. At the same time, the lesions were also observed in the kidney and liver of high vanadium groups III, IV, and V. The renal tubular epithelial cells showed granular degeneration and vacuolar degeneration, and hepatocytes showed granular degeneration, vacuolar degeneration, and fatty degeneration. It was concluded that dietary vanadium in the range of 30-60 mg/kg could cause oxidative damage and vanadium accumulation, which induced renal and hepatic toxicity and lesions. The renal and hepatic function was finally impaired in boilers. PMID:21882068

Liu, Juan; Cui, Hengmin; Liu, Xiaodong; Peng, Xi; Deng, Junliang; Zuo, Zhicai; Cui, Wei; Deng, Yuanxin; Wang, Kangping



Alcohol and Hepatitis C Virus -Interactions in Immune Dysfunctions and Liver Damage  

PubMed Central

Hepatitis C virus infection affects 170 million people worldwide and the majority of individuals exposed to HCV develop chronic hepatitis leading to progressive liver damage, cirrhosis and hepatocellular cancer. The natural history of HCV infection is influenced by genetic and environmental factors of which chronic alcohol use is an independent risk factor for cirrhosis in HCV infected individuals. Both the hepatitis C virus and alcohol damage the liver and result in immune alterations contributing to both decreased viral clearance and liver injury. This review will capture the major components of the interactions between alcohol and HCV infection to provide better understanding for the molecular basis of the dangerous combination of alcohol use and HCV infection. Common targets of HCV and alcohol involve innate immune recognition and dendritic cells, the critical cell type in antigen presentation and antiviral immunity. In addition, both alcohol and HCV affect intracellular processes critical for hepatocyte and immune cell functions including mitochondrial and proteasomal activation. Finally, both chronic alcohol use and hepatitis C virus infection increase the risk of hepatocellular cancer. The common molecular mechanisms underlying the pathological interactions between alcohol and HCV include the modulation of cytokine production, lipopolysaccharide (LPS)-TLR4 signaling, and reactive oxygen species (ROS) production. LPS-induced chronic inflammation is not only a major cause of progressive liver injury and fibrosis but it can also contribute to modification of the tissue environment and stem cells to promote hepatocellular cancer development. Alteration of these processes by alcohol and HCV produces an environment of impaired antiviral immune response, greater hepatocellular injury and activation of cell proliferation and dedifferentiation.

Szabo, Gyongyi; Wands, Jack R.; Eken, Ahmet; Osna, Natalia A.; Weinman, Steven A.; Machida, Keigo; Wang, H. Joe



Neuroprotection with metformin and thymoquinone against ethanol-induced apoptotic neurodegeneration in prenatal rat cortical neurons  

PubMed Central

Background Exposure to ethanol during early development triggers severe neuronal death by activating multiple stress pathways and causes neurological disorders, such as fetal alcohol effects or fetal alcohol syndrome. This study investigated the effect of ethanol on intracellular events that predispose developing neurons for apoptosis via calcium-mediated signaling. Although the underlying molecular mechanisms of ethanol neurotoxicity are not completely determined, mitochondrial dysfunction, altered calcium homeostasis and apoptosis-related proteins have been implicated in ethanol neurotoxicity. The present study was designed to evaluate the neuroprotective mechanisms of metformin (Met) and thymoquinone (TQ) during ethanol toxicity in rat prenatal cortical neurons at gestational day (GD) 17.5. Results We found that Met and TQ, separately and synergistically, increased cell viability after ethanol (100 mM) exposure for 12 hours and attenuated the elevation of cytosolic free calcium [Ca2+]c. Furthermore, Met and TQ maintained normal physiological mitochondrial transmembrane potential (??M), which is typically lowered by ethanol exposure. Increased cytosolic free [Ca2+]c and lowered mitochondrial transmembrane potential after ethanol exposure significantly decreased the expression of a key anti-apoptotic protein (Bcl-2), increased expression of Bax, and stimulated the release of cytochrome-c from mitochondria. Met and TQ treatment inhibited the apoptotic cascade by increasing Bcl-2 expression. These compounds also repressed the activation of caspase-9 and caspase-3 and reduced the cleavage of PARP-1. Morphological conformation of cell death was assessed by TUNEL, Fluoro-Jade-B, and PI staining. These staining methods demonstrated more cell death after ethanol treatment, while Met, TQ or Met plus TQ prevented ethanol-induced apoptotic cell death. Conclusion These findings suggested that Met and TQ are strong protective agents against ethanol-induced neuronal apoptosis in primary rat cortical neurons. The collective data demonstrated that Met and TQ have the potential to ameliorate ethanol neurotoxicity and revealed a possible protective target mechanism for the damaging effects of ethanol during early brain development.



Reduced Adrenomedullin Expression in Gastric Mucosa of Portal Hypertensive Rats After Ethanol-Induced Injury  

PubMed Central

Objective To determine the expression and localization of adrenomedullin (AM) and its receptor (AM-R) in portal hypertensive (PHT) gastric mucosa after intragastric ethanol administration. Summary Background Data The repair of gastric mucosal injury requires reestablishment of the microvascular network. The authors previously demonstrated impaired angiogenesis of PHT gastric mucosa after ethanol-induced injury. Because AM, a potent vasodilatory peptide, is also a novel growth and angiogenic factor, the authors hypothesized that AM is involved in the impaired repair of PHT gastric mucosa and its microvasculature after damage. Methods Either PHT or sham-operated rats received intragastrically 100% ethanol, and the stomachs were excised at 1, 6, and 24 hours later. Expression and localization of AM and AM-R mRNA were examined by competitive reverse transcription–polymerase chain reaction and in situ hybridization. AM protein expression was examined by Western blot analysis. Results One hour after ethanol administration, AM mRNA expression in PHT gastric mucosa was significantly decreased by 81%, especially in the superficial mucosa, compared with the gastric mucosa in sham-operated rats. The significant decrease lasted for 24 hours. AM protein expression was significantly decreased by 43% compared with the sham-operated gastric mucosa. Although AM-R mRNA expression in both groups was significantly increased 1 hour after ethanol administration and lasted for 24 hours compared with baseline, there were no differences between the two groups. Conclusions The expression of AM in PHT gastric mucosa after ethanol-induced injury is significantly decreased compared with controls. This finding could explain one mechanism for the impaired angiogenesis after injury of PHT gastric mucosa.

Tomikawa, Morimasa; Wang, Hongtao; Jones, Michael K.; Sugimachi, Keizo; Sarfeh, I. James; Tarnawski, Andrzej S.



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


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

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



Effect of ethanolic leaf extract of Trianthema portulacastrum L. On aflatoxin induced hepatic damage in rats.  


The aim of this study was to investigate the ethanolic leaf extract of Trianthema portulacastrum L. (Family: Aizoaceae) on aflatoxin induced hepatic damage in rats. Aflatoxin intoxication in rats significantly (p < 0.001) elevated the levels of serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (ALP), and total bilirubin, which indicated acute hepatocellular damage and biliary obstruction. Ethanolic leaf extract of T. portulacastrum showed dose dependent decrease in the levels of SGPT, SGOT, ALP and total bilirubin. Minimum effective dose of extract was found to be 100 mg/kg body weight. Results obtained from histopathological studies also supported hepatoprotective activity against aflatoxin-induced hepatotoxicity. Thus the study demonstrates that T. portulacastrum possess antihepatotoxic effect against aflatoxin. PMID:23105870

Sharmila Banu, G; Kumar, G; Murugesan, A G



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


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

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



Ethanol-induced hypothermia and hyperglycemia in genetically obese mice  

SciTech Connect

Blood glucose and rectal temperatures were monitored in two strains of genetically obese mice (C57 BL/6J ob/ob) prior to and following intragastric ethanol administration in an attempt to relate the hypothermic response to ethanol to extracellular glucose concentration. In contrast to expectation, ethanol administration was typically associated with a hyperglycemia and a hypothermic response. In the ob/ob genotype, the hypothermic response was associated with pronounced hyperglycemia which was more emphatic in older animals. The data support the conclusion that ethanol-induced hypothermia is independent of blood glucose levels. In light of the known sensitivity of ob/ob mice to insulin, it is suggested further that the observed hypothermic response was not a function of the animals' ability to transport glucose into peripheral cells. The observed hyperglycemia of the obese animals was most likely stress-related

Haller, E.W.; Wittmers, L.E. Jr.



Ethanol-induced male infertility: impairment of spermatozoa.  


Ethanol is generally regarded as a reproductive toxin. However, the mechanism(s) of ethanol-induced infertility remain poorly understood. As male fertility depends upon the ability of spermatozoa to fertilize ova, it was the purpose of the present study to examine the effects of chronic ethanol treatment on several parameters related to sperm fertility. Male C57Bl/6J mice of proven fertility were administered liquid diets as follows: 5% (v/v) ethanol for either 1) 5 weeks; 2) 10 weeks; 3) 20 weeks; or 4) 6% (v/v) ethanol for 5 weeks. After each treatment, epididymal spermatozoa were evaluated with respect to quantity, motility, morphology and the ability to fertilize. A biphasic effect on sperm content was noted: 5- and 10-week treatments with 5% ethanol increased content by 80 and 65%, respectively, whereas 20-week treatment with 5% ethanol and 5-week treatment with 6% ethanol decreased content by 52 and 71%, respectively. Although the proportion of motile spermatozoa was unaffected by ethanol, average forward progression velocity was reduced, the effect being dependent on ethanol dose and duration of exposure. Similarly, the frequency of abnormal spermatozoa was increased; 20-week treatment with 5% ethanol and 5-week treatment with 6% ethanol increased the frequency of sperm morphological anomalies by 50 and 40%, respectively. Fertility of spermatozoa was reduced as a function of ethanol dose and duration of exposure. The ability of sperm to fertilize mouse ova in vitro was reduced by 34% (P less than .02) and 62% (P less than .001) subsequent to 20-week treatment with 5% ethanol and 5-week treatment with 6% ethanol, respectively. An animal model has been developed which describes ethanol-induced male infertility. The degree of reproductive impairment varies with the amount of ethanol ingested, and the duration of ethanol exposure. The continuum of effects should make possible the evaluation of putative mechanisms of male sterility resulting from chronic ethanol consumption. PMID:6682442

Anderson, R A; Willis, B R; Oswald, C; Zaneveld, L J





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Immunohistochemical studies on early stage of hepatic damage induced by subacute inhalation of toluene vapor in rats.  


Toluene is one of the most widely used organic solvents and is commonly recognized as a noxious substance inducing chronically toxic damage to neural, hepatic and renal functions in the workers engaged in printing and painting. Although hepatic cells are generally considered to be vulnerable and susceptible to various organic solvents, particularly chloroform and other halogenated hydrocarbons, the hepatotoxic effects of aromatic hydrocarbons including toluene have not yet been sufficiently characterized. In particular, it still seems unclear whether toluene itself can directly act on hepatic cells, inducing toxic damage to their metabolism and function. To assess the toxic effect of toluene inhalation on rat liver, immunohistochemical analyses of the histological markers for hepatic damage were carried out in animals exposed subacutely to toluene vapor. The immunoreactivities of heat shock proteins (HSP-70 and HSP-90) and cytochrome P4502E1 (CYP2E1) in the liver were analyzed to assess the hepatotoxic damage induced by toluene inhalation, and the expression of these histological markers was shown to be substantially enhanced by the subacute exposure to toluene vapor. Toluene inhalation was furthermore shown to enhance the immunoreactivities of alpha-smooth muscle actin (alpha-SMA), collagen, glucocorticoid receptors (GR) and leptin receptors (Ob-R) in the liver. Additional studies using human hepatoma HepG2 cells showed that toluene can directly induce toxic damage to cells. These findings suggest that toluene inhalation may primarily induce hepatic damage, which may be secondarily exacerbated by the activation of systemic processes possibly connected with glucocorticoids and leptin. PMID:19391120

Gotohda, Takako; Nishimura, Akiyoshi; Morita, Kyoji



Hepatopoietin Cn reduces ethanol-induced hepatoxicity via sphingosine kinase 1 and sphingosine 1-phosphate receptors.  


The hepatic growth factor hepatopoietin Cn (HPPCn) prevents liver injury induced by carbon tetrachloride in rats. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid produced by sphingosine kinase (SphK). S1P and S1P receptors (S1PRs) are involved in liver fibrogenesis and oxidative injury. This work sought to understand the mechanism by which SphK/S1P/S1PRs are involved in the protective effects of HPPCn on ethanol-induced liver injury and fibrosis. Transgenic mice with liver-specific overexpression of HPPCn (HPPCn(liver) (+/+)) were generated. Two ethanol feeding protocols were used to assess the protective effect of HPPCn on acute and chronic liver injury in mice. Specific inhibitors of S1PR1, S1PR2 and S1PR3 and siRNA were used to examine the roles of S1PRs in hepatic stellate cell (HSC) activation and hepatocyte apoptosis. Increased HPPCn expression in transgenic mice attenuated fibrosis induced by ethanol and carbon tetrachloride (CCl4). Treatment with recombinant human HPPCn prevented human hepatocyte apoptosis and HSC activation. JTE-013 or S1PR2-siRNA attenuated the effect of HPPCn on HSC activation induced by tumour necrosis factor-? (TNF-?). Consistent with the effect of N,N-dimethylsphingosine (DMS), suramin or S1PR3-siRNA treatment blocked HPPCn-induced Erk1/2 phosphorylation in human hepatocytes. This study demonstrated that HPPCn attenuated oxidative injury and fibrosis induced by ethanol feeding and that the SphK1/S1P/S1PRs signalling pathway contributes to the protective effect of HPPCn on hepatocyte apoptosis and HSC activation. PMID:23839903

Liu, Yang; Saiyan, Saiyan; Men, Tong-Yi; Gao, Hui-Ying; Wen, Chuan; Liu, Yong; Zhou, Xu; Wu, Chu-Tse; Wang, Li-Sheng; Cui, Chun-Ping



Coartemether induced oxidative and hepatic damage in Plasmodium berghei strain Anka infected mice.  


This study investigated the effect of coartemether on antioxidant and hepatotoxic biomarkers in Plasmodium berghei infected mice. Erythrocyte, hepatic and renal superoxide dismutase (2.71 ± 0.51; 1.96 ± 0.87; 2.84 ± 0.22 Units/mg protein respectively) and catalase (4.10 ± 0.10; 8.25 ± 1.24; 6.28 ± 0.11 Units/mg protein respectively) activities were significantly (p < 0.05) elevated in "parasitized and treated" (PnT) animals. Renal glutathione level (19.02 ± 0.20 ?g/mL) was elevated in PnT animals. Glutathione S-transferase and malondialdehyde levels in hepatic (8.76 ± 0.49 ?mol/min/mg; 527.23 ± 24.56 mmol/dL) and renal (3.35 ± 0.30 ?mol/min/mg; 464.42 ± 59.13 mmol/dL) tissues were significantly high (p < 0.05) in coartemether-treated animals alone. Plasma aspartate transferase (9.45 ± 3.59 U/L) and alanine transferase (5.78 ± 2.36 U/L) were high in PnT animals. Therefore, data indicates that in the presence of P. berghei, coartemether could alter the antioxidant status and induce hepatotoxic damage in mice. PMID:22057281

Anyasor, God'swill Nduka; Oyewole, Isaac Olayinka; Ogunwenmo, Kayode Olushola; Ayowole, Adegoke



Betulinic acid and betulin ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro.  


Ethanol consumption leads to many kinds of liver injury and suppresses innate immunity, but the molecular mechanisms have not been fully delineated. The present study was conducted to determine whether betulinic acid (BA) or betulin (BT) would ameliorate acute ethanol-induced fatty liver in mice, and to characterize whether Toll like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) were involved in ethanol-stimulated hepatic stellate cells (HSCs). EtOH (5mg/kg) and BA or BT (20 or 50mg/kg) were applied in vivo, while EtOH (50mM) and BA or BT (12.5 or 25?M) were applied in vitro. Administration of BA or BT significantly prevented the increases of serum ALT and AST caused by ethanol, as well as serum TG. Supplement of BA or BT prevented ethanol-induced acidophilic necrosis, increased hepatocyte nuclei and stromal inflammation infiltration as indicated by liver histopathological studies. Administration of BA or BT significantly decreased CYP2E1 activities and expression of SREBP-1caused by ethanol, however, lower dosage of BA or BT showed slight effects on CYP2E1 activity or expression of SREBP-1c. BA or BT administration significantly decreased the expression of TLR4, and increased the phosphorylation of STAT3. In vitro, BA or BT treatment reduced the expressions of ?-SMA and collagen-I in ethanol-stimulated HSCs via regulation of TLR4 and STAT3, coincided with in vivo. All of these findings demonstrated that BA or BT might ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro, promising agents for ethanol-induced fatty liver therapies. PMID:23816536

Wan, Ying; Jiang, Shuang; Lian, Li-Hua; Bai, Ting; Cui, Peng-He; Sun, Xiao-Ting; Jin, Xue-Jun; Wu, Yan-Ling; Nan, Ji-Xing



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

PubMed Central

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 beneficial effect in the prevention of gastric diseases related to generation of reactive oxygen species.

Alvarez-Suarez, Jose M.; Dekanski, Dragana; Ristic, Slavica; Radonjic, Nevena V.; Petronijevic, Natasa D.; Giampieri, Francesca; Astolfi, Paola; Gonzalez-Paramas, Ana M.; Santos-Buelga, Celestino; Tulipani, Sara; Quiles, Jose L.; Mezzetti, Bruno; Battino, Maurizio



The guggulsterone derivative GG-52 inhibits NF-?B signaling in gastric epithelial cells and ameliorates ethanol-induced gastric mucosal lesions in mice.  


Gastric mucosal inflammation can develop after challenge with noxious stimuli such as alcohol. Specially, alcohol stimulates the release of inflammatory cytokines but does not increase gastric acid secretion, leading to gastric mucosal damage. The plant sterol guggulsterone and its novel derivative GG-52 have been reported to inhibit nuclear factor-?B (NF-?B) signaling in intestinal epithelial cells and experimental colitis. In the present study, we investigated the anti-inflammatory effects of GG-52 on gastric epithelial cells and on ethanol-induced gastric mucosal inflammation in mice. GG-52 inhibited the expression of interleukin-8 (IL-8) in gastric epithelial AGS and MKN-45 cell lines stimulated with tumor necrosis factor (TNF)-? in a dose-dependent manner. Pretreatment with GG-52 suppressed TNF-?-induced activation of I?B kinase (IKK) and NF-?B signaling in MKN-45 cells. In contrast, the inactive analog GG-46 did not produce significant changes in IL-8 expression or NF-?B activation. In a model of ethanol-induced murine gastritis, administration of GG-52 significantly reduced the severity of gastritis, as assessed by macroscopic and histological evaluation of gastric mucosal damage. In addition, the ethanol-induced upregulation of chemokine KC, a mouse homolog of IL-8, and phosphorylated p65 NF-?B signals were significantly inhibited in murine gastric mucosa pretreated with GG-52. These results indicate that GG-52 suppresses NF-?B activation in gastric epithelial cells and ameliorates ethanol-induced gastric mucosal lesions in mice, suggesting that GG-52 may be a potential gastroprotective agent. PMID:23125156

Kim, Jung Mogg; Kim, Su Hyun; Ko, Su Hyuk; Jung, Jireh; Chun, Jaeyoung; Kim, Nayoung; Jung, Hyun Chae; Kim, Joo Sung



Sphingosine-1 phosphate prevents ethanol-induced corneal epithelial apoptosis  

PubMed Central

Background: Apoptosis is a programmed cell death in multicellular organisms, found in a wide variety of conditions, including inflammatory process, everywhere in the body, including the cornea and conjunctiva. Aim: To evaluate the effect of a new topical formulation of sphingosine-1 phosphate on preventing apoptosis of the corneal epithelium. Setting: Medical University. Materials and Methods: We tested several formulations suitable for topical application. Twenty-five rabbits were distributed among five groups. Group 1 comprised the controls. In Group 2, 20% ethanol was applied topically for 20 seconds; in Group 3, 50 ?M topical sphingosine-1 phosphate was applied 2 hours prior to 20% ethanol application. In Group 4, 200 ?M topical sphingosine-1 phosphate was applied 2 hours before the 20% ethanol application. In Group 5, only 200 ?M topical sphingosine-1 phosphate was applied. Apoptosis was evaluated using the terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (TUNEL) assay. Pairwise comparisons were performed using t-tests with Scheffe's correction. Data were analyzed using STATA 9.0 statistical software. Results: A suspension of sphingosine-1 phosphate in the presence of Montanox 80 was stable and could be formulated without sonication. Epithelial apoptosis was detected only in Groups 2 and 3. Conclusion: Sphingosine-1 phosphate can prevent ethanol-induced apoptosis in the corneal epithelium of rabbits.

Fournie, Pierre; Galiacy, Stephane; Ranty, Marie-Laure; Rico-Lattes, Isabelle; Malecaze, Francois; Quintyn, Jean-Claude



Histomorphometric Study of Fructus Psoralea on Ethanol Induced Neurodegeneration of Hippocampus in Rat  

PubMed Central

Aim: The histomophometric study of Fructus Psoralea (FP) on ethanol induced neurodegeneration of hippocampus was investigated in a rat by using micrometry. Material and Methods: The study was conducted on thirty healthy female adult wistar albino rats with regular 4-day estrus cycles. The experiment was carried out for a period of 2–4 months. The rats were divided into- SHAM operated control group (Group I) and experimental groups - overiectomised vehicle control rat ((Group II), OVX and orally treated with FP(Group III) OVX and induced with ethanol (Group IV), OVX rats induced with ethnaol and orally treated with FP (Group V). ANOVA tool was used to test the mean positive behavioural activity of all the groups. The diameter, packing density and the total number of neurons were calculated from toluidine blue stained histological section by using micrometry. The statistical package SPSS (17.0 VERSION) was used. Statistical significance was defined as p < 0.05. Data was expressed as mean ± SEM. Discussion: In animal studies, ethanol was found to significantly inhibit neuronal activity in the CA1 and CA3 pyramidal cell layers of the hippocampus. FP increase the number of cholinergic neurons in the basal forebrain which in turn leads to increased function of hippocampus, a structure heavily implicated in behavioural activity and memory consolidation. Conclusion: People with extensive hippocampal damage may experience amnesia, learning and memory disabilities. Hence the herb FP may be used as an adjuvant to treat the above neurological disorders.

Ramar, Sivanandan; P., Saraswathi



Histomorphometric study of fructus psoralea on ethanol induced neurodegeneration of hippocampus in rat.  


Aim: The histomophometric study of Fructus Psoralea (FP) on ethanol induced neurodegeneration of hippocampus was investigated in a rat by using micrometry. Material and Methods: The study was conducted on thirty healthy female adult wistar albino rats with regular 4-day estrus cycles. The experiment was carried out for a period of 2-4 months. The rats were divided into- SHAM operated control group (Group I) and experimental groups - overiectomised vehicle control rat ((Group II), OVX and orally treated with FP(Group III) OVX and induced with ethanol (Group IV), OVX rats induced with ethnaol and orally treated with FP (Group V). ANOVA tool was used to test the mean positive behavioural activity of all the groups. The diameter, packing density and the total number of neurons were calculated from toluidine blue stained histological section by using micrometry. The statistical package SPSS (17.0 VERSION) was used. Statistical significance was defined as p < 0.05. Data was expressed as mean ± SEM. Discussion: In animal studies, ethanol was found to significantly inhibit neuronal activity in the CA1 and CA3 pyramidal cell layers of the hippocampus. FP increase the number of cholinergic neurons in the basal forebrain which in turn leads to increased function of hippocampus, a structure heavily implicated in behavioural activity and memory consolidation. Conclusion: People with extensive hippocampal damage may experience amnesia, learning and memory disabilities. Hence the herb FP may be used as an adjuvant to treat the above neurological disorders. PMID:24086839

Ramar, Sivanandan; P, Saraswathi



Ethanol induces TLR4/TLR2 association, triggering an inflammatory response in microglial cells.  


Alcohol consumption can induce brain damage, demyelination, and neuronal death, although the mechanisms are poorly understood. Toll-like receptors are sensors of the innate immune system and their activation induces inflammatory processes. We have reported that ethanol activates and recruits Toll-like receptor (TLR)4 receptors within the lipid rafts of glial cells, triggering the production of inflammatory mediators and causing neuroinflammation. Since TLR2 can also participate in the glial response and in the neuroinflammation, we investigate the effects of ethanol on TLR4/TLR2 responses. Here, we demonstrate that ethanol up-regulates TLR4 and TLR2 expression in microglial cells, inducing the production of inflammatory mediators which triggers reactive oxygen species generation and neuronal apoptosis. Ethanol also promotes TLR4/TLR2 recruitment into lipid rafts-caveolae, mimicking their activation by their ligands, lipopolysaccharide, and lipoteichoic acid (LTA). Immunoprecipitation and confocal microscopy studies reveal that ethanol induces a physical association between TLR2 and TLR4 receptors, suggesting the formation of heterodimers. Using microglia from either TLR2 or TLR4 knockout mice, we show that TLR2 potentiates the effects of ethanol on the TLR4 response reflected by the activation of MAPKs and inducible NO synthase. In summary, we provide evidence for a mechanism by which ethanol triggers TLR4/TLR2 association contributing to the neuroinflammation and neurodegeneration associated with alcohol abuse. PMID:23600947

Fernandez-Lizarbe, Sara; Montesinos, Jorge; Guerri, Consuelo



Therapeutic efficacy of silymarin from milk thistle in reducing manganese-induced hepatic damage and apoptosis in rats.  


Oxidative stress has been proposed as a possible mechanism involved in manganese (Mn) toxicity. Using natural antioxidants against metal-induced hepatotoxicity is a modern approach. The present study investigated the beneficial role of silymarin, a natural flavonoid, in Mn-induced hepatotoxicity focusing on histopathology and biochemical approaches. Male Wistar rats were exposed orally to manganese chloride (20 mg/mL) for 30 days followed by intraperitoneal cotreatment with silymarin (100 mg/kg). Exposure to Mn resulted in a significant elevation of the plasma marker enzyme activities and bilirubin level related to liver dysfunction of reactive oxygen species (ROS) production and hepatic oxidative stress indices. This metal reduced the activities of superoxide dismutase, catalase and glutathione peroxidase and nonenzymatic antioxidant levels such as reduced glutathione, total sulfhydryl groups and vitamin C. In addition, it caused hepatic hemorrhage, cellular degeneration and necrosis of hepatocytes as indicated by liver histopathology and DNA fragmentation studies. Coadministration of silymarin alleviated Mn oxidative damage effects by inhibiting ROS generation. Histological studies also supported the beneficial role of silymarin against Mn-induced hepatic damages. Combining all, results suggested that silymarin could protect hepatic tissues against Mn-induced oxidative stress probably through its antioxidant activity. Therefore, its supplementation could provide a new approach for the reduction in hepatic complication due to Mn poisoning. PMID:22899727

Chtourou, Y; Garoui, Em; Boudawara, T; Zeghal, N



Ethanol-induced Changes in Proenkephalin mRNA Expression in the Rat Nigrostriatal Pathway  

Microsoft Academic Search

Endogenous opioid systems have been suggested to play a key role in ethanol reinforcement mechanisms and alcohol-drinking\\u000a behavior. Ethanol induces differential alterations in opioid peptide expression in brain areas of the reward circuits, which\\u000a may be linked to the reinforcing effects of ethanol. In addition, ethanol-induced alterations in opioidergic nigrostriatal\\u000a transmission could be involved in brain sensitivity to ethanol and

Milagros Méndez; Marcela Morales-Mulia; José Manuel Pérez-Luna



The Catalase Inhibitor Sodium Azide Reduces Ethanol-Induced Locomotor Activity  

Microsoft Academic Search

SANCHIS-SEGURA, C., M. MIQUEL, M. CORREA AND C. M. G. ARAGON. The catalase inhibitor sodium azide reduces ethanol-induced locomotor activity. ALCOHOL 19(1) 37–42, 1999.—The involvement of brain catalase in modulating the psychopharmacological effects of ethanol was investigated by examining ethanol-induced locomotor activity in sodium azide-treated mice. Mice were pretreated with IP injections of the catalase inhibitor sodium azide (5, 10,

Carles Sanchis-Segura; Marta Miquel; Mercè Correa; Carlos M. G Aragon



Hepatitis C virus-induced up-regulation of protein phosphatase 2A inhibits histone modification and DNA damage repair.  


The molecular mechanisms underlying hepatocarcinogenesis in chronic viral hepatitis are poorly understood. A potential tumorigenic pathway could involve protein phosphatase 2A (PP2A) and protein arginine methyltransferase 1 (PRMT1), because both enzymes are dysregulated in chronic hepatitis C, and both enzymes have been involved in chromatin remodeling and DNA damage repair. We used cell lines that allow the inducible expression of hepatitis C virus proteins (UHCV57.3) and of the catalytic subunit of PP2A (UPP2A-C8) as well as Huh7.5 cells infected with recombinant cell culture-derived hepatitis C virus (HCVcc) to study epigenetic histone modifications and DNA damage repair. The induction of viral proteins, the overexpression of PP2Ac, or the infection of Huh7.5 cells with HCVcc resulted in an inhibition of histone H4 methylation/acetylation and histone H2AX phosphorylation, in a significantly changed expression of genes important for hepatocarcinogenesis, and inhibited DNA damage repair. Overexpression of PP2Ac in NIH-3T3 cells increased anchorage-independent growth. These changes were partially reversed by the treatment of cells with the methyl-group donor S-adenosyl-L-methionine (SAMe). Conclusion: Hepatitis C virus-induced overexpression of PP2Ac contributes to hepatocarcinogenesis through dysregulation of epigenetic histone modifications. The correction of defective histone modifications by S-adenosyl-L-methionine makes this drug a candidate for chemopreventive therapies in patients with chronic hepatitis C who are at risk for developing hepatocellular carcinoma. PMID:20043320

Duong, Francois H T; Christen, Verena; Lin, Shanshan; Heim, Markus H



The mitochondrial permeability transition contributes to acute ethanol-induced apoptosis in rat hepatocytes.  


Acute ethanol intoxication induces oxidative stress and apoptosis in primary cultured hepatocytes. Oxidative stress can trigger mitochondrial cytochrome c release initiating the mitochondrial pathway of apoptosis. Based on this information, we formulated the hypothesis that ethanol induced oxidative stress causes mitochondrial dysfunction resulting in apoptosis. In the present study, we found that the mitochondrial membrane permeability transition (MPT) is essential for induction of mitochondrial cytochrome c release and caspase activation of ethanol. The short-term incubation with ethanol (50 mmol/L) induced the MPT, cytochrome c release, caspase activation, and apoptosis of cultured rat hepatocytes. Hepatocyte apoptosis was prevented by caspase inhibitors (i.e., Z-VAD-fmk, DEVD-cho, and DMQD-cho). An MPT inhibitor, cyclosporin A, also prevented ethanol-induced cytochrome c release, caspase activation, and apoptosis, suggesting that acute ethanol-induced apoptosis is MPT dependent. Ethanol-induced MPT was also attenuated by N'N'-dimethylthiourea (DMTU, a scavenger of hydrogen peroxide, 10 mmol/L) and N-acetyl-cysteine (NAC, an antioxidant, 5 mmol/L). Preventing hepatocyte MPT by DMTU or NAC attenuated cytochrome c release as well as caspase activation, suggesting that ethanol-induced oxidative stress mediates the MPT. Thus, acute ethanol induces MPT via oxidative stress, and the MPT mediates mitochondrial pathway of apoptosis in hepatocytes exposed to acute ethanol. PMID:11481617

Higuchi, H; Adachi, M; Miura, S; Gores, G J; Ishii, H



Hawk tea (Litsea coreana Levl. var. lanuginose) attenuates CCl(4)-induced hepatic damage in Sprague-Dawley rats.  


Hawk tea (Litsea coreana Levl. var. lanuginose) is a traditional Chinese drink similar to green tea. In the present study, the preventive effects of Hawk tea on hepatic damage induced by carbon tetrachloride (CCl(4)) were studied in Sprague-Dawley rats. Silymarin was used as a positive control. Hawk tea was successfully shown to prevent hepatic damage in the rats. Serum levels of AST, ALT and LDH were significantly decreased when the rats were treated with varying concentrations of Hawk tea compared with silymarin (P<0.05). The lowest enzyme activities were exhibited in the 400 mg/kg Hawk tea group. This group showed reduced levels of the serum proinflammatory cytokines IL-6, IFN-? and TNF-?. In particular, the IFN-? level decreased markedly compared with the other concentration groups. The histopathology sections of liver tissue in the 400 mg/kg Hawk tea group recovered well from the CCl(4) damage, but the sections of the other concentration groups showed necrosis to a more serious degree. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot analyses of the inflammation-related genes iNOS, COX-2, TNF-? and IL-1? in the rat livers were tested. The 400 mg/kg Hawk tea group showed significantly decreased mRNA and protein expression levels of iNOS, COX-2, TNF-? and IL-1? compared with the control group. Accordingly, 400 mg/kg Hawk tea potentially contributes to the prevention of CCl(4)-induced hepatic damage in vivo. A 200 or 100 mg/kg dose of Hawk tea also demonstrated preventive effects against hepatic damage. PMID:23403509

Zhao, Xin



Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury.  


Hepatocyte cell death via apoptosis and necrosis are major hallmarks of ethanol-induced liver injury. However, inhibition of apoptosis is not sufficient to prevent ethanol-induced hepatocyte injury or inflammation. Because receptor-interacting protein kinase (RIP) 3-mediated necroptosis, a nonapoptotic cell death pathway, is implicated in a variety of pathological conditions, we tested the hypothesis that ethanol-induced liver injury is RIP3-dependent and RIP1-independent. Increased expression of RIP3 was detected in livers of mice after chronic ethanol feeding, as well as in liver biopsies from patients with alcoholic liver disease. Chronic ethanol feeding failed to induce RIP3 in the livers of cytochrome P450 2E1 (CYP2E1)-deficient mice, indicating CYP2E1-mediated ethanol metabolism is critical for RIP3 expression in response to ethanol feeding. Mice lacking RIP3 were protected from ethanol-induced steatosis, hepatocyte injury, and expression of proinflammatory cytokines. In contrast, RIP1 expression in mouse liver remained unchanged following ethanol feeding, and inhibition of RIP1 kinase by necrostatin-1 did not attenuate ethanol-induced hepatocyte injury. Ethanol-induced apoptosis, assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive nuclei and accumulation of cytokeratin-18 fragments in the liver, was independent of RIP3. Conclusion: CYP2E1-dependent RIP3 expression induces hepatocyte necroptosis during ethanol feeding. Ethanol-induced hepatocyte injury is RIP3-dependent, but independent of RIP1 kinase activity; intervention of this pathway could be targeted as a potential therapeutic strategy. PMID:23319235

Roychowdhury, Sanjoy; McMullen, Megan R; Pisano, Sorana G; Liu, Xiuli; Nagy, Laura E



Hepatitis C Virus NS2 Protein Inhibits DNA Damage Pathway by Sequestering p53 to the Cytoplasm  

PubMed Central

Chronic hepatitis C virus (HCV) infection is an important cause of morbidity and mortality globally, and often leads to end-stage liver disease. The DNA damage checkpoint pathway induces cell cycle arrest for repairing DNA in response to DNA damage. HCV infection has been involved in this pathway. In this study, we assess the effects of HCV NS2 on DNA damage checkpoint pathway. We have observed that HCV NS2 induces ataxia-telangiectasia mutated checkpoint pathway by inducing Chk2, however, fails to activate the subsequent downstream pathway. Further study suggested that p53 is retained in the cytoplasm of HCV NS2 expressing cells, and p21 expression is not enhanced. We further observed that HCV NS2 expressing cells induce cyclin E expression and promote cell growth. Together these results suggested that HCV NS2 inhibits DNA damage response by altering the localization of p53, and may play a role in the pathogenesis of HCV infection.

Bittar, Cintia; Shrivastava, Shubham; Bhanja Chowdhury, Joydip; Rahal, Paula; Ray, Ratna B.



Potential of Piper guineense and Aframomum longiscapum to reduce radiation induced hepatic damage in male Wistar rats.  


The ameliorative effect of aqueous extracts of Piper guineense and Aframomum longiscapum on radiation-induced hepatic damage was evaluated. Rats were treated with a single dose of 600 rads (6 Gy) y-radiation to induce hepatic damage. Aqueous extracts of Piper guineense and Aframomum longiscapum (200 and 400 mg/kg b. wt) were administered orally to rats for two weeks prior to radiation and four weeks after radiation. Hepatic malondialdehyde (MDA), glutathione (GSH) levels and glutathione peroxidase (GPx) and catalase (CAT) activities were determined for their antioxidant capacity. The activities of serum markers such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and the histological changes were examined to evaluate potential ameliorative effects. Results from this study confirmed that exposure of animals to radiation led to induction of lipid peroxidation (LPO), reduced the level of GSH as well as CAT and GPx activities while simultaneously a significant elevation in the activities of serum ALT and AST was observed. Administration of varying doses of P.G. and A.L. before and after irradiation inhibited the elevated levels of LPO, restored the GSH level and enhanced CAT and GPx activities as well as significantly decreased the elevated levels of serum ALT and AST activities. This findings demonstrated that aqueous extracts of Piper guineense and Aframomum longiscapum might mitigate the liver gamma-radiation-induced damage probably by increasing antioxidant activities. PMID:23033796

Nwozo, S O; Okameme, P E; Oyinloye, B E


Prevention of HCl-ethanol induced gastric mucosal injury in rats by Garcinia cambogia extract and its possible mechanism of action.  


Oral pretreatment of rats with G. cambogia fruit extract (1 g/kg body weight/day at interval of 7 and 15 days) protected gastric mucosa against HCl-ethanol induced damage by decreasing the volume and acidity of gastric juice. Increased lipid peroxidation, decreased activity of antioxidant enzymes, altered levels of protein and glycoproteins in the ulcerated mucosa, and gastric juice were maintained at near normal levels in G. cambogia pretreated rats. The results suggest the anti-ulcer activity of G. cambogia by virtue of its ability to decrease acidity and increase mucosal defense. PMID:12561970

Mahendran, P; Sabitha, K E; Devi, C S Shyamala



Protective effect of apricot (Prunus armeniaca L.) on hepatic steatosis and damage induced by carbon tetrachloride in Wistar rats.  


The present study was planned to investigate the protective effect of 10 % and 20 % apricot-containing feed on carbon tetrachloride (CCl4)-induced hepatic steatosis and damage. Adult male Wistar rats (n 42) were divided into six groups of seven each, as follows: control group; CCl4 group; CCl4+10 % apricot group; CCl4+20 % apricot group; 10 % apricot group; 20 % apricot group. All apricot groups were fed with 10 % or 20 % apricot-containing feed for 5 months. CCl4 injections were applied to the CCl4 groups at the dose of 1 mg/kg for 3 d at the end of 5 months. In the CCl4 group, vacuolated hepatocytes and hepatic necrosis were seen, especially in the centrilobular area. Hepatocytes showed an oedematous cytoplasmic matrix, large lipid globules and degenerated organelles. The area of liver injury was found significantly decreased with apricot feeding. Malondialdehyde and total glutathione levels and catalase, superoxide dismutase and glutathione peroxidase activities were significantly changed in the CCl4 group and indicated increased oxidative stress. Apricot feeding decreased this oxidative stress and ameliorated histological damage. We concluded that apricot feeding had beneficial effects on CCl4-induced liver steatosis and damage probably due to its antioxidant nutrient (beta-carotene and vitamin) contents and high radical-scavenging capacity. Dietary intake of apricot can reduce the risk of liver steatosis and damage caused by free radicals. PMID:19822030

Ozturk, Feral; Gul, Mehmet; Ates, Burhan; Ozturk, I Cetin; Cetin, Asli; Vardi, Nigar; Otlu, Ali; Yilmaz, Ismet



Diabetes-Induced Hepatic Pathogenic Damage, Inflammation, Oxidative Stress, and Insulin Resistance Was Exacerbated in Zinc Deficient Mouse Model  

PubMed Central

Objectives Zinc (Zn) deficiency often occurs in the patients with diabetes. Effects of Zn deficiency on diabetes-induced hepatic injury were investigated. Methods Type 1 diabetes was induced in FVB mice with multiple low-dose streptozotocin. Hyperglycemic and age-matched control mice were treated with and without Zn chelator, N,N,N?,N?-tetrakis (2-pyridylemethyl) ethylenediamine (TPEN), at 5 mg/kg body-weight daily for 4 months. Hepatic injury was examined by serum alanine aminotransferase (ALT) level and liver histopathological and biochemical changes. Results Hepatic Zn deficiency (lower than control level, p<0.05) was seen in the mice with either diabetes or TPEN treatment and more evident in the mice with both diabetes and TPEN. Zn deficiency exacerbated hepatic injuries, shown by further increased serum ALT, hepatic lipid accumulation, inflammation, oxidative damage, and endoplasmic reticulum stress-related cell death in Diabetes/TPEN group compared to Diabetes alone. Diabetes/TPEN group also showed a significant decrease in nuclear factor-erythroid 2-related factor 2 (Nrf2) expression and transcription action along with significant increases in Akt negative regulators, decrease in Akt and GSK-3? phosphorylation, and increase in nuclear accumulation of Fyn (a Nrf2 negative regulator). In vitro study with HepG2 cells showed that apoptotic effect of TPEN at 0.5–1.0 µM could be completely prevented by simultaneous Zn supplementation at the dose range of 30–50 µM. Conclusions Zn is required for maintaining Akt activation by inhibiting the expression of Akt negative regulators; Akt activation can inhibit Fyn nuclear translocation to export nuclear Nrf2 to cytoplasm for degradation. Zn deficiency significantly enhanced diabetes-induced hepatic injury likely through down-regulation of Nrf2 function.

Zhang, Chi; Lu, Xuemian; Tan, Yi; Li, Bing; Miao, Xiao; Jin, Litai; Shi, Xue; Zhang, Xiang; Miao, Lining; Li, Xiaokun; Cai, Lu



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


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

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



Cyanamide reduces brain catalase and ethanol-induced locomotor activity: is there a functional link?  

Microsoft Academic Search

The present study was designed in an attempt to assess a previously suggested role of brain catalase activity in ethanol-induced\\u000a behaviour by examining ethanol-induced locomotor activity in cyanamide-treated mice. Mice were pretreated with IP injections\\u000a of the catalase inhibitor cyanamide (3.75, 7.5, 15, 30 or 45?mg\\/kg) or saline. Following this treatment, animals in each group\\u000a received IP injections of ethanol

Carles Sanchis-Segura; Marta Miquel; Mercè Correa; Carlos M. G. Aragon



Protective Role of Ficus carica Stem Extract against Hepatic Oxidative Damage Induced by Methanol in Male Wistar Rats  

PubMed Central

The present study was aimed to investigate the antioxidant activity of Ficus carica stem extract (FE) in methanol-induced hepatotoxicity in male Wistar rats. The rats were divided into two batches: 16 control rats (C) drinking tap water and 16 treated rats drinking Ficus carica stem extract for six weeks. Then, each group was divided into two subgroups, and one of them was intraperitoneally injected (i.p.) daily methanol at a dose of 2.37?g/kg body weight i.p. for 30 days, for four weeks. The results showed that FE was found to contain large amounts of polyphenols and carotenoids. The treatment with methanol exhibited a significant increase of serum hepatic biochemical parameters (ALT, AST, ALP, and LDH) and hepatic lipid peroxidation. Hepatic antioxidant enzymes, namely, SOD, CAT, and GSH-Px, were significantly decreased in methanol-treated animals. FE treatment prior to methanol intoxication has significant role in protecting animals from methanol-induced hepatic oxidative damage.

Saoudi, Mongi; El Feki, Abdelfattah



Protective Role of Ficus carica Stem Extract against Hepatic Oxidative Damage Induced by Methanol in Male Wistar Rats.  


The present study was aimed to investigate the antioxidant activity of Ficus carica stem extract (FE) in methanol-induced hepatotoxicity in male Wistar rats. The rats were divided into two batches: 16 control rats (C) drinking tap water and 16 treated rats drinking Ficus carica stem extract for six weeks. Then, each group was divided into two subgroups, and one of them was intraperitoneally injected (i.p.) daily methanol at a dose of 2.37?g/kg body weight i.p. for 30 days, for four weeks. The results showed that FE was found to contain large amounts of polyphenols and carotenoids. The treatment with methanol exhibited a significant increase of serum hepatic biochemical parameters (ALT, AST, ALP, and LDH) and hepatic lipid peroxidation. Hepatic antioxidant enzymes, namely, SOD, CAT, and GSH-Px, were significantly decreased in methanol-treated animals. FE treatment prior to methanol intoxication has significant role in protecting animals from methanol-induced hepatic oxidative damage. PMID:22203864

Saoudi, Mongi; El Feki, Abdelfattah



Bile composition, plasma lipids and oxidative hepatic damage induced by calcium supplementation; effects of goat or cow milk consumption.  


Calcium-fortified foods, especially milk and dairy products are recommended to be consumed daily for groups in risk of nutritional deficiency, including children, young adults, menopausal women, pregnant women and the elderly, however Ca-supplementation promotes gallstone formation because Ca is a nucleating factor. The objective of the current study was to assess the influence of cow or goat milk-based diets, either normal or Ca-supplemented, on bile composition, biochemical parameters and hepatic antioxidant status. Weanling male rats were randomly divided into six groups, fed standard, goat or cow milk-based diets, either with normal Ca content (5.0 g/kg), or Ca-supplemented (10.0 g/kg), for 2 weeks. Bile cholesterol concentration and output was higher in rats fed goat milk in comparison with those fed with standard and cow-milk-based diet. Ca-supplementation increased lithogenic index with the standard and cow-milk based diets, this change was not observed with the goat milk diet. Activities of plasma transaminases were also lower in the animals fed Ca-supplemented goat milk, in comparison with the other diets assayed. In general, Ca-supplement in the diet led to an increase in the hepatic oxidative damage, with an increase in the activities of all the antioxidant enzymes studied in the standard and cow milk diet, but not with goat milk. The habitual consumption of goat milk has positive effects on the plasma lipid profile, biliary composition and hepatic antioxidant defence. In addition, under our experimental conditions, Ca-supplementation of this type of milk does not increase the lithogenic index, or hepatic oxidative damage. PMID:23470261

Díaz-Castro, Javier; Alférez, María J M; López-Aliaga, Inmaculada; Nestares, Teresa; Sánchez-Alcover, Ana; Campos, Margarita S




Technology Transfer Automated Retrieval System (TEKTRAN)

Clinical surveys indicate that heavy drinking is a risk factor for the development of osteoporosis. However, the molecular mechanisms underlying ethanol-induced bone loss remain the subject of dispute with some studies showing ethanol effects on bone formation and others on bone breakdown. In thes...


Microcirculatory stasis precedes tissue necrosis in ethanol-induced gastric mucosal injury in the rat  

Microsoft Academic Search

The relation of blood flow stasis to the development of unequivocal histologic necrosis (loss of parietal cells from the column of contiguous cells) in ethanol-induced gastric mucosal injury was studied in anesthetized rats. The most rapid vascular change that occurred when the gastric mucosa was exposed to 100% ethanol was a severe segmental constriction of the large submucosal venules. At

Charles F. Bou-Abboud; Harold Wayland; Gary Paulsen; Paul H. Guth




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...


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

Microsoft Academic Search

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

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



Zinc inhibits ethanol-induced HepG2 cell apoptosis  

SciTech Connect

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.

Szuster-Ciesielska, Agnieszka [Department of Virology and Immunology, Maria Curie-Sklodowska University, Akademicka 19, 20-033 Lublin (Poland)], E-mail:; Plewka, Krzysztof [Department of Virology and Immunology, Maria Curie-Sklodowska University, Akademicka 19, 20-033 Lublin (Poland); Daniluk, Jadwiga [Department and Clinic of Gastroenterology, University Medical School, Jaczewskiego 8, 20-950 Lublin (Poland); Kandefer-Szerszen, Martyna [Department of Virology and Immunology, Maria Curie-Sklodowska University, Akademicka 19, 20-033 Lublin (Poland)



Basal and Ethanol-Induced Cardiac Contractile Response in Lean and Obese Zucker Rat Hearts  

Microsoft Academic Search

Obesity plays a pivotal role in metabolic and cardiovascular diseases. Certain types of obesity may be related to alcohol ingestion, which itself leads to impaired cardiac function. This study analyzed basal and ethanol-induced cardiac contractile response using left-ventricular papillary muscles and myocytes from lean and obese Zucker rats. Contractile properties analyzed include: peak tension development (PTD), peak shortening amplitude (PS),

Jun Ren; Mary F. Walsh; LeQuishia Jefferson; Melissa Natavio; Karl J. Ilg; James R. Sowers; Ricardo A. Brown



Basal and ethanol-induced cardiac contractile response in lean and obese zucker rat hearts  

Microsoft Academic Search

Obesity plays a pivotal role in metabolic and cardiovascular diseases. Certain types of obesity may be related to alcohol ingestion, which itself leads to impaired cardiac function. This study analyzed basal and ethanol-induced cardiac contractile response using left-ventricular papillary muscles and myocytes from lean and obese Zucker rats. Contractile properties analyzed include: peak tension development (PTD), peak shortening amplitude (PS),

Jun Ren; Mary F. Walsh; LeQuishia Jefferson; Melissa Natavio; Karl J. Ilg; James R. Sowers; Ricardo A. Brown



Mitochondrial Permeability Transition Pore Inhibitors Prevent Ethanol-Induced Neuronal Death in Mice.  


Ethanol induces brain injury by a mechanism that remains partly unknown. Mitochondria play a key role in cell death processes, notably through the opening of the permeability transition pore (PTP). Here, we tested the effect of ethanol and PTP inhibitors on mitochondrial physiology and cell viability both in vitro and in vivo. Direct addition of ethanol up to 100 mM on isolated mouse brain mitochondria slightly decreased oxygen consumption but did not affect PTP regulation. In comparison, when isolated from ethanol-treated (two doses of 2 g/kg, 2 h apart) 7-day-old mouse pups, brain mitochondria displayed a transient decrease in oxygen consumption but no change in PTP regulation or H(2)O(2) production. Conversely, exposure of primary cultured astrocytes and neurons to 20 mM ethanol for 3 days led to a transient PTP opening in astrocytes without affecting cell viability and to a permanent PTP opening in 10 to 20% neurons with the same percentage of cell death. Ethanol-treated mouse pups displayed a widespread caspase-3 activation in neurons but not in astrocytes and dramatic behavioral alterations. Interestingly, two different PTP inhibitors (namely, cyclosporin A and nortriptyline) prevented both ethanol-induced neuronal death in vivo and ethanol-induced behavioral modifications. We conclude that PTP opening is involved in ethanol-induced neurotoxicity in the mouse. PMID:23268549

Lamarche, Frederic; Carcenac, Carole; Gonthier, Brigitte; Cottet-Rousselle, Cecile; Chauvin, Christiane; Barret, Luc; Leverve, Xavier; Savasta, Marc; Fontaine, Eric



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

SciTech Connect

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.

Chakraborty, Goutam [Laboratory of Neurobehavior Genetics, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 (United States); Department of Chemistry and Biochemistry, Montclair State University, Upper Montclair, NJ 07043 (United States); Saito, Mitsuo [Division of Analytical Psychopharmacology, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 (United States); Department of Psychiatry, New York University Medical Center, New York, NY 10016 (United States); Mao, Rui-Fen; Wang, Ray [Laboratory of Neurobehavior Genetics, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 (United States); Vadasz, Csaba [Laboratory of Neurobehavior Genetics, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 (United States); Department of Psychiatry, New York University Medical Center, New York, NY 10016 (United States); Saito, Mariko [Laboratory of Neurobehavior Genetics, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962 (United States); Department of Psychiatry, New York University Medical Center, New York, NY 10016 (United States)], E-mail:



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

NASA Astrophysics Data System (ADS)

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.

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



Calcium/calmodulin-dependent protein kinase IV limits organ damage in hepatic ischemia-reperfusion injury through induction of autophagy  

PubMed Central

Sterile inflammatory insults, such as ischemia-reperfusion (I/R) injury, result from pathogenic factors, including damage-associated molecular pattern signaling, activation of innate immunity, and upregulation of proinflammatory cytokines. At the same time, a number of protective, or prosurvival, pathways are also activated, and the extent of end-organ damage is ultimately determined by the balance between these two systems. In liver I/R, members of the calcium/calmodulin-dependent protein kinase (CaMK) family are known to be activated, but their individual roles are largely unknown. In this study, we show that one CaMK member, CaMKIV, is protective in hepatic I/R by activating the prosurvival pathway of autophagy in hepatocytes. CaMKIV knockout mice experience significantly worse organ damage after I/R and are deficient in hepatocyte autophagic signaling. Restoration of autophagic signaling with rapamycin reduces organ damage in CaMKIV knockout mice to wild-type levels. In vitro, we show that CaMKIV activation induces autophagy in mouse hepatocytes, and that CaMKIV activation protects hepatocytes from oxidative stress-induced cell death. In conclusion, the protective autophagic signaling pathway serves to reduce organ damage following I/R and is regulated by activation of CaMKIV signaling in hepatocytes.

Evankovich, John; Zhang, Ruilin; Cardinal, Jon S.; Zhang, Lemeng; Chen, Junda; Huang, Hai; Beer-Stolz, Donna; Billiar, Timothy R.; Rosengart, Matthew R.



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

SciTech Connect

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.

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



Experimental toxic liver damage and hepatic plasma clearance of 99mTc-mebrofenin (iminodiacetate derivative). II. Recovery from the acute, CCl4-induced liver damage.  


Liver parenchyma damage was induced in rabbits by the administration of carbon tetrachloride. The animals were serially sacrificed 3, 10, 17 and 31 days post intoxication and examined morphometrically for the extent of necrosis, steatosis and balloon degeneration of hepatocytes. Biochemical indices of the liver damage were studied as well as hepatic clearance of blood plasma from Tc-99m complex of an IDA derivative Tc99m complex (99mTc-mebrofenin--99mTc-MBF) and its uptake and liver transfer characterizing parameters. It was found that toxic effects of CCl4 were conspicuous up to 10 days after administration of carbon tetrachloride. In that period elevated activity of AspAT, ALAT, GGTP and elevated cholesterol and triglycerides were found in the plasma. As in the first paper of this series of works there has been a highly significant statistical association between the Tc-MBF plasma clearance, the uptake and liver transfer of the compound and parenchyma damage in the organ. PMID:8019202

Kapu?ci?ski, J; Kuroszczyk, J; Liniecki, J; Bie?kiewicz, M; Zieli?ski, K; Tuszyner, K



Aldehyde Dehydrogenase 2 Knockout Accentuates Ethanol-Induced Cardiac Depression: Role of Protein Phosphatases  

PubMed Central

Alcohol consumption leads to myocardial contractile dysfunction possibly due to the toxicity of ethanol and its major metabolite acetaldehyde. This study was designed to examine the influence of mitochondrial aldehyde dehydrogenase-2 (ALDH2) knockout (KO) on acute ethanol exposure-induced cardiomyocyte dysfunction. Wild-type (WT) and ALDH2 KO mice were subjected to acute ethanol (3 g/kg, i.p.) challenge and cardiomyocyte contractile function was assessed 24 hrs later using an IonOptix® edge-detection system. Western blot analysis was performed to evaluate ALDH2, protein phosphatase 2A (PP2A), phosphorylation of Akt and glycogen synthase kinase-3? (GSK-3?). ALDH2 KO accentuated ethanol-induced elevation in cardiac acetaldehyde levels. Ethanol exposure depressed cardiomyocyte contractile function including decreased cell shortening amplitude and maximal velocity of shortening/relengthening as well as prolonged relengthening duration and a greater decline in peak shortening in response to increasing stimulus frequency, the effect of which was significantly exaggerated by ALDH2 KO. ALDH2 KO also unmasked an ethanol-induced prolongation of shortening duration. In addition, short-term in vitro incubation of ethanol-induced cardiomyocyte mechanical defects were exacerbated by the ALDH inhibitor cyanamide. Ethanol treatment dampened phosphorylation of Akt and GSK-3? associated with up-regulated PP2A, which was accentuated by ALDH2 KO. ALDH2 KO aggravated ethanol-induced decrease in mitochondrial membrane potential. These results suggested that ALDH2 deficiency led to worsened ethanol-induced cardiomyocyte function, possibly due to upregulated expression of protein phosphatase, depressed Akt activation and subsequently impaired mitochondrial function. These findings depict a critical role of ALDH2 in the pathogenesis of alcoholic cardiomyopathy.

Ma, Heng; Byra, Emily A.; Yu, Lu; Hu, Nan; Kitagawa, Kyoko; Nakayama, Keiichi I.; Kawamoto, Toshihiro; Ren, Jun



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

SciTech Connect

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. VA-13 cells incubated with ethanol appears to be mediated by release of mitochondrial cytochrome c via activation of caspase-9 and caspase-3. These results strongly support our hypothesis that diminished hepatic ADH activity facilitates nonoxidative metabolism of ethanol and the products of ethanol nonoxidative metabolism cause apoptosis in HepG2 cells via intrinsic pathway.

Wu Hai [University of Texas Medical Branch, Department of Pathology, 3 118A Keiller Building, Galveston, TX 77555 (United States); Cai Ping [University of Texas Medical Branch, Department of Pathology, 3 118A Keiller Building, Galveston, TX 77555 (United States); Clemens, Dahn L. [Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198 (United States); Jerrells, Thomas R. [Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198 (United States); Ansari, G.A. Shakeel [University of Texas Medical Branch, Department of Pathology, 3 118A Keiller Building, Galveston, TX 77555 (United States); Kaphalia, Bhupendra S. [University of Texas Medical Branch, Department of Pathology, 3 118A Keiller Building, Galveston, TX 77555 (United States)]. E-mail:



Hepatoprotective potential of Decalepis hamiltonii (Wight and Arn) against carbon tetrachloride-induced hepatic damage in rats.  


Hepatoprotective activity of the roots of Decalepis hamiltonii (Wight and Arn) was studied using carbon tetrachloride (CCl(4)) induced liver injury model in albino rats. The hepatotoxicity produced by acute CCl(4) administration was found to be inhibited by pretreating the rats with crude methanolic extract of the roots of D. hamiltonii (Dh) prior to CCl(4) induction. Hepatotoxic inhibition was measured with the decreased levels of hepatic serum marker enzymes (glutamate-pyruvate transaminase (GPT), glutamate oxaloacetate transaminase (GOT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) and lipid peroxide formation. Imbalance level of glutathione (GSH) and antioxidant enzymes such as catalase, glutathione peroxidase, and glutathione reductase were normalized in rats pretreated with Dh extract followed by CCl(4) administration. Pathological changes of hepatic lesions caused by CCl(4) were also improved by pretreatment with the Dh root extract. The results of this study indicate that roots of D. hamiltonii could afford a significant protective action in the alleviation of CCl(4)-induced hepatic damage in rats. PMID:21180469

Harish, R; Shivanandappa, T



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


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

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



Hydroxyethyl starch 130\\/0.4 attenuates early hepatic damage in ischemia\\/reperfusion injury  

Microsoft Academic Search

Purpose  Ischemia\\/reperfusion injury (IRI) remains a clinical challenge. We tested the hypothesis that fluid therapy using hydroxyethyl\\u000a starch (HES) 130\\/0.4 during the early phase of IRI in rat liver decreases markers of hepatic injury.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  We induced liver IRI in three groups of rats anesthetized with ketamine and chlorpromazine by means of 60 min of segmental\\u000a hepatic ischemia followed by 120 min of reperfusion.

Dora Catre ´; Joaquim S. Viana; António M. Cabrita; Manuel Oliveira; Andreia Felizes; Maria F. Lopes



Drug-induced hepatitis  


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 ...


Binge ethanol-induced neurodegeneration in rat organotypic brain slice cultures: effects of PLA2 inhibitor mepacrine and docosahexaenoic acid (DHA).  


Using rat organotypic hippocampal-entorhinal cortical (HEC) slice cultures, we examined whether phospholipase A2 (PLA2) activity is involved in binge alcohol (ethanol)-induced neurodegeneration, and whether docosahexaenoic acid (DHA; 22:6n-3), a fish oil-enriched fatty acid that is anti-inflammatory in brain damage models, is neuroprotective. Assessed with propidium iodide and lactate dehydrogenase (LDH) leakage, neurodamage from ethanol (6 days 100 mM ethanol with four withdrawal periods) was prevented by the PLA2 pan-inhibitor, mepacrine. Also, ethanol-dependent neurodegeneration-particularly in the entorhinal region-was significantly ameliorated by DHA supplementation (25 microM); however, adrenic acid, a 22:4n-6 analog, was ineffective. Consistent with PLA2 activation, [(3)H] liberation was approximately fivefold greater in [(3)H]arachidonic acid-preloaded HEC slice cultures during ethanol withdrawal compared to controls, and DHA supplementation suppressed [(3)H] release to control levels. DHA might antagonize PLA2 activity directly or suppress upstream activators (e.g., oxidative stress); however, other DHA mechanisms could be important in subdueing ethanol-induced PLA2-dependent and independent neuroinflammatory processes. PMID:18592376

Brown, James; Achille, Nicholas; Neafsey, Edward J; Collins, Michael A



Occult hepatitis B virus infection with low viremia induces DNA damage, apoptosis and oxidative stress in peripheral blood lymphocytes.  


Occult HBV infections (OHBI) are often associated with poor therapeutic response and increased risk of developing hepatocellular carcinoma. Despite a decade of research, OHBI still remains an intricate issue and much is yet to be defined about their possible immune implications. As HBV is known to infect peripheral blood lymphocytes, the present study aimed to explore the molecular mechanisms underlying DNA damage response triggered due to OHBI in host cells. The study was divided into three groups i.e. group A (OHBI patients n=30, viral load damage response, apoptosis and oxidative stress were the studied parameters. A significant increase in the phosphorylation of DNA damage response proteins (ATM, ATR, H2AX and p53) in OHBI in comparison to controls suggested that OHBI induces DNA damage in peripheral blood lymphocytes and elicit a PI3 kinase mediated cellular response. In addition, increased DNA fragmentation, circulating nucleosome levels and mitochondrial membrane depolarization observed in OHBI group indicated that this damage might lead to cellular demise and immune hypo-responsiveness. Moreover, OHBI was also observed to be strongly associated with oxidative stress as suggested by the augmented levels of DCF fluorescence and depleted GR activity. Collectively, these results provide the basic knowledge about the genotoxic effects of OHBI in peripheral blood lymphocytes. Such studies may possibly open up new avenues for identifying novel therapeutic targets for viral hepatitis. PMID:20667493

Bhargava, Arpit; Khan, Saba; Panwar, Hariom; Pathak, Neelam; Punde, Ram P; Varshney, Subodh; Mishra, Pradyumna K



Ethanol-induced hyponatremia augments brain edema after traumatic brain injury.  


Alcohol consumption augments brain edema by expression of brain aquaporin-4 after traumatic brain injury. However, how ethanol induces brain aquaporin-4 expression remains unclear. Aquaporin-4 can operate with some of ion channels and transporters. Therefore, we hypothesized that ethanol may affect electrolytes through regulating ion channels, leading to express aquaporin-4. To clarify the hypothesis, we examined role of AQP4 expression in ethanol-induced brain edema and changes of electrolyte levels after traumatic brain injury in the rat. In the rat traumatic brain injury model, ethanol administration reduced sodium ion concentration in blood significantly 24 hr after injury. An aquaporin-4 inhibitor recovered sodium ion concentration in blood to normal. We observed low sodium ion concentration in blood and the increase of brain aquaporin-4 in cadaver with traumatic brain injury. Therefore, ethanol increases brain edema by the increase of aquaporin-4 expression with hyponatremia after traumatic brain injury. PMID:22746038

Katada, Ryuichi; Watanabe, Satoshi; Ishizaka, Atsushi; Mizuo, Keisuke; Okazaki, Shunichiro; Matsumoto, Hiroshi



Protective effect of Matricaria chamomilla on ethanol-induced acute gastric mucosal injury in rats.  


The antiulcerogenic and antioxidant properties of Matricaria chamomilla L. (Compositae) hydroalcoholic extract (MCE) on ethanol-induced gastric mucosal injury were investigated in rats. After the induction of gastric mucosal injury, all groups were sacrificed; the gastric ulcer index was calculated, and malondialdehyde (MDA) and reduced glutathione (GSH) in whole blood and gastric tissue, and serum ascorbic acid, retinol, and beta-carotene levels were measured in all groups. Pretreatment with MCE at some doses significantly reduced gastric lesions. Again, some doses of MCE significantly reduced the MDA, and significantly increased GSH levels in gastric tissue or whole blood. Serum beta-carotene and retinol levels were significantly higher in the 200 mg/kg MCE-administered group with respect to control. As a result, MCE clearly has a protective effect against ethanol-induced gastric mucosal lesions, and this effect, at least in part, depends upon the reduction in lipid peroxidation and augmentation in antioxidant activity. PMID:20645773

Cemek, Mustafa; Yilmaz, Ezgi; Büyükokuro?lu, Mehmet Emin



Prenatal ethanol exposure leads to greater ethanol-induced appetitive reinforcement.  


Prenatal ethanol significantly heightens later alcohol consumption, but the mechanisms that underlie this phenomenon are poorly understood. Little is known about the basis of 'this effect of prenatal ethanol on the sensitivity to ethanol's reinforcing effects. One possibility is that prenatal ethanol exposure makes subjects more sensitive to the appetitive effects of ethanol or less sensitive to ethanol's aversive consequences. The present study assessed ethanol-induced second-order conditioned place preference (CPP) and aversion and ethanol-induced conditioned taste aversion (CTA) in infant rats prenatally exposed to ethanol (2.0 g/kg) or vehicle (water) or left untreated. The involvement of the ? opioid receptor system in ethanol-induced CTA was also explored. When place conditioning occurred during the ascending limb of the blood-ethanol curve (Experiment 1), the pups exposed to ethanol in utero exhibited greater CPP than untreated controls, with a shift to the right of the dose-response curve. Conditioning during a later phase of intoxication (30-45 min post-administration; Experiment 2) resulted in place aversion in control pups exposed to vehicle during late gestation but not in pups that were exposed to ethanol in utero. Ethanol induced a reliable and similar CTA (Experiment 3) in the pups treated with vehicle or ethanol during gestation, and CTA was insensitive to ? antagonism. These results suggest that brief exposure to a moderate ethanol dose during late gestation promotes ethanol-mediated reinforcement and alters the expression of conditioned aversion by ethanol. This shift in the motivational reactivity to ethanol may be an underlying basis of the effect of prenatal ethanol on later ethanol acceptance. PMID:22698870

Pautassi, Ricardo M; Nizhnikov, Michael E; Spear, Norman E; Molina, Juan C



Brain catalase activity is highly correlated with ethanol-induced locomotor activity in mice  

Microsoft Academic Search

It has been demonstrated that acute administration of lead to mice enhances brain catalase activity and ethanol-induced locomotion. These effects of lead seem to be related, since they show similar time courses and occur at similar doses. In the present study, in an attempt to further evaluate the relation between brain catalase activity and lead-induced changes in ethanol-stimulated locomotion, the

Mercè Correa; Carles Sanchis-Segura; Carlos M. G. Aragon



Varenicline ameliorates ethanol-induced deficits in learning in C57BL\\/6 mice  

Microsoft Academic Search

Ethanol is a frequently abused drug that impairs cognitive processes such as learning. Varenicline, an ?4?2 nicotinic receptor partial agonist and ?7 nicotinic receptor full agonist prescribed for smoking cessation, has been shown to decrease ethanol consumption. The current study investigated whether varenicline could ameliorate ethanol-induced deficits in learning and whether varenicline alters blood alcohol concentration in C57BL\\/6 mice. Conditioning

Danielle Gulick; Thomas J. Gould



Characterization of the ethanol-inducible alc gene expression system in tomato  

Microsoft Academic Search

The efficacy of the ethanol-inducible alc transgene expression system, derived from the filamentous fun- gus Aspergillus nidulans, has been demonstrated in transgenic tomato. Two direct comparisons have been made. First, this study has utilized two transgenic lines carrying distinct reporter genes (chloramphenicol acetyltransferase and b-glucuronidase) to distinguish aspects of induction determined by the nature of the gene\\/gene product rather than

G. Ali Garoosi; Michael G. Salter; Mark X. Caddick; A. Brian Tomsett



Ethanol induces calcium influx via the Cch1Mid1 transporter in Saccharomyces cerevisiae  

Microsoft Academic Search

Yeast suffers from a variety of environmental stresses, such as osmotic pressure and ethanol produced during fermentation.\\u000a Since calcium ions are protective for high concentrations of ethanol, we investigated whether Ca2+ flux occurs in response to ethanol stress. We find that exposure of yeast to ethanol induces a rise in the cytoplasmic concentration\\u000a of Ca2+. The response is enhanced in

William E. Courchesne; Christopher Vlasek; Rachel Klukovich



Ethanol-induced increase in portal blood glow: Role of adenosine  

SciTech Connect

The mechanism by which ethanol induces an increase in portal vein blood flow was studied in rats using radiolabeled microspheres. Ethanol by gavage resulted in an increase of 50-70% in portal vein blood flow. The ethanol-induced increase in portal blood flow was suppressed by the adenosine receptor blocker 8-phenyltheophylline. By itself, 8-phenyltheophylline was without effect on cardiac output or portal blood flow. Adenosine infusion resulted in a dose-dependent increase in portal blood flow. This adenosine-induced increase in portal blood flow was inhibited by 8-phenyltheophylline in a dose-dependent manner. Both alcohol and adenosine significantly reduced preportal vascular resistance by 40% and 60%, respectively. These effects were fully suppressed by 8-phenyltheophylline. It is concluded that adenosine is a likely candidate to mediate the ethanol-induced increase in portal vein blood flow. It is suggested that an increase in circulating acetate and liver hypoxia may mediate the effects of alcohol by increasing tissue and interstitial adenosine levels.

Orrego, H.; Carmichael, F.J.; Saldivia, V.; Giles, H.G.; Sandrin, S.; Israel, Y. (Univ. of Toronto, Ontario (Canada))



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

SciTech Connect

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/ 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.

Pennington, S.; Kalmus, G.



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

SciTech Connect

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.

Kvietys, P.R.; Carter, P.R. (Louisiana State Univ. Medical Center, Shreveport (United States))



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

PubMed Central

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.

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



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


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

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



Hepatic Cytochrome P450 2E1 Level Rather Than Cecal Condition Contributes to Induction of Early Stage of the Alcoholic Liver Damage in Rats  

Microsoft Academic Search

Intestinal condition and ethanol toxicity have been discussed as predictors of alcoholic liver damage. In this study, we investigated the association of hepatic antioxidant enzymes and cecal condition, including intestinal bac- teria estimated by terminal restriction fragment length polymorphism (T-RFLP), in the early stage of alcoholic fatty liver. Three liquid isocaloric diets, control (CT) diet, ethanol (ET) diet, or ethanol

Naoto Hashimoto; Hiroyuki Sekiguchi; Akira Masunaka; Katsuichi Saito; Hiroaki Yamauchi; Takahiro Noda; Kyu-Ho Han; Michihiro Fukushima



Evaluating the genotoxic damage and hepatic tissue alterations in demersal fish species: a case study in the Ligurian Sea (NW-Mediterranean).  


A protocol for detecting hepatic micronuclei in fish was performed to check genotoxic damage, as an indicator of environmental hydrocarbons exposure, in relation to the "Haven" oil spill. As target fish, we have chosen three demersal species with different habitats and feeding behaviour (i.e., Lepidorhombus boscii, Merluccius merluccius and Mullus barbatus) collected from two differently impacted areas and a control site. Additional analysis was performed by histological detection of hepatic tissue damages such as the presence of necrotic and tumour-like aspects. The three studied species showed different sensitivity to environmental pollutants exposure, L. boscii resulting the more sensitive in terms of both micronuclei incidence and tissue damage. The results of this study show that: (1) the micronucleus test could be an effective and fast method to detect oil pollution; (2) a clear response of L. boscii only to oil contamination for both micronucleus test and liver tissue alterations. PMID:11954741

Pietrapiana, D; Modena, M; Guidetti, P; Falugi, C; Vacchi, M




EPA Science Inventory

Two oral administrations of 1,2-dibromoethane to adult female rats at doses above 10 micromoles/kg (1.9 mg/kg) caused DNA damage as determined by the alkaline elution technique. Far greater doses (300 micromoles/kg, 56.4 mg/kg) of 1,2-dibromoethane were required to cause other he...


Is the intercellular adhesion molecule-1/leukocyte function associated antigen 1 pathway of leukocyte adhesion involved in the tissue damage of alcoholic hepatitis?  

PubMed Central

Alcoholic hepatitis is characterised histologically by an intense inflammatory cell infiltrate made up predominantly of neutrophils but including other cell types, particularly lymphocytes. Leukocyte cytotoxicity requires cell adhesion, which is mediated via receptors on the leukocyte surface including leukocyte function associated antigen-1 (LFA-1) which binds to the ligand intercellular adhesion molecule-1 (ICAM-1) on the target cell. The distribution of ICAM-1 and LFA-1 expression in liver biopsy specimens from patients with alcoholic liver disease was examined to ascertain whether this pathway of leukocyte adhesion is involved in the tissue damage of alcoholic hepatitis. Specimens were stained for ICAM-1 and LFA-1 by a three step immunoalkaline-phosphatase method using monoclonal antibodies against ICAM-1 and LFA-1. LFA-1 staining on portal tract inflammatory cells and parenchymal inflammatory cells and ICAM-1 staining on liver components were examined. ICAM-1 expression on hepatocytes was significantly greater in alcoholic hepatitis compared with fatty liver (p less than 0.001) and normal controls (p less than 0.01). ICAM-1 expression correlated with the histological degree of hepatocellular damage (tau = 0.79; p = 0.0005) and parenchymal inflammation (tau = 0.65; p less than 0.001, and with LFA-1 expression on parenchymal leukocytes (tau = 0.63; p = 0.01). The ICAM-1/LFA-1 pathway may therefore be involved in leukocyte mediated tissue damage during alcoholic hepatitis. Images Figure 2 Figure 3 Figure 4

Burra, P; Hubscher, S G; Shaw, J; Elias, E; Adams, D H



Hepatitis B Virus in Pregnancy  


What is hepatitis B virus? Hepatitis B virus is one of a number of hepatitis viruses that attack and damage the liver. Other types include hepatitis A, ... upper-right side of your abdomen. How is hepatitis B transmitted? Hepatitis B virus is passed from ...


Evaluation of hepatoprotective potential of jigrine post-treatment against thioacetamide induced hepatic damage  

Microsoft Academic Search

Jigrine a polypharmaceutical herbal formulation containing aqueous extracts of 14 medicinal plants developed on the principles of unani system of medicine is used for liver ailments. The hepatoprotective potential of jigrine post-treatment at the dose of 0.5 ml\\/kg per day p.o. for 21 days was evaluated against thiocetamide induced liver damage in rats. Biochemical parameters like AST, ALT in serum

Aftab Ahmad; K. K Pillai; Abul K Najmi; Shibli J Ahmad; S. N Pal; D. K Balani



The process of freezing and the mechanism of damage during hepatic cryosurgery.  


Experiments were performed to correlate the structures of liver tissue frozen during cryosurgery, liver frozen at various constant cooling rates, and unfrozen, dried normal liver. The results show that during freezing of tissue ice forms and propagates along the vascular system, expanding during freezing at low cooling rates. This expansion occurs over most of the region frozen during cryosurgery and may be one of the mechanisms of damage to tissue during cryosurgery. PMID:2311412

Rubinsky, B; Lee, C Y; Bastacky, J; Onik, G



Kupffer cells inhibition prevents hepatic lipid peroxidation and damage induced by carbon tetrachloride  

Microsoft Academic Search

The aim of this work was to determine if the action mechanism of gadolinium on CCl4-induced liver damage is by preventing lipid peroxidation (that may be induced by Kupffer cells) and its effects on liver carbohydrate metabolism. Four groups of rats were treated with CCl4, CCl4+GdCl3, GdCl3, and vehicles. CCl4 was given orally (0.4 g 100 g?1 body wt.) and

Pablo Muriel; Nicolas Alba; Victor M Pérez-Álvarez; Mineko Shibayama; Victor K Tsutsumi



Alpha7 nicotinic receptor mediated protection against ethanol-induced cytotoxicity in PC12 cells.  


Ethanol caused a concentration-dependent loss of PC12 cells over a 24 h interval, accompanied by an increase in intracellular calcium. The specific alpha7 nicotinic receptor partial agonist DMXB attenuated both of these ethanol-induced actions at a concentration (3 microM) found previously to protect against apoptotic and necrotic cell loss. The alpha7 nicotinic receptor antagonist methylylaconitine blocked the neuroprotective action of DMXB when applied with but not 30 min after the agonist. These results indicate that activation of alpha7 nicotinic receptors may be therapeutically useful in preventing ethanol-neurotoxicity. PMID:9878750

Li, Y; King, M A; Grimes, J; Smith, N; de Fiebre, C M; Meyer, E M



Ameliorating effect of balloon flower saponin on the ethanol-induced memory impairment in mice.  


The ameliorating effect of the root extract of Platycodon grandiflorum (Campanulaceae) on ethanol-induced cognitive dysfunction in mice was investigated. The mice with repeated administration of the root extract of P. grandiflorum, crude saponin fraction and platycoside E, a main ingredient of crude saponin fraction, showed a markedly prolonged step-through latency period (STL) on the passive avoidance task performed after acute ethanol intoxication, respectively. The present results suggest that the memory enhancing effect of the extract was ascribed mainly to the saponin fraction and that saponin of P. grandiflorum, particularly platycoside E could exert a beneficial effect on memory impairment in mice. PMID:18521966

Choi, Yeon Hee; Kim, Young Sup; Yeo, Su Jeong; Roh, Seong Hwan; Jeong, Young Chul; Kang, Jong Seong; Ryu, Shi Yong



Ethanol-induced death of Saccharomyces cerevisiae at low and intermediate growth temperatures  

SciTech Connect

In the upper range of growth temperatures ethanol, at physiological concentrations, affects the viability of cells of Saccharomyces cerevisiae and similar yeasts by enhancing thermal death. There is evidence, however, that yeast viability may also be affected by ethanol in such concentrations at much lower temperatures. Difficulties with yeast viability in the brewing of high-alcohol beers at low temperatures point in the same direction. Here the authors present results indicating that in addition to ethanol-enhanced thermal death, another form of ethanol-induced death occurs in S. cerevisiae that can be distinguished from the former by its temperature relations and its thermodynamic activation parameters.

Sa-Correia, I.; van Uden, N.



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

PubMed Central

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 of ethanol on the developing mouse brain when given shortly after ethanol exposure. These results suggest that nicotinamide, which has been used in humans for the treatment of diabetes and bullous pemphigoid, may hold promise as a preventive therapy of FAS.

Ieraci, Alessandro; Herrera, Daniel G



Autoconditioning factor relieves ethanol-induced growth inhibition of Saccharomyces cerevisiae  

SciTech Connect

Viable Saccharomyces cerevisiae suspended in medium containing growth-inhibiting concentrations of ethanol produce a metabolite that relieves growth inhibition. This autoconditioning of the medium by yeasts is due to the formation of small amounts (0.01%, vol/vol) of acetaldehyde. The effect is duplicated precisely in fresh medium by the addition of acetaldehyde. Acetaldehyde does not increase the yield of or accelerate ethanol production by the organism. Ethanol-induced modifications of membrane order in the plasma membranes, as measured by steady-state fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene, were not resolved by exogenously added acetaldehyde.

Walker-Caprioglio, H.M.; Parks, L.W.



Autoconditioning factor relieves ethanol-induced growth inhibition of Saccharomyces cerevisiae.  

PubMed Central

Viable Saccharomyces cerevisiae suspended in medium containing growth-inhibiting concentrations of ethanol produce a metabolite that relieves growth inhibition. This autoconditioning of the medium by yeasts is due to the formation of small amounts (0.01%, vol/vol) of acetaldehyde. The effect is duplicated precisely in fresh medium by the addition of acetaldehyde. Acetaldehyde does not increase the yield of or accelerate ethanol production by the organism. Ethanol-induced modifications of membrane order in the plasma membranes, as measured by steady-state fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene, were not resolved by exogenously added acetaldehyde.

Walker-Caprioglio, H M; Parks, L W



Protective effects of resveratrol on ethanol-induced apoptosis in embryonic stem cells and disruption of embryonic development in mouse blastocysts  

Microsoft Academic Search

Previous studies have established that ethanol induces apoptosis, but the precise molecular mechanisms are currently unclear. Here, we show that 0.3–1.0% (w\\/v) ethanol induces apoptosis in mouse blastocysts and that resveratrol, a grape-derived phytoalexin with known antioxidant and anti-inflammatory properties, prevents ethanol-induced apoptosis and inhibition of cell proliferation. Moreover, ethanol-treated blastocysts show normal levels of implantation on culture dishes in

Lien-Hung Huang; Nion-Heng Shiao; Yan-Der Hsuuw; Wen-Hsiung Chan



Evidence for the Involvement of RhoA Signaling in the Ethanol-Induced Increase in Intestinal Epithelial Barrier Permeability.  


In this work, we investigated the potential role of the small G protein RhoA in ethanol-induced tight junction (TJ) protein disassembly and increased intestinal epithelial barrier (IEB) permeability. Our study used Caco-2 cells as an in vitro IEB model and RhoA short hairpin RNA (shRNA) interference to establish whether RhoA plays a role in ethanol-induced TJ opening. RhoA shRNA interference partially inhibited epithelial leakage and restored normal transepithelial electrical resistance (TEER) values in the IEB. Moreover, RhoA shRNA interference prevented a shift in occludin distribution from insoluble to soluble fractions. Additionally, RhoA shRNA interference inhibited the ethanol-induced expression of zonula occludens-1 (ZO-1). Finally, RhoA shRNA interference inhibited an ethanol-induced increase in RhoA activity. The contributions of RhoA to an ethanol-induced increase in IEB permeability are associated with TJ disassembly. PMID:23429187

Tong, Jing; Wang, Ying; Chang, Bing; Zhang, Dai; Wang, Bingyuan



Ethanol-induced alterations in sup 14 C-glucose utilization: Modulation by brain adenosine in mice  

SciTech Connect

The possible role of brain adenosine (Ado) in acute ethanol-induced alteration in glucose utilization in the cerebellum and brain stem was investigated. The slices were incubated for 100 min in a glucose medium in Warburg flasks using {sup 14}C-glucose as a tracer. Trapped {sup 14}CO{sub 2} was counted to estimate glucose utilization. Ethanol markedly increased the glucose utilization in both areas of brain. Theophylline, an Ado antagonist, significantly reduced ethanol-induced increase in glucose utilization in both brain areas. Ado agonist CHA significantly accentuated ethanol-induced increase in glucose utilization in both motor areas. Ado agonist CHA significantly accentuated ethanol-induced increase in glucose utilization in both motor areas. Ethanol was still able to produce a smaller but significant increase in glucose utilization in both brain areas when theophylline and CHA were given together, suggesting an additional mechanism. Collectively, the data indicate that ethanol-induced glucose utilization in the cerebellum and brain stem is modulated by brain Ado receptor and by non-adenosinergic mechanism.

Anwer, J.; Dar, M.S. (East Carolina Univ., Greenville, NC (United States))



Serum IL-33 Levels Are Associated with Liver Damage in Patients with Chronic Hepatitis B  

PubMed Central

This aim of this study was to assess the potential role of IL-33 in the pathogenic process of chronic hepatitis B (CHB). The levels of serum IL-33 and soluble ST2 (sST2) in CHB patients and healthy controls (HC) were determined using enzyme-linked-immunosorbent serologic assay, and the Th1 (IFN-?, TNF–?, IL-2) and Th2 (IL-4, IL-6, IL-10) cytokines by cytometric bead array. It was found that the levels of serum IL-33 in CHB patients were significantly higher than that of HC at the base line, but decreased after treatment with adefovir dipivoxil for 12 weeks. The levels of serum sST2, as a decoy receptor of IL-33, were significantly higher in CHB patients than the HC. There was no correlation between the levels of serum sST2 and IL-33. The concentrations of serum Th1 (IFN-?, IL-2) and Th2 (IL-6, IL-10) cytokines in CHB patients significantly increased after treatment compared to the baseline. These results suggest that IL-33 is involved in the pathogenesis of CHB and that adefovir dipivoxil therapy can attenuate the production of IL-33 in patients with CHB.

Wang, Juan; Cai, Yanjun; Ji, Huifan; Feng, Junyan; Ayana, Desalegn Admassu; Niu, Junqi



Hepatoprotection by freshwater clam extract against CCl4-induced hepatic damage in rats.  


Freshwater clam is traditionally used as a food and has been mentioned in ancient books to have a hepatoprotective effect. The hepatoprotective effect of freshwater clam extract was evaluated in the model of chronic hepatic fibrosis induced by carbon tetrachloride (CCl4). Male Sprague-Dawley rats were orally treated with freshwater clam extract (0.3, 0.6 and 1.5 g/kg of bw) or silymarin (0.2 g/kg of bw) along with the administration of CCl4 (0.5 ml/rat, 20% CCl4 in olive oil) for eight consecutive weeks. Blood samples were collected for assaying serum biochemical parameters. The livers were excised for evaluating peroxidation products and antioxidant substances, as well as the activities of antioxidant enzymes. Pathological histology was also performed. The data showed that supplementation of freshwater clam extract (0.6 g/kg bw) significantly reduced the serum levels of alanine aminotransferase and aspartate aminotransferase in rats treated with CCl4, and also decreased the thiobarbituric acid reactive substances, hydroxyproline and excessive inflammation in the livers of CCl4-treated rats. Histopathological analysis of the liver showed that freshwater clam extract (0.6 g/kg bw) markedly reduced the injury score of the fibrosis induced by CCl4 in rats. The data suggest that oral administration with freshwater clam extract might provide a novel and alternative approach for treating chronic liver failure. PMID:20821820

Hsu, Chin-Lin; Hsu, Chien-Chen; Yen, Gow-Chin



Hepatoprotective effect of pinoresinol on carbon tetrachloride-induced hepatic damage in mice.  


Forsythiae Fructus is known to have diuretic, anti-bacterial, and anti-inflammatory activities. This study examined the hepatoprotective effects of pinoresinol, a lignan isolated from Forsythiae Fructus, against carbon tetrachloride (CCl(4))-induced liver injury. Mice were treated intraperitoneally with vehicle or pinoresinol (25, 50, 100, and 200 mg/kg) 30 min before and 2 h after CCl4 (20 microl/kg) injection. In the vehicle-treated CCl(4 )group, serum aminotransferase activities were significantly increased 24 h after CCl4 injection, and these increases were attenuated by pinoresinol at all doses. Hepatic glutathione contents were significantly decreased and lipid peroxidation was increased after CCl4 treatment. These changes were attenuated by 50 and 100 mg/kg of pinoresinol. The levels of protein and mRNA expression of inflammatory mediators, including tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclooxygenase-2, were significantly increased after CCl4 injection; and these increases were attenuated by pinoresinol. Nuclear translocation of nuclear factor-kappaB (NF-kappaB) and phosphorylation of c-Jun, one of the components of activating protein 1 (AP-1), were inhibited by pinoresinol. Our results suggest that pinoresinol ameliorates CCl4)-induced acute liver injury, and this protection is likely due to anti-oxidative activity and down-regulation of inflammatory mediators through inhibition of NF-kappaB and AP-1. PMID:20093790

Kim, Hyo-Yeon; Kim, Joon-Ki; Choi, Jun-Ho; Jung, Joo-Yeon; Oh, Woo-Yong; Kim, Dong Chun; Lee, Hee Sang; Kim, Yeong Shik; Kang, Sam Sik; Lee, Seung-Ho; Lee, Sun-Mee



Pinus massoniana bark extract protects against oxidative damage in L-02 hepatic cells and mice.  


The hepatoprotective activity of Pinus massoniana bark extract (PMBE) against hydrogen peroxide (H2O2)-induced damage in normal human liver L-02 cells and carbon tetrachloride (CCl4)-induced acute hepatotoxicity in mice was investigated. The L-02 cells were pre-treated with PMBE for 24 hours prior to exposure to 0.5 mM H2O2 for 3 or 24 hours. The cell viability, level of malondialdehyde (MDA) and glutathione (GSH), and the catalase (CAT) activity were evaluated. For in vivo experiments, mice were divided into groups and PMBE administered orally, after which each group was assigned a further treatment. Histopathological examination, the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and GSH, the liver tissue levels of MDA and GSH, the activities of CAT and glutathione peroxidase (GSH-Px), were evaluated. PMBE treatment decreased the level of MDA and increased the cell viability, GSH content and CAT activity in H2O2 treated L-02 cells treated for 3 hours. PMBE obviously decreased serum ALT, AST, ALP, and liver tissue MDA, while increasing serum GSH, and liver tissue CAT and GSH-Px activities. In conclusion, PMBE treatment prevents H2O2 and CCl4-induced liver damage, and therefore could have a potential clinical usage. PMID:20821822

Wang, Mei; Ma, Hong-Ling; Liu, Bing; Wang, Hong-Bin; Xie, Heng; Li, Ruo-Da; Wang, Jin-Fa



Green tea extract (Camellia sinensis) fermented by Lactobacillus fermentum attenuates alcohol-induced liver damage.  


Here, the impact of an extract derived from green tea (Camellia sinensis) and fermentation with Lactobacilli fermentum strain OCS19 was explored with acute alcohol-induced liver damage. The study employed the HepG2 hepatic cell line and an in vivo murine model of liver damage. L. fermentum-fermented green tea extract (FGTE) was found to possess pronounced alcohol metabolizing enzyme activity. It significantly enhanced the cell viability of HepG2 cells following of them exposure, to ethanol (p<0.05) as compared with an extract derived from Hovenia dulcis, a positive control that is known for its action as an alcohol antagonist. Our in vivo studies indicated that prior administration of FGTE to alcohol-exposed mice significantly prevented subsequent increases in blood alcohol concentration (p<0.05), in addition to the induction of serum alanine aminotransferase (ALT) and triglycerides (p<0.05). Furthermore, the activity of hepatic alcohol dehydrogenase (ADH) and its mRNA expression level both increased in the livers of mice treated with FGTE, similarly to the H. dulcis-treated group. Taken together, these results may suggest that green tea extract coupled with L. fermentum fermentation attenuates the risk of ethanol-induced liver damage. PMID:23221715

Park, Jong Ho; Kim, Younghoon; Kim, Sae Hun



Characterization of the ethanol-inducible alc gene expression system in tomato.  


The efficacy of the ethanol-inducible alc transgene expression system, derived from the filamentous fungus Aspergillus nidulans, has been demonstrated in transgenic tomato. Two direct comparisons have been made. First, this study has utilized two transgenic lines carrying distinct reporter genes (chloramphenicol acetyltransferase and beta-glucuronidase) to distinguish aspects of induction determined by the nature of the gene/gene product rather than that of the plant. Second, comparisons have been made to data generated in other species in order to identify any species-specific effects. The induction profiles for different genes in different species have shown remarkable similarity indicating the broad applicability of this gene switch. While there are minor differences observed between species, these probably arise from diversity in their metabolism. A series of potential alternative inducers have also been tested, revealing that ethanol (through metabolism to acetaldehyde) is better than other alcohols and ketones included in this study. Expression driven by alc was demonstrated to vary spatially, the upper younger leaves having higher activity than the lower older leaves; this will be important for some applications, and for experimental design. The highest levels of activity from ethanol-inducible transgene expression were determined to be the equivalent of those from the constitutive Cauliflower Mosaic Virus 35S promoter. This suggests that the alc system could be an important tool for plant functional genomics. PMID:15851414

Garoosi, G Ali; Salter, Michael G; Caddick, Mark X; Tomsett, A Brian



Alpha 7 nicotinic acetylcholine receptor-mediated protection against ethanol-induced neurotoxicity.  


The alpha(7)-selective nicotinic partial agonist 3-[2,4-dimethoxybenzylidene]anabaseine (DMXB) was examined for its ability to modulate ethanol-induced neurotoxicity in primary cultures of rat neurons. Primary cultures of hippocampal neurons were established from Long-Evans, embryonic day (E)-18 rat fetuses and maintained for 7 days. Ethanol (0-150 mM), DMXB (0-56 microM), or both were subsequently co-applied to cultures. Ethanol was added two additional times to the cultures to compensate for evaporation. After 5 days, neuronal viability was assessed with the MTT cell proliferation assay. Results demonstrated that ethanol reduces neuronal viability in a concentration-dependent fashion and that DMXB protects against this ethanol-induced neurotoxicity, also in a concentration-dependent fashion. These results support the suggestion that nicotinic partial agonists may be useful in treating binge drinking-induced neurotoxicity and may provide clues as to why heavy drinkers are usually smokers. PMID:14693263

de Fiebre, NancyEllen C; de Fiebre, Christopher M



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


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

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



Elevation of GM2 ganglioside during ethanol-induced apoptotic neurodegeneration in the developing mouse brain  

PubMed Central

GM2 ganglioside in the brain increased during ethanol-induced acute apoptotic neurodegeneration in 7-day-old mice. A small but a significant increase observed 2 h after ethanol exposure was followed by a marked increase around 24 h. Subcellular fractionation of the brain 24 h after ethanol treatment indicated that GM2 increased in synaptic and non-synaptic mitochondrial fractions as well as in a lysosome-enriched fraction characteristic to the ethanol-exposed brain. Immunohistochemical staining of GM2 in the ethanol-treated brain showed strong punctate staining mainly in activated microglia, in which it partially overlapped with staining for LAMP1, a late endosomal/lysosomal marker. Also, there was weaker neuronal staining, which partially co-localized with complex IV, a mitochondrial marker, and was augmented in cleaved caspase-3-positive neurons. In contrast, the control brain showed only faint and diffuse GM2 staining in neurons. Incubation of isolated brain mitochondria with GM2 in vitro induced cytochrome c release in a manner similar to that of GD3 ganglioside. Because ethanol is known to trigger mitochondria-mediated apoptosis with cytochrome c release and caspase-3 activation in the 7-day–old mouse brain, the GM2 elevation in mitochondria may be relevant to neuroapoptosis. Subsequently, activated microglia accumulated GM2, indicating a close relationship between GM2 and ethanol-induced neurodegeneration.

Saito, Mitsuo; Chakraborty, Goutam; Shah, Relish; Mao, Rui-Fen; Kumar, Asok; Yang, Dun-Sheng; Dobrenis, Kostantin; Saito, Mariko



Neuroprotective profile of pyruvate against ethanol-induced neurodegeneration in developing mice brain.  


Exposure to ethanol during developmental stages leads to several types of neurological disorders. Apoptotic neurodegeneration due to ethanol exposure is a main feature in alcoholism. Exposure of developing animals to alcohol induces apoptotic neuronal death and causes fetal alcohol syndrome. In the present study, we observed the possible protective effect of pyruvate against ethanol-induced neurodegeneration. Exposure of developing mice to ethanol (2.5 g/kg) induces apoptotic neurodegeneration and widespread neuronal cell death in the cortex and thalamus. Co-treatment of pyruvate (500 mg/kg) protects neuronal cell against ethanol by the reduced expression of caspase-3 in these brain regions. Immunohistochemical analysis and TUNNEL at 24 h showed that apoptotic cell death induced by ethanol in the cortex and thalamus is reduced by pyruvate. Histomorphological analysis at 24 h with cresyl violet staining also proved that pyruvate reduced the number of neuronal cell loss in the cortex and thalamus. The results showed that ethanol increased the expression of caspase-3 and thus induced apoptotic neurodegeneration in the developing mice cortex and thalamus, while co-treatment of pyruvate inhibits the induction of caspase-3 and reduced the cell death in these brain regions. These findings, therefore, showed that treatment of pyruvate inhibits ethanol-induced neuronal cell loss in the postnatal seven (P7) developing mice brain and may appear as a safe neuroprotectant for treating neurodegenerative disorders in newborns and infants. PMID:23494720

Ullah, Najeeb; Naseer, Muhammad Imran; Ullah, Ikram; Kim, Tae Hyun; Lee, Hae Young; Kim, Myeong Ok



Protective effect of Quercetin in the Regression of Ethanol-Induced Hepatotoxicity  

PubMed Central

This study examined the protective effects of quercetin on chronic ethanol-induced liver injury. Rats were treated with ethanol at a dose of 4 g/100 g/day for 90 days. After ethanol intoxication, levels of serum amino transferases were significantly elevated. Decreased activity of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase was also observed on ethanol administration. Increased amounts of lipid peroxidation products viz. hydroperoxides, conjugated dienes and malodialdehyde were observed on ethanol intoxication. Ethanol administration resulted in significant decrease in liver glutathione content. After 90 days, the control animals were divided into two groups, the control group and the control+quercetin group. Ethanol-treated group was divided into two groups, abstention group and quercetin-supplemented group. After 30 days, the animals were sacrificed and various biochemical parameters were analyzed. The changes in enzyme activities as well as levels of lipid peroxidation products were reversed to a certain extent by quercetin. Quercetin supplementation resulted in increase of glutathione content to a significant level compared to normal abstention group. Quercetin supplemented group showed a faster recovery than abstention group. This shows the protective effect of quercetin against chronic ethanol induced hepatotoxicity. Histopathological study is also in line with these results.

Vidhya, A.; Indira, M.



Hepatoprotective effect of total flavonoids from Laggera alata against carbon tetrachloride-induced injury in primary cultured neonatal rat hepatocytes and in rats with hepatic damage  

Microsoft Academic Search

Summary  The hepatoprotective activities of total flavonoids of Laggera alata (TFLA) were evaluated by carbon tetrachloride (CCl4)-induced injury in primary cultured neonatal rat hepatocytes and in rats with hepatic damage. In vitro, TFLA at a concentration range of 1–100  $$\\\\upmu$$g\\/ml improved cell viability and inhibited cellular leakage of two enzymes, hepatocyte aspartate aminotransferase (AST) and alanine aminotransferase (ALT), caused by CCl4.

Yihang Wu; Fang Wang; Qunxiong Zheng; Longxi Lu; Hongtian Yao; Changxin Zhou; Xiumei Wu; Yu Zhao



Hepatoprotective effect of a protein-enriched fraction from the maggots ( Musca domestica ) against CCl 4 -induced hepatic damage in rats  

Microsoft Academic Search

The hepatoprotective potential of a protein-enriched fraction (PEF) isolated from the maggots of housefly (Musca domestica) was evaluated in rats against carbon tetrachloride (CCl4)-induced acute hepatic damage. Activities of serum aspartate aminotransferase and alanine aminotransferase increased by 4-\\u000a and 13-fold induced by CCl4, were significantly inhibited by pretreatment with 50, 100 and 200 mg PEF\\/kg. The formation of malondialdehyde was also

Fu-Rong Wang; Hui Ai; Xiao-Min Chen; Chao-Liang Lei



Xanthohumol, a main prenylated chalcone from hops, reduces liver damage and modulates oxidative reaction and apoptosis in hepatitis C virus infected Tupaia belangeri.  


Hepatitis C virus (HCV) infection in Tupaia belangeri (Tupaia) represents an important model of HCV infection. Xanthohumol (XN), a major prenylated chalcone from hops, has various biological activities including hepatopreventive and anti-viral activities. In this study, Tupaias infected with HCV RNA positive serum were used to evaluate the effects of XN on liver damage, oxidative reaction, apoptosis and viral protein expression in liver tissues. The Tupaias inoculated with HCV positive serum had elevated serum aminotransferase levels and inflammation, especially hepatic steatosis, and HCV core protein expression in liver tissue. In the animals inoculated with HCV positive serum, XN significantly decreased aminotransferase levels, histological activity index, hepatic steatosis score and transforming growth factor ?1 expression in liver tissue compared with the animals without XN intervention. XN reduced HCV core protein expression in liver tissue compared with those without XN intervention but the difference was not significant. XN significantly decreased malondialdehyde, potentiated superoxide dismutase and glutathione peroxidase, reduced Bax expression, promoted Bcl-xL and inhibited caspase 3 activity in liver tissues compared with the animals without XN intervention. These results indicate that XN may effectively improve hepatic inflammation, steatosis and fibrosis induced by HCV in Tupaias primarily through inhibition of oxidative reaction and regulation of apoptosis and possible suppression of hepatic stellate cell activation. The anti-HCV potential of XN needs further investigation. PMID:23669332

Yang, Mingbo; Li, Na; Li, Fang; Zhu, Qianqian; Liu, Xi; Han, Qunying; Wang, Yawen; Chen, Yanping; Zeng, Xiaoyan; Lv, Yi; Zhang, Pingping; Yang, Cuiling; Liu, Zhengwen



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

PubMed Central

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-?B protein and TNF-? 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-? expression, NF-?B activation, and oxidative DNA damage as well as restoring normal hepatic levels of retinoic acid in DEN-treated rats.

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



Hepatoprotective action of Radix Paeoniae Rubra aqueous extract against CCl4-induced hepatic damage.  


In the present study the capacity of Radix Paeoniae Rubra aqueous extract (RPRAE) as an antioxidant to protect against carbon tetrachloride (CCl(4))-induced oxidative stress and hepatotoxicity in Wistar rats was investigated. Six groups of rats were used. Radix Paeoniae Rubra aqueous extract (100 or 200 or 300 mg/kg of bw) or bifendate (100 mg/kg of bw) were given daily by gavage to the animals on 28 consecutive days to elucidate the protective effects against CCl(4)-induced hepatotoxicity. The 20% CCl(4)/olive oil was gavage of gastric tube twice a week (on the third and seventh days of each week). The animals of normal control group were given only vehicle. The animals of CCl(4)-treated group were administered with CCl(4) twice a week (on the third and seventh days of each week) and with vehicle on rest of the days. The test materials were found effective as hepatoprotective agents, as evidenced by plasma and liver biochemical parameters. Therefore, the results of this study show that Radix Paeoniae Rubra aqueous extract can protect the liver against CCl(4)-induced oxidative damage in rats, and the hepatoprotective effects might be correlated with its antioxidant and free radical scavenger effects. PMID:22005833

Li, Ruidong; Guo, Wenyuan; Fu, Zhiren; Ding, Guoshan; Zou, You; Wang, Zhengxin



Amelioration of cyclosporine A-induced renal, hepatic and cardiac damages by ellagic acid in rats.  


Treatment with cyclosporine A has significantly improved long-term survival after organ transplantations. Cyclosporine A also causes a dose-related decrease in body functions in experimental animals and human beings. The generation of reactive oxygen species has been implicated in cyclosporine A-induced dysfunctions. The aim of this study was to determine the effects of ellagic acid on cyclosporine A-induced alterations in the kidney, liver and heart oxidant/antioxidant system. The control group was treated with placebo and subcutaneous injection of 0.5 ml isotonic saline + 0.5 ml slightly alkaline solution for 21 days. The cyclosporine A group received a subcutaneous injection of cyclosporine A (15 mg/kg) + 0.5 ml slightly alkaline solution for 21 days. The ellagic acid group was treated with a subcutaneous injection of 0.5 ml isotonic saline + ellagic acid (10 mg/kg) for 21 days. The cyclosporine A plus ellagic acid group received a subcutaneous injection of cyclosporine A + ellagic acid for 21 days. Ellagic acid and slightly alkaline solution were administered by gavage. The rats were killed at the end of the treatment period. Malondialdehyde (MDA) and reduced glutathione (GSH) levels, glutathione peroxidase (GSH-Px) and catalase (CAT) activities were determined in kidney, liver and heart tissues. While administration of cyclosporine A increased the MDA levels in kidney, liver and heart tissues, it decreased the GSH, GSH-Px and CAT in these samples when compared to the control group. However, the simultaneously administration of ellagic acid markedly normalized the cyclosporine A-induced liver and heart MDA levels, liver CAT activities and GSH-Px activities of all samples. Cyclosporine A caused marked damages in the histopathological status of kidney, liver and heart tissues, which were partially ameliorated by ellagic acid administration. In conclusion, ellagic acid may be used in combination with cyclosporine A in transplantation treatment to improve the cyclosporine A-induced oxidative stress parameters and other adverse effects. PMID:18816304

Yüce, Abdurrauf; Ate??ahin, Ahmet; Ceriba?i, Ali Osman



Ethanol-induced urticaria: elevated tryptase levels after double-blind, placebo-controlled challenge.  


We present a 48-year-old patient who complained for 1 year about urticarial reactions which appeared always when he ingested alcoholic beverages. Skin prick tests with ethanol were negative but positive with 10% acetic acid in the patient. Normal controls tested negative with acetic acid. Skin prick tests to common immediate-type allergens were negative. The patient underwent a double-blind, placebo-controlled challenge test. A few minutes after challenge with ethanol but not with placebo, the patient developed erythema and wheals on the chest and the upper arms. The tryptase serum level rose from undetectable (0.1 U/ml) before challenge to 3.8 U/ml after skin lesions had appeared. This case demonstrates that increased tryptase serum levels can help in the diagnosis of ethanol-induced urticaria. PMID:9732172

Emonet, S; Hogendijk, S; Voegeli, J; Eigenmann, P A; Roux, N; Hauser, C



Ethanol induces oxidative stress in alveolar macrophages via upregulation of NADPH oxidases  

PubMed Central

BACKGROUND Chronic alcohol abuse is a comorbid variable of Acute Respiratory Distress Syndrome (ARDS). Previous studies showed that, in the lung, chronic alcohol consumption increased oxidative stress and impaired alveolar macrophage (AM) function. NADPH oxidases (Nox) are the main source of reactive oxygen species (ROS) in AMs. Therefore, we hypothesized that chronic alcohol consumption increases AM oxidant stress through modulation of Nox1, Nox2 and Nox4 expression. METHODS AMs were isolated from male C57BL/6J mice, aged 8-10 weeks, which were treated ± ethanol in drinking water (20% w/v, 12 weeks). MH-S cells, a mouse AM cell line, were treated ± ethanol (0.08%, 3 days) for in vitro studies. Selected cells were treated with apocynin (300 ?M), a Nox1 and Nox2 complex formation inhibitor, or were transfected with Nox siRNAs (20-35 nM), prior to ethanol exposure. Human AMs were isolated from alcoholic and control patients’ bronchoalveolar lavage fluid. Nox mRNA levels (qRT-PCR), protein levels (western blot and immunostaining), oxidative stress (DCFH-DA and Amplex Red analysis), and phagocytosis (S. aureus internalization) were measured. RESULTS Chronic alcohol increased Nox expression and oxidative stress in mouse AMs in vivo and in vitro. Experiments using apocynin and Nox siRNAs demonstrated that ethanol-induced Nox4 expression, oxidative stress, and AM dysfunction were modulated through Nox1 and Nox2 upregulation. Further, Nox1, Nox2 and Nox4 protein levels were augmented in human AMs from alcoholics compared with controls. CONCLUSIONS Ethanol induces AM oxidative stress initially through upregulation of Nox1 and Nox2 with downstream Nox4 upregulation and subsequent impairment of AM function.

Yeligar, Samantha M.; Harris, Frank L.; Hart, C. Michael; Brown, Lou Ann S.



Cross-talk between phosphatidic acid and ceramide during ethanol-induced apoptosis in astrocytes  

PubMed Central

Background Ethanol inhibits proliferation in astrocytes, an effect that was recently linked to the suppression of phosphatidic acid (PA) formation by phospholipase D (PLD). The present study investigates ethanol's effect on the induction of apoptosis in astrocytes and the formation of ceramide, an apoptotic signal. Evidence is presented that the formation of PA and ceramide may be reciprocally linked during ethanol exposure. Results In cultured rat cortical astrocytes, ethanol (0.3–1 %, v/v) induced nuclear fragmentation and DNA laddering indicative of apoptosis. Concomitantly, in cells prelabeled with [3H]-serine, ethanol caused a dose-dependent, biphasic increase of the [3H]-ceramide/ [3H]-sphingomyelin ratio after 1 and 18 hours of incubation. As primary alcohols such as ethanol and 1-butanol were shown to inhibit the phospholipase D (PLD)-mediated formation of PA, a mitogenic lipid messenger, we tested their effects on ceramide formation. In astrocytes prelabeled with [3H]-serine, ethanol and 1-butanol, in contrast to t-butanol, significantly increased the formation of [3H]-ceramide. Moreover, exogenous PA, added to transiently permeabilized astrocytes, suppressed ethanol-induced [3H]-ceramide formation. Vice versa, addition of C2-ceramide to astrocytes inhibited PLD activity induced by serum or phorbol ester. Conclusion We propose that the formation of ceramide in ethanol-exposed astrocytes is secondary to the disruption of phospholipase D signaling. Ethanol reduces the PA:ceramide ratio in fetal astrocytes, a mechanism which likely participates in ethanol-induced glial apoptosis during brain development.

Schatter, Beate; Jin, Shenchu; Loffelholz, Konrad; Klein, Jochen



Protective effect of silymarin against ethanol-induced gastritis in rats: role of sulfhydryls, nitric oxide and gastric sensory afferents.  


Silymarin has been known to exert antioxidant, anti-carcinogenic and anti-inflammatory effects. In this study, we examined the effect of silymarin on gastritis in rats. Oral administration of silymarin dose-dependently decreased gastric lesions in ethanol-induced gastritis model. Silymarin also significantly suppressed the development of gastric lesions in aspirin- or water immersion-restraint stress-induced gastritis models. Further study demonstrated that the gastroprotective effect of silymarin was blocked by nitric oxide (NO) synthase inhibitor l-NAME, SH blocker N-ethylmaleimide or TRPV1 antagonist capsazepine in ethanol-induced gastritis model. In addition, ex vivo analysis revealed that ethanol-induced decrease in gastric mucus and non-protein sulfhydryl (NPSH) groups was significantly reversed by silymarin treatment and lipid peroxidation was also suppressed by silymarin in ethanol-induced gastritis model. Taken together, these results suggest that silymarin exerts gastroprotective effects and the gastroprotective effects of silymarin might be related to the protection of gastric mucosal NO and NP-SH and the modulation of capsaicin-sensitive gastric sensory afferents. PMID:23357565

Shin, Jung Hyu; Lee, Chang Woo; Oh, Soo Jin; Yun, Jieun; Lee, Kiho; Park, Song-Kyu; Kim, Hwan Mook; Han, Sang-Bae; Kim, Youngsoo; Kim, Hyoung-Chin; Kang, Jong Soon




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...


Cytisine modulates chronic voluntary ethanol consumption and ethanol-induced striatal up-regulation of ?FosB in mice.  


Chronic administration of ethanol induces persistent accumulation of ?FosB, an important transcription factor, in the midbrain dopamine system. This process underlies the progression to addiction. Previously, we have shown that cytisine, a neuronal nicotinic acetylcholine receptor (nAChR) partial agonist, reduces various ethanol-drinking behaviors and ethanol-induced striatal dopamine function. However, the effects of cytisine on chronic ethanol drinking and ethanol-induced up-regulation of striatal ?FosB are not known. Therefore, we examined the effects of cytisine on chronic voluntary ethanol consumption and associated striatal ?FosB up-regulation in C57BL/6J mice using behavioral and biochemical methods. Following the chronic voluntary consumption of 15% (v/v) ethanol under a 24-h two-bottle choice intermittent access (IA; 3 sessions/week) or continuous access (CA; 24 h/d and 7 d/week) paradigm, mice received repeated intraperitoneal injections of saline or cytisine (0.5 or 3.0 mg/kg). Ethanol and water intake were monitored for 24 h post-treatment. Pretreatment with cytisine (0.5 or 1.5 mg/kg) significantly reduced ethanol consumption and preference in both paradigms at 2 h and 24 h post-treatment. The ?FosB levels in the ventral and dorsal striatum were determined by Western blotting 18-24 h after the last point of ethanol access. In addition, cytisine (0.5 mg/kg) significantly attenuated up-regulation of ?FosB in the ventral and dorsal striatum following chronic ethanol consumption in IA and CA paradigms. The results indicate that cytisine modulates chronic voluntary ethanol consumption and reduces ethanol-induced up-regulation of striatal ?FosB. Further, the data suggest a critical role of nAChRs in chronic ethanol-induced neurochemical adaptations associated with ethanol addiction. PMID:23601929

Sajja, Ravi Kiran; Rahman, Shafiqur



Dilinoleoylphosphatidylcholine is responsible for the beneficial effects of polyenylphosphatidylcholine on ethanol-induced mitochondrial injury in rats.  


Chronic ethanol consumption depletes phosphatidylcholines (PC) in membranes and hepatic mitochondria are an early target of this toxicity. Our previous studies showed that soybean-derived polyenylphosphatidylcholine (PPC), attenuated mitochondrial liver injury. Since dilinoleoylphosphatidylcholine (DLPC) is the major component of PPC, we assessed whether it is responsible for the protection of PPC. Forty-two male rats were fed the following liquid diets for 8 weeks: Control; Control with DLPC (1.5 g/1000 Calories (Cal); Alcohol (36% of Cal); Alcohol with DLPC (1.5 g/1000 Cal) and Alcohol with PPC (3 g/1000 Cal). As expected, ethanol feeding diminished the capacity of hepatic mitochondria to oxidize glutamate and palmitoyl-1-carnitine, and also decreased the activity of mitochondrial cytochrome oxidase. These effects were equally prevented by either PPC or DLPC. In conclusion, DLPC fully reproduced PPC's protective action and may be effective in the prevention or delay of more severe liver damage. PMID:11866479

Navder, Khursheed P; Lieber, Charles S



Inhibitive effect of cordyceps sinensis on experimental hepatic fibrosis and its possible mechanism  

Microsoft Academic Search

AIM: To investigate the inhibitive effect and its possible mechanism of Cordyceps Sinensis (CS) on CCl4-plus ethanol- induced hepatic fibrogenesis in experimental rats. METHODS: Rats were randomly allocated into a normal control group, a model control group and a CS group. The latter two groups were administered with CCl4 and ethanol solution at the beginning of the experiment to induce

Yu-Kan Liu; Wei Shen



Hepatic failure and liver cell damage in acute Wilson's disease involve CD95 (APO-1/Fas) mediated apoptosis.  


Wilson's disease can result in fulminant liver failure due to hepatic copper overload. The CD95 system mediates apoptosis and has been demonstrated to be involved in liver disease. In this study CD95 mediated apoptosis was investigated in patients with fulminant hepatic failure in the course of Wilson's disease and in an in vitro model of copper treated human hepatoma cells. In patients, hepatic expression of CD95 and CD95L mRNA and apoptosis were detected. Copper overload in vitro resulted in hepatocytic apoptosis which could be reduced with a neutralizing anti-CD95L antibody. Copper treatment of hepatocytes results in activation of the CD95 system and induction of apoptosis which is operative during the course of hepatic failure in acute Wilson's disease. PMID:9585233

Strand, S; Hofmann, W J; Grambihler, A; Hug, H; Volkmann, M; Otto, G; Wesch, H; Mariani, S M; Hack, V; Stremmel, W; Krammer, P H; Galle, P R



Ontogeny of the Enhanced Fetal-Ethanol-Induced Behavioral and Neurophysiologic Olfactory Response to Ethanol Odor  

PubMed Central

Background Studies report a fundamental relationship between chemosensory function and the responsiveness to ethanol, its component orosensory qualities, and its odor as a consequence of fetal ethanol exposure. Regarding odor, fetal exposed rats display enhanced olfactory neural and behavioral responses to ethanol odor at postnatal (P) day 15. Although these consequences are absent in adults (P90), the behavioral effect has been shown to persist into adolescence (P37). Given the developmental timing of these observations, we explored the decay in the response to ethanol odor by examining ages between P37 and young adulthood. Moreover, we sought to determine whether the P15 neurophysiologic effect persists, at least, to P40. Methods Behavioral and olfactory epithelial (OE) responses of fetal ethanol exposed and control rats were tested at P40, P50, P60, or P70. Whole-body plethysmography was used to quantify each animal’s innate behavioral response to ethanol odor. We then mapped the odorant-induced activity across the OE in response to different odorants, including ethanol, using optical recording methods. Results Relative to controls, ethanol exposed animals showed an enhanced behavioral response to ethanol odor that, while significant at each age, decreased in magnitude. These results, in conjunction with previous findings, permitted the development of an ontologic odor response model of fetal exposure. The fitted model exemplifies that odor-mediated effects exist at birth, peak in adolescence and then decline, becoming absent by P90. There was no evidence of an effect on the odor response of the OE at any age tested. Conclusions Fetal exposure yields an enhanced behavioral response to ethanol odor that peaks in adolescence and wanes through young adulthood. This occurs absent an enhanced response of the OE. This latter finding suggests that by P40 the OE returns to an ethanol “neutral” status and that central mechanisms, such as ethanol-induced alterations in olfactory bulb circuitry, underlie the enhanced behavioral response. Our study provides a more comprehensive understanding of the ontogeny of fetal-ethanol-induced olfactory functional plasticity and the behavioral response to ethanol odor.

Eade, Amber M.; Sheehe, Paul R.; Youngentob, Steven L.



Experimental toxic liver damage and hepatic plasma clearance of 99mTc-mebrofenin (iminodiacetate derivative). III. Chronic CCl4-induced liver damage with eventual cirrhosis in rabbits.  


Chronic damage to liver parenchyma was induced in rabbits by the long-term administration of carbon tetrachloride. The animals were serially sacrificed 3, 6 and 9 months after the start of intoxication, and examined histopathologically. The biological response was qualitatively assessed from results of histological studies, and measured utilizing series of typical biochemical indices of liver damage, 99mTc-mebrofenin (an-IDA-derivative) plasma clearance by the liver, and quantified indices of uptake and organ transfer of the compound. It was found that the plasma clearance and transfer parameters show association with chronic liver damage. The reduction of plasma 99mTc-mebrofenin clearance in intoxicated rabbits was also associated with changes in the biochemical indices of liver function and damage. PMID:8581333

Kapu?ci?ski, J; Kuroszczyk, J; Liniecki, J; Bie?kiewicz, M; Tuszyner, K



Relation between ethanol induced changes in plasma catecholines during stress and voluntary ethanol preference  

SciTech Connect

N/NIH rats (N = 10) were implanted with venous catheters to permit stressless chronic, repeated blood withdrawal. Following surgical recovery, the rats were restrained to a lab counter top for 30 min after injection with saline or low dose (0.5 g/kg) ethanol. Blood was repeatedly withdrawn to determine AUC production of NE and E to assess the effect that low dose ethanol has on stress responsiveness. Between saline injection restraint and ethanol injection restraint conditions no differences in NE or E AUC were apparent. A 2- bottle preference test for ethanol was then performed over 21 days. Multiple regression analyses of NE saline restraint and ethanol restraint could predict ethanol consumption to the p = .02 level with R/sup 2/ = .681. Multiple regressions of E saline restraint and E ethanol restraint could predict ethanol consumption to the p = .01 level with R/sup 2/ = .746. These data suggest that ethanol induced increases in plasma NE and E during stress can predict later voluntary ethanol consumption between the ranges of .13 and 1.05 g ethanol/kg/day. This data seems to be more in line with an arousal or withdrawal relationship between ethanol consumption and stress than by a simple tension reduction formulation based on plasma NE or E.

Pashko, S.



Testing Time: Can Ethanol-Induced Pulses of Proposed Oscillator Components Phase Shift Rhythms in Arabidopsis?  

PubMed Central

Circadian rhythms are generated by endogenous central oscillators that respond to input from the environment and regulate rhythmic outputs. In Arabidopsis, more than a dozen components that affect rhythms have been identified and used to propose models of the central oscillator. However, none has been shown to fulfill one of the expected characteristics of an oscillator component: that a pulse of its expression shifts the phase of circadian rhythms. Here we show that a pulse of the proposed oscillator components CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY) causes dramatic phase shifts in rhythms of expression of the circadian reporter CAB2?LUC, as well as of the clock-associated genes TIMING OF CAB EXPRESSION 1 (TOC1) and GIGANTEA (GI). These results demonstrate that pulses of either CCA1 or LHY are capable of resetting the circadian clock. In contrast, a pulse of TOC1 expression did not elicit phase shifts. Control of TOC1 protein level is in part posttranscriptional; thus a pulse of TOC1 protein could be induced only at times when it is already high. Our work also shows that the ethanol-inducible system can be useful for achieving relatively short (<8 h) pulses of gene expression in seedlings.

Knowles, Stephen M.; Lu, Sheen X.; Tobin, Elaine M.



Ethanol-inducible gene expression using gld1 (+) promoter in the fission yeast Schizosaccharomyces pombe.  


In the fission yeast Schizosaccharomyces pombe, the gld1 (+) gene encoding glycerol dehydrogenase is repressed by glucose and induced by ethanol and 1-propanol. The promoter region of gld1 (+) was cloned into a multicopy vector designated as pEG1 for evaluation as an ethanol-inducible expression vector using EGFP as a model heterologous protein. Expression of EGFP was repressed in the presence of high glucose and induced in the presence of ethanol, low-glucose, and 1-propanol in the absence of glucose. Addition of ethanol to cells harboring pEG1-EGFP was found to be the most effective means for inducing EGFP production. Protein yields were found to increase in proportion to ethanol concentration. As a further test of effectiveness, secreted recombinant human growth hormone was produced using the pEG1 expression vector in medium containing glycerol and ethanol. The pEG1 gene expression system is an effective tool for the production of heterologous proteins under glucose-limiting conditions, including medium containing glycerol as a carbon source. PMID:23525885

Matsuzawa, Tomohiko; Tohda, Hideki; Takegawa, Kaoru



Substance P against ethanol-induced alterations in central mechanisms of feeding and escape in rabbits.  


Rabbits were treated with 0.5 g/kg ethanol intravenously and alterations of limbic-midbrain interactions in both feeding and escape elicited by threshold electrical stimulation of the lateral (LH) and ventromedial hypothalamus (VMH) were observed. Decrease of the VMH excitability and abolishing of inhibitory effects of the dorsal hippocampus (HPC) and facilitatory influences of the midbrain reticular formation (MRF) on both motivational hypothalamic centres were found in animals after ethanol administration. Subsequent single injection of substance P (SP) (30 microgram-kg i.v.) just at the height of alcohol manifestations in central mechanisms of feeding and escape led to restoration of the VMH excitability and facilitatory MRF influences on this motivational centre. SP administration was also found to restore the inhibitory hippocampal and facilitatory MRF effects on the excitability of the LH feeding centre. Partial and selective SP restoration of ethanol-induced alterations in feeding and escape which are observed in the present study, as well as the data of some other researchers, led to the suggestion that peptides could be used as factors of enhancing tolerance to ethanol or curing deleterious acute alcohol-induced effects in motivated behaviours in animals. PMID:2483314

Zilov, V G; Rogacheva, S K; Ivanova, L I



Antioxidant neuroprotection against ethanol-induced apoptosis in HN2-5 cells  

PubMed Central

Earlier studies from this and other laboratories show that ethanol induces apoptotic death of fetal and neonatal neurons. One mechanism that underlies these effects is the ethanol-associated reduction in the phosphatidylinositol 3? kinase pro-survival pathway. Another mechanism involves the oxidative stress caused by the ethanol-associated increase in reactive oxygen species (ROS). In the present study, we used the murine HN2-5 hippocampal-derived cell line to investigate the effects of ethanol on ROS levels and apoptosis. We also investigated the potential neuroprotective effects of two structurally unrelated antioxidants: N-acetylcysteine (NAC) and melatonin. The results demonstrate that NAC blocked an ethanol-associated increase in ROS. In addition, NAC and melatonin prevented the augmentation of apoptosis in ethanol-treated neurons. Both antioxidants significantly elevated the expression of the anti-apoptotic gene XIAP in ethanol-treated and/or control neurons and melatonin increased Bcl-2 expression in ethanol-treated neurons. Thus, it is possible that the neuroprotective effects of NAC and melatonin involve their ability to augment the expression of one or more anti-apoptotic gene as well as their classical antioxidant actions. Additional studies are needed to establish the effectiveness of these antioxidants to prevent the loss of neurons which accompanies in utero exposure to ethanol.

Sheth, Dhara S.; Tajuddin, Nuzhath F.; Druse, Mary J.



Ethanol-induced neurodegeneration in NRSF/REST neuronal conditional knockout mice.  


The transcription regulator, neuron-restrictive silencer factor (NRSF), also known as repressor element-1 silencing transcription factor (REST), plays an important role in neurogenesis and various neuronal diseases such as ischaemia, epilepsy, and Huntington's disease. In these disease processes, neuronal loss is associated with abnormal expression and/or localization of NRSF. Previous studies have demonstrated that NRSF regulates the effect of ethanol on neuronal cells in vitro, however, the role of NRSF in ethanol-induced neuronal cell death remains unclear. We generated nrsf conditional knockout mice using the Cre-loxP system to disrupt neuronal expression of nrsf and its truncated forms. At postnatal day 6, ethanol significantly increased the expression of REST4, a neuron-specific truncated form of NRSF, in the brains of wild type mice, and this effect was diminished in nrsf conditional knockout mice. The apoptotic effect of ethanol was pronounced in multiple brain regions of nrsf conditional mutant mice. These results indicate that NRSF, specifically REST4, may protect the developing brain from ethanol, and provide new evidence that NRSF can be a therapeutic target in foetal alcohol syndrome (FAS). PMID:21396985

Cai, L; Bian, M; Liu, M; Sheng, Z; Suo, H; Wang, Z; Huang, F; Fei, J



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

PubMed Central

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

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



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

SciTech Connect

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.

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



Hepatic Fibrosis and Carcinogenesis in ?1-Antitrypsin Deficiency: A Prototype for Chronic Tissue Damage in Gain-of-Function Disorders  

PubMed Central

In ?1-antitrypsin (AT) deficiency, a point mutation renders a hepatic secretory glycoprotein prone to misfolding and polymerization. The mutant protein accumulates in the endoplasmic reticulum of liver cells and causes hepatic fibrosis and hepatocellular carcinoma by a gain-of-function mechanism. Genetic and/or environmental modifiers determine whether an affected homozygote is susceptible to hepatic fibrosis/carcinoma. Two types of proteostasis mechanisms for such modifiers have been postulated: variation in the function of intracellular degradative mechanisms and/or variation in the signal transduction pathways that are activated to protect the cell from protein mislocalization and/or aggregation. In recent studies we found that carbamazepine, a drug that has been used safely as an anticonvulsant and mood stabilizer, reduces the hepatic load of mutant AT and hepatic fibrosis in a mouse model by enhancing autophagic disposal of this mutant protein. These results provide evidence that pharmacological manipulation of endogenous proteostasis mechanisms is an appealing strategy for chemoprophylaxis in disorders involving gain-of-function mechanisms.

Perlmutter, David H.; Silverman, Gary A.



The greater susceptibility of North Ronaldsay sheep compared with Cambridge sheep to copper-induced oxidative stress, mitochondrial damage and hepatic stellate cell activation.  


Sheep of the semi-feral North Ronaldsay (copper-sensitive) and domesticated Cambridge (copper-tolerant) breeds were compared in respect of pathological changes and protein expression in the liver as a result of excessive dietary copper. Acute mitochondrial damage and hepatic stellate cell (HSC) activation with collagen synthesis occurred in response to moderate copper overload in North Ronaldsay but not in Cambridge sheep. Mitochondrial degradative changes occurred either as ballooning degeneration and rupture with subsequent autophagic degradation or as mitochondrial matrical condensation (pyknosis). In North Ronaldsay sheep prolonged exposure to copper produced mitochondrial hyperplasia and hypertrophy, and nuclear damage with necrosis. Cytosolic isocitrate dehydrogenase (IDH), an enzyme responsive to oxidative stress, was induced in the liver of Cambridge sheep receiving a Cu-supplemented diet but was undetectable in the non-supplemented control sheep. Conversely, IDH was detected at similar levels in both control and copper-supplemented North Ronaldsay sheep, indicating a lower threshold response, and an enhanced susceptibility, to oxidative stress. "Upregulation" of mitochondrial thioredoxin-dependent peroxidase reductase (antioxidant protein-1) in the hepatic cytosol of the North Ronaldsay (but not Cambridge) sheep affirmed the increased susceptibility of the mitochondria to Cu-induced oxidative stress in this breed. Likewise the upregulation of cathepsin-D indicated increased lysosomal activity and HSC activation. The findings may be relevant to copper toxicosis in human infants. PMID:16099232

Haywood, S; Simpson, D M; Ross, G; Beynon, R J


Neuroactive steroid 3?-hydroxy-5?-pregnan-20-one modulates ethanol-induced loss of righting reflex in rats  

Microsoft Academic Search

Systemic ethanol administration elevates plasma and brain levels of GABAergic neuroactive steroids, including 3?-hydroxy-5?-pregnan-20-one (3?,5?-THP) that contribute to specific behavioral actions of ethanol. The present study determined the effect of adrenalectomy and 5?-reductase type-1\\/type-2 enzyme inhibition, known to reduce neuroactive steroids, on ethanol-induced increases in cerebral cortical levels of 3?,5?-THP and hypnotic effects in male rats. Systemic ethanol administration to

Rahul T. Khisti; Margaret J. VanDoren; Todd O’Buckley; A. Leslie Morrow



Hypertension Augments Ethanol-Induced Depression of Cell Shortening and Intracellular Ca 2+ Transients in Adult Rat Ventricular Myocytes  

Microsoft Academic Search

Ethanol, a risk factor for myocardial dysfunction, depresses myocardial contraction. This study was to determine whether ethanol-induced myocardial depression is affected by hypertension. Mechanical properties of ventricular myocytes isolated from both normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were evaluated using a video edge-detection system. Myocytes were electrically stimulated to contract at 0.5 Hz. Contractile properties analyzed include peak

Jun Ren; Ricardo A. Brown



Effects of curcumin on ethanol-induced hepatocyte necrosis and apoptosis: implication of lipid peroxidation and cytochrome c  

Microsoft Academic Search

Ethanol-induced hepatocyte necrosis and apoptosis are valid in vitro models to investigate the modulatory effects of hepatoprotective\\/toxic\\u000a agents such as curcumin. In this study, suspension and monolayer cultures of isolated rat hepatocytes were used. Levels of\\u000a trypan blue uptake, reduced glutathione, and lipid peroxidation were quantified. Chromatin condensation, caspase-3 activity,\\u000a and cytochrome c extramitochondrial translocation were also evaluated. Results revealed

Asser I. Ghoneim



Selective suppression of NF-kBp65 in hepatitis virus-infected pregnant women manifesting severe liver damage and high mortality.  


Fulminant hepatitis in Asian pregnant women is generally caused by hepatitis E virus infection, and extremely high mortality is most common in them. Decreased cell-mediated immunity is considered a major cause of death in these cases, but what exactly influences decreased immunity and high mortality specifically during pregnancy is not known. We used electrophoretic mobility shift assays, immunoblotting, and immunohistochemical analysis to study the expression and DNA binding activity of NF-kB p50 and NF-kB p65 in pregnant fulminant hepatic failure (FHF) patients and compared them with their nonpregnant counterparts. In both PBMC and postmortem liver biopsy specimens the DNA-binding activity of NF-kB was very high in samples from pregnant FHF patients compared with those from nonpregnant women as well as pregnant women with acute viral hepatitis (AVH) without FHF. Further dissection of the NF-kB complex in supershift assays demonstrated complete absence of p65 in the NF-kB complex, which is formed by homodimerization of the p50 component in pregnant FHF patients. Western blotting and immunohistochemical analysis of the expression of p50 and p65 proteins both showed higher levels of p50 expression and a complete absence or a minimal expression of p65, indicating its nonparticipation in NF-kB-dependent transactivation in pregnant FHF patients. We suggest that the exclusion of p65 from the NF-kB transactivation complex seems to be a crucial step that may cause deregulated immunity and severe liver damage, leading to the death of the patient. Our findings provide a molecular basis, for developing novel therapeutic approaches. PMID:17660862

Prusty, Bhupesh K; Hedau, Suresh; Singh, Ajay; Kar, Premasis; Das, Bhudev C


Experimental toxic liver damage and hepatic plasma clearance of 99mTc-mebrofenin (iminodiacetate derivative). I. Early, acute CCl4-induced liver damage in rabbits.  


Liver damage was induced in rabbits by graded doses of carbon tetrachloride. The damage was assessed by means of quantitative morphometry using necrosis and steatosis of the parenchyma as end points. Biological response was measured utilizing a series of typical biochemical indices of liver damage as well as plasma clearance by the liver 99mTc-mebrofenin (an IDA derivative) and quantified indices of uptake and organ transfer of the compound. No correlation was found between the CCl4 dose and its effect (i.e. degree of necrosis and steatosis of liver). However, a very strong negative correlation was found between the degree of necrosis in individual animals and value of the clearance. The extent of the damage was positively correlated with liver transfer rate of 99mTc-MBF. Plasma activity of ALAT, TG, GGTP and AspAT were higher in the poisoned animals, however, only increments of activity of GGTP, ALAT and LDH showed statistically significant correlation with the individually assessed damage (necrosis). PMID:8219908

Kapu?ci?ski, J; Kuroszczyk, J; Liniecki, J; Bie?kiewicz, M; Zieli?ski, K; Tuszyner, K



Oxidative stress mediated toxicity exerted by ethanol-inducible CYP2E1  

SciTech Connect

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 biochemical and toxicological properties of CYP2E1.

Wu Defeng [Department of Pharmacology and Biological Chemistry, Box 1603, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029 (United States); Cederbaum, Arthur I. [Department of Pharmacology and Biological Chemistry, Box 1603, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029 (United States)]. E-mail:



Study on the Mechanism of Oxidative Damage and Genotoxicity induced by BBP in Hepatic cells of Mice  

Microsoft Academic Search

To illustrate the possible function of genotoxicity of BBP on DNA, this study took mice livers as experimental materials to detect the levels of DNA-protein crosslinks (DPC), the activity of surperoxide dismutase (SOD), and the contents of malondialdehyde (MDA) with intraperitioneal injection of different doses of BBP for two consecutive 14 days. DPC levels in hepatic cells showed a dose-dependent

Guo Jing; Wei Chenxi; Hu Chuanlu; Liu Dandan; Yang Xu



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


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)-? 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-? 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-?. PMID:23830375

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



Protective effects of antioxidants against endrin-induced hepatic lipid peroxidation, DNA damage, and excretion of urinary lipid metabolites.  


Oxidative stress is believed to play a pivotal role in endrin-induced hepatic and neurologic toxicity. Therefore, the effects of the antioxidants vitamin E succinate and ellagic acid have been examined on hepatic lipid peroxidation, DNA single-strand breaks (SSB), and the urinary excretion of lipid metabolites following an acute oral dose of 4.5 mg endrin/kg. Groups of rats were pretreated with 100 mg/kg vitamin E succinate for 3 d followed by 40 mg/kg on day 4, or 6.0 mg ellagic acid/kg for 3 d p.o. followed by 3.0 mg/kg on day 4 or the vehicle. Endrin was administered p.o. on day 4 2 hr after treatment with the antioxidant. All animals were killed 24 h after endrin administration. Vitamin E succinate pretreatment decreased the endrin-induced increase in hepatic mitochondrial and microsomal lipid peroxidation by approximately 60% and 40%, respectively. Ellagic acid pretreatment reduced the endrin-induced increased in mitochondrial and microsomal lipid peroxidation by approximately 76 and 79%, respectively. Both vitamin E succinate and ellagic acid alone produced small but nonsignificant decreases in hepatic mitochondrial and microsomal lipid peroxidation. A 3.3-fold increase in the incidence of hepatic nuclear DNA single-strand breaks was observed 24 h after endrin administration. Pretreatment of rats with vitamin E succinate, vitamin E, and ellagic acid decreased endrin-induced DNA-SSB by approximately 47%, 22%, and 21%, respectively. Pretreatment of rats with vitamin E succinate decreased the endrin-induced increase in the urinary excretion of malondialdehyde, acetaldehyde, formaldehyde, and acetone by approximately 68, 65, 70, and 55%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8375695

Bagchi, D; Hassoun, E A; Bagchi, M; Stohs, S J



Molecular mechanisms of ethanol-induced pathogenesis revealed by RNA-sequencing.  


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

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



Deficiency in AMPK attenuates ethanol-induced cardiac contractile dysfunction through inhibition of autophagosome formation  

PubMed Central

Aims Binge drinking often triggers compromised myocardial contractile function while activating AMP-activated protein kinase (AMPK). Given the role of AMPK in the initiation of autophagy through the mammalian target of rapamycin complex 1 (mTORC1) and Unc51-like kinase (ULK1), this study was designed to examine the impact of AMPK deficiency on cardiac function and the mechanism involved with a focus on autophagy following an acute ethanol challenge. Methods and results Wild-type (WT) and transgenic mice overexpressing a kinase-dead (KD) ?2 isoform (K45R mutation) of AMPK were challenged with ethanol. Glucose tolerance, echocardiography, Langendorff heart and cardiomyocyte contractile function, autophagy, and autophagic signalling including AMPK, acetyl-CoA carboxylase (ACC), mTOR, the mTORC1-associated protein Raptor, and ULK1 were examined. Ethanol exposure triggered glucose intolerance and compromised cardiac contraction accompanied by increased phosphorylation of AMPK and ACC as well as autophagosome accumulation (increased LC3II and p62), the effects of which were attenuated or mitigated by AMPK deficiency or inhibition. Ethanol dampened and stimulated, respectively, the phosphorylation of mTOR and Raptor, the effects of which were abolished by AMPK deficiency. ULK1 phosphorylation at Ser757 and Ser777 was down-regulated and up-regulated, respectively, by ethanol, the effect of which was nullified by AMPK deficiency or inhibition. Moreover, the ethanol challenge enhanced LC3 puncta in H9c2 cells and promoted cardiac contractile dysfunction, and these effects were ablated by the inhibition of autophagy or AMPK. Lysosomal inhibition failed to accentuate ethanol-induced increases in LC3II and p62. Conclusion In summary, these data suggest that ethanol exposure may trigger myocardial dysfunction through a mechanism associated with AMPK-mTORC1-ULK1-mediated autophagy.

Guo, Rui; Ren, Jun




PubMed Central

Background Age-specific characteristics may contribute to the elevation in ethanol intake commonly reported among adolescents compared to adults. The present study was designed to examine age-related differences in sensitivity to ethanol’s aversive properties using a conditioned taste aversion (CTA) procedure with sucrose serving as the conditioned stimulus. Given that ontogenetic differences in responsiveness to stressors have been previously reported, the role of stressor exposure on the development of CTA was also assessed. Methods Experiment 1 examined the influence of 5 days of prior restraint stress exposure on the expression of CTA in a 2-bottle test following 1 pairing of a sucrose solution with ethanol. In Experiment 2, the effects of 7 days of social isolation on the development of CTA were observed using a 1-bottle test following multiple sucrose-ethanol pairings. Results The present study revealed age-related differences in the development of ethanol-induced CTA. In Experiment 1, adolescents required a higher dose of ethanol than adults to demonstrate an aversion. In Experiment 2, adolescents required not only a higher ethanol dose but also more pairings of ethanol with the sucrose conditioned stimulus. No effects of prior stressor exposure were observed in either experiment. Conclusions Together, these experiments demonstrate an adolescent-specific insensitivity to the aversive properties of ethanol that elicit CTA, a pattern not influenced by repeated restraint stress or housing in social isolation. This age-related insensitivity to the dysphoric effects of ethanol is consistent with other work from our laboratory, adding further to the evidence that adolescent rats are less susceptible to negative consequences of ethanol that may serve as cues to curb consumption.

Anderson, Rachel I.; Varlinskaya, Elena I.; Spear, Linda P.



Chemokines mediate ethanol-induced exacerbations of murine cockroach allergen asthma.  


Asthma imposes considerable patient and economic burdens, with the most severe cases causing the greatest affliction. Identifying stimuli that worsen asthma severity is an essential step to controlling both disease morbidity and the lessening economic impact. This study provides the first mechanistic investigation into how acute ethanol exposure will increase asthma severity in a murine model of mild cockroach allergen (CRA)-induced asthma. Outbred mice were sensitized to induce mild allergic asthma, with intratracheal CRA exposures on days 0 and 14. On day 21 mice were gavaged with water or 32% ethanol, and the third allergen exposure was given 30?min post-gavage. Asthmatic responses were measured at several time-points up to 42?h after the third allergen challenge. Ethanol-gavaged mice showed increased asthma severity within 90?min post-allergen challenge, with exacerbations lasting for 24?h. Ethanol caused greater airways obstruction, including an eightfold increase in epithelial cell mucin and increased mucus plugs, resulting in a 50% reduction in bronchiole patency. Ethanol gavage also induced significant increases in airways hyperreactivity. While T helper type 1 (Th1) and Th2 cytokines were not altered by ethanol gavage, pulmonary neutrophil and eosinophil recruitment were augmented. This increase was associated with increased chemokine production. Administration 2?h prior to ethanol gavage of a neutralizing antibody cocktail to keratinocyte-derived chemokine, macrophage inflammatory protein-2, eotaxin-1 and eotaxin-2 prevented ethanol-induced eosinophil recruitment and airways hyperreactivity. These data provide evidence that acute alcohol exposure immediately prior to a mild allergen-triggered asthmatic episode will exacerbate asthma severity mediated by increased production of chemokines. PMID:23574317

Bouchard, J C; Beal, D R; Kim, J; Vaickus, L J; Remick, D G



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


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

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



Central adenosinergic system involvement in ethanol-induced motor incoordination in mice  

SciTech Connect

To clarify if the behavioral interaction between ethanol and adenosine reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. adenosine agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. Adenosine agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of adenosine modulation of this effect of ethanol and confirmed our previous reports in which adenosine agonists and antagonists were given i.p. Enprofylline, a weak adenosine antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain adenosine receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of adenosine A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of adenosine A2. No effect of ethanol on blood or brain levels of (3H)R-PIA was noted and sufficient amount of the latter entered the brain to suggest adenosine receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered (3H)R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.

Dar, M.S. (East Carolina Univ., Greenville, NC (USA))



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

PubMed Central

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.

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



CYP2E1: biochemistry, toxicology, regulation and function in ethanol-induced liver injury.  


Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of the CYP2E1 form of cytochrome P450 enzymes by ethanol. CYP2E1 is of interest because of its ability to metabolize and activate many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of HepG2 cell lines developed to constitutively express the human CYP2E1 in assessing the actions of CYP2E1. Regulation of CYP2E1 is quite complex and will be briefly reviewed. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury. PMID:14527082

Kessova, Irina; Cederbaum, Arthur I



Effects of hepatic stimulator substance, herbal medicine, selenium\\/vitamin E, and ciprofloxacin on cirrhosis in the rat  

Microsoft Academic Search

BACKGROUND & AIMS: Cirrhosis is a potentially lethal condition for which there is no proven effective therapy. The aim of this study was to compare the effects of hepatic stimulator substance, traditional Chinese herbal medicine, selenium plus vitamin E, and ciprofloxacin treatment on biochemical and histological features of fibrosis in rats with carbon tetrachloride (CCl4)\\/ethanol-induced cirrhosis. METHODS: One hundred twenty

M Zhang; G Song; GY Minuk



Hepatitis C  

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Ethanol Exposure Depletes Hepatic Pigment Epithelium-Derived Factor, a Novel Lipid Regulator  

PubMed Central

Background & Aims Ethanol abuse can lead to hepatic steatosis and evolve into cirrhosis and hepatocellular carcinoma. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein that is expressed by hepatocytes. Proteomic, experimental, and clinical studies implicate PEDF’s role in lipid regulation. Because matrix metalloproteinase (MMP)-2/9 activity regulates PEDF levels, we investigated whether PEDF degradation by MMPs has a permissive role in ethanol-induced hepatic steatosis. Methods PEDF levels were examined in liver biopsy specimens from patients with ethanol-induced steatosis. Hepatic PEDF levels and MMP activity were assessed in 2 animal models of ethanol feeding (rats on an alcohol-containing liquid diet and mice given intragastric infusion of ethanol). The consequences of PEDF depletion in the liver were examined in PEDF-null mice. Results Liver biopsy samples from patients with ethanol-induced steatosis had reduced PEDF levels, compared with normal liver samples. Ethanol-fed animals had histologic steatosis and increased liver triglyceride content (P < .05), as well as reduced levels of hepatic PEDF and increased MMP-2/9 activity. Ethanol-exposed hepatic lysates degraded PEDF in a MMP-2/9-dependent manner, and liver sections demonstrated abundant MMP-2/9 activity in situ. Addition of recombinant PEDF to PEDF-null hepatocytes, reduced their triglyceride content. Conclusions Ethanol exposure leads to marked loss of hepatic PEDF in human livers and in 2 animal models of ethanol feeding. Loss of PEDF contributes to the accumulation of lipids in ethanol-induced hepatic steatosis.

Chung, Chuhan; Shugrue, Christine; Nagar, Anil; Doll, Jennifer A.; Cornwell, Mona; Gattu, Arijeet; Kolodecik, Tom; Pandol, Stephen J.; Gorelick, Fred



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

Microsoft Academic Search

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\\/T-cytotoxic type-1 cell (Th1\\/Tc1) response. These chemokines consist of CCL3 (macrophage inflammatory protein-1?; MIP-1?), CCL4 (MIP- 1?), CCL5 (regulated on activation normal T cell

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



Alcohol Dehydrogenase Accentuates Ethanol-Induced Myocardial Dysfunction and Mitochondrial Damage in Mice: Role of Mitochondrial Death Pathway  

Microsoft Academic Search

ObjectivesBinge drinking and alcohol toxicity are often associated with myocardial dysfunction possibly due to accumulation of the ethanol metabolite acetaldehyde although the underlying mechanism is unknown. This study was designed to examine the impact of accelerated ethanol metabolism on myocardial contractility, mitochondrial function and apoptosis using a murine model of cardiac-specific overexpression of alcohol dehydrogenase (ADH).MethodsADH and wild-type FVB mice

Rui Guo; Jun Ren; Piero Anversa



Red wine antioxidants protect hippocampal neurons against ethanol-induced damage: A biochemical, morphological and behavioral study  

Microsoft Academic Search

Chronic ethanol consumption increases oxidative stress, which accounts for the striking neurological changes seen in this condition. Notwithstanding, there is well-documented evidence that polyphenols, present in grape skin and seeds, exhibit a strong antioxidant activity. As red wine is rich in polyphenols, the aim of the present work was to evaluate their putative protective effects on the hippocampal formation by

M. Assunção; M. J. Santos-Marques; V. de Freitas; F. Carvalho; J. P. Andrade; N. V. Lukoyanov; M. M. Paula-Barbosa



Depletion of activated hepatic stellate cell correlates with severe liver damage and abnormal liver regeneration in acetaminophen-induced liver injury.  


Hepatic stellate cells (HSCs) are important part of the local 'stem cell niche' for hepatic progenitor cells (HPCs) and hepatocytes. However, it is unclear as to whether the products of activated HSCs are required to attenuate hepatocyte injury, enhance liver regeneration, or both. In this study, we performed 'loss of function' studies by depleting activated HSCs with gliotoxin. It was demonstrated that a significantly severe liver damage and declined survival rate were correlated with depletion of activated HSCs. Furthermore, diminishing HSC activation resulted in a 3-fold increase in hepatocyte apoptosis and a 66% decrease in the number of proliferating hepatocytes. This was accompanied by a dramatic decrease in the expression levels of five genes known to be up-regulated during hepatocyte replication. In particular, it was found that depletion of activated HSCs inhibited oval cell reaction that was confirmed by decreased numbers of Pank-positive cells around the portal tracts and lowered gene expression level of cytokeratin 19 (CK19) in gliotoxin-treated liver. These data provide clear evidence that the activated HSCs are involved in both hepatocyte death and proliferation of hepatocytes and HPCs in acetaminophen (APAP)-induced acute liver injury. PMID:21335335

Shen, Kuntang; Chang, Wenju; Gao, Xiaodong; Wang, Hongshan; Niu, Weixin; Song, Lujun; Qin, Xinyu



Role of dorsal motor nucleus of vagus in gastric function and mucosal damage induced by ethanol in rats  

Microsoft Academic Search

Experimental evidence indicates that the autonomic nervous system, especially the cholinergic pathway, modulates the mucosal defensive mechanism and affects mucosal damage in the stomach. The present study investigated the role of the dorsal motor nucleus of vagus (DMV) in gastric function and its influences on ethanol-induced mucosal damage in pentobarbitone-anesthetized rats. Electrolytic lesion of the DMV as compared with sham

Y. S. Chan; J. K. S. Ko; C. H. Cho



Alpha - Lipoic Acid Decreases DNA Damage and Oxidative Stress Induced by Alcohol in the Developing Hippocampus and Cerebellum of Rat  

Microsoft Academic Search

Background \\/ aims: The present study was initiated in order to investigate the protective effects of ?-lipoic acid upon ethanol-induced DNA damage, lipid peroxidation and protein oxidation in the developing rat hippocampus and cerebellum. Methods: Pregnant Wistar rats received ethanol with, or without lipoic acid from gestation day (GD) 7 throughout lactation. The changes in DNA damage, protein carbonyl, lipid

Alireza Shirpoor; Syranush Minassian; Siamak Salami; Mohammad Hassan Khadem-Ansari; Marine Yeghiazaryan



Ethanol-Induced Microphthalmia is Not Mediated by Changes in Retinoic Acid or Sonic Hedgehog Signaling During Retinal Neurogenesis  

PubMed Central

Background Microphthalmia (reduced eye size), generally accompanied by vision defects, is a hallmark of fetal alcohol spectrum disorder (FASD) in humans. In zebrafish, embryonic ethanol exposure over the time of retinal neurogenesis also results in microphthalmia. This microphthalmia is in part the consequence of reduced retinal cell differentiation, including photoreceptors. Here we pursue 2 signaling pathways implicated in other aspects of FASD pathogenesis: retinoic acid (RA) and Sonic hedgehog (Shh). Methods We evaluated markers for RA and Shh signaling within the eyes of embryos treated with ethanol during the period of retinal neurogenesis. We also perrormed rescue experiments using administration of exogenous RA and microinjection of cholesterol, which augments Shh signaling. Results Using sequential or co-treatments, RA did not rescue ethanol-induced microphthalmia at any concentration tested. In addition, RA itself caused microphthalmia, although the underlying mechanisms were distinct from those or ethanol. Interestingly, RA treatment appeared to recover photoreceptor differentiation in a concentration-dependent manner. This may be an independent effect or exogenous RA, as ethanol treatment alone did not alter RA signaling in the eye. Cholesterol injection also did not rescue ethanol-induced microphthalmia at any concentration tested, and ethanol treatments did not alter expression of shh, or of ptc-2, which is normally regulated by Shh signaling. Conclusions Together these findings indicate that, during the time of retinal neurogenesis, effects of ethanol on eye development are likely independent of the RA and Shh signaling pathways. These studies suggest that FASD intervention strategies based upon augmentation or RA or Shh signaling may not prevent ethanol-induced microphthalmia.

Kashyap, Bhavani; Frey, Ruth A.; Stenkamp, Deborah L.



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

Microsoft Academic Search

The involvement of oxidative stress in the pathogenesis of alcoholic diseases in the liver has been repeatedly confirmed. Resveratrol, a natural phytoalexin present in grape skin and red wine possesses a variety of biological activities including antioxidant. This study was conducted to evaluate whether resveratrol has a preventive effect on the main indicators of hepatic oxidative status as an expression

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



Nuclear DNA strand breaks during ethanol-induced oxidative stress in rat brain  

Microsoft Academic Search

Free radical-mediated oxidative damage has been implicated in the pathophysiological mechanisms of apoptosis. In this study we report that statistically significant strand breaks were induced primarily in the hippocampus and cerebellum during chronic, and not acute, ethanol treatment. Damage to DNA observed in hippocampus and cerebellum was also correlated with significant modification in the activities of mitochondrial respiratory complexes I

M. Renis; V. Calabrese; A. Russo; A. Calderone; M. L. Barcellona; V. Rizza



Oxidative damage induced by chlorpyrifos in the hepatic and renal tissue of Kunming mice and the antioxidant role of vitamin E.  


Chlorpyrifos is a broad-spectrum, chlorinated organophosphate pesticide employed for pest control in various agricultural and animal husbandries. Acute and chronic exposure to CPF can elicit several adverse effects, including oxidative stress. We investigated neurotoxicity of CPF-treated mice, and evaluated the antioxidant effect of vitamin E against oxidative stress and histological changes in the livers and kidneys of CPF-treated mice. Kunming mice were divided randomly into five exposure groups of six: (A) peanut oil; (B) 3mg/kg CPF; (C) 6 mg/kg CPF; (D) 12 mg/kg CPF; (E) vitamin E (100 mg/kg), 3h after administration of CPF (12 mg/kg) and used as a post-treatment group. Oral administration of high-dose groups (12 mg/kg) CPF led to a significant increase in levels of reactive oxygen species, DNA-protein crosslinks, 8-hydroxy-2-deoxyguanosine and malondialdehyde, decreases in acetylcholinesterase activity and glutathione level, as well as causing hepatic and renal histopathological change. Except for AChE activity levels, administration of vitamin E to CPF-treated mice restored these biochemical parameters to within normal levels, and resulted in overall improvement in damage to livers and kidneys. These data suggest that oxidative stress is involved in CPF-induced toxicity and that vitamin E can protect against the tissue damage induced by CPF. PMID:23624379

Ma, Ping; Wu, Yang; Zeng, Qiang; Gan, Yaping; Chen, Jiaoe; Ye, Xin; Yang, Xu



Effect of juice and fermented vinegar from Hovenia dulcis peduncles on chronically alcohol-induced liver damage in mice.  


The protective effects of juice and fermented vinegar from Hovenia dulcis peduncles on chronically ethanol-induced biochemical changes in male mice were investigated. Administration of ethanol (50%, v/v, 10 mL kg?¹) to mice for 6 weeks induced liver damage with a significant increase (P < 0.01) of the liver index, aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl transferase (?-GT) in the serum and the hepatic lipid peroxidation (LPO) level. In contrast, administration of juice or fermented vinegar from Hovenia dulcis peduncles (10 mL kg?¹ bw) along with alcohol significantly (P < 0.05) decreased the activities of the enzymes (AST, ALT and ?-GT), liver index, concentrations of triglyceride (TG) and total cholesterol (TCH) in the serum and the hepatic TG and LPO levels. Mice treated with juice or fermented vinegar from Hovenia dulcis peduncles showed better profiles of the antioxidant systems with relatively higher glutathione (GSH) content, total superoxide dismutase (T-SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities. All these results were accompanied by histological observations in liver. The results demonstrate that both of the juice and fermented vinegar from Hovenia dulcis peduncles have beneficial effects in reducing the adverse effect of alcohol. PMID:22648047

Xiang, Jinle; Zhu, Wenxue; Li, Zhixi; Ling, Shengbao



Administration of high doses of copper to capuchin monkeys does not cause liver damage but induces transcriptional activation of hepatic proliferative responses.  


Liver cells respond to copper loading upregulating protective mechanisms. However, to date, except for liver content, there are no good indicators that identify individuals with excess liver copper. We hypothesized that administering high doses of copper to young (5.5 mg Cu · kg?¹ . d?¹) and adult (7.5 mg Cu · kg?¹ . d?¹) capuchin monkeys would induce detectable liver damage. Study groups included adult monkeys (2 females, 2 males) 3-3.5 y old at enrollment treated with copper for 36 mo (ACu); age-matched controls (1 female, 3 males) that did not receive additional copper (AC); young monkeys (2 female, 2 males) treated from birth with copper for 36 mo (YCu); and young age-matched controls (2 female, 2 males) that did not receive additional copper (YC). We periodically assessed clinical, blood biochemical, and liver histological indicators and at 36 mo the hepatic mRNA abundance of MT2a, APP, DMT1, CTR1, HGF, TGF?, and NF?? only in adult monkeys. After 36 mo, the liver copper concentration was 4-5 times greater in treated monkeys relative to controls. All monkeys remained healthy with normal routine serum biochemical indices and there was no evidence of liver tissue damage. Relative mRNA abundance of HGF, TGF? and NF?B was significantly greater in ACu than in AC monkeys. In conclusion, capuchin monkeys exposed to copper at doses up to 50 times the current upper level enhanced expression of genes related to inflammation and injury without clinical, blood biochemical, or histological evidence of liver damage. PMID:22223567

Araya, Magdalena; Núñez, Héctor; Pavez, Leonardo; Arredondo, Miguel; Méndez, Marco; Cisternas, Felipe; Pizarro, Fernando; Sierralta, Walter; Uauy, Ricardo; González, Mauricio



Raf-1 Kinase Inhibitory Protein (RKIP) Mediates Ethanol-induced Sensitization of Secretagogue Signaling in Pancreatic Acinar Cells*  

PubMed Central

Excessive alcohol consumption is associated with most cases of chronic pancreatitis, a progressive necrotizing inflammatory disease that can result in pancreatic insufficiency due to acinar atrophy and fibrosis and an increased risk of pancreatic cancer. At a cellular level acute alcohol exposure can sensitize pancreatic acinar cells to secretagogue stimulation, resulting in dysregulation of intracellular Ca2+ homeostasis and premature digestive enzyme activation; however, the molecular mechanisms by which ethanol exerts these toxic effects have remained undefined. In this study we identify Raf-1 kinase inhibitory protein as an essential mediator of ethanol-induced sensitization of cholecystokinin- and carbachol-regulated Ca2+ signaling in pancreatic acinar cells. We show that exposure of rodent acinar cells to ethanol induces protein kinase C-dependent Raf-1 kinase inhibitory protein phosphorylation, sensitization of cholecystokinin-stimulated Ca2+ signaling, and potentiation of both basal and cholecystokinin-stimulated extracellular signal-regulated kinase activation. Furthermore, we show that either suppression of Raf-1 kinase inhibitory protein expression using short hairpin RNA or gene ablation prevented the sensitizing effects of ethanol on cholecystokinin- and carbachol-stimulated Ca2+ signaling and intracellular chymotrypsin activation in pancreatic acinar cells, suggesting that the modulation of Raf-1 inhibitory protein expression may have future therapeutic utility in the prevention or treatment of alcohol-associated pancreatitis.

Kim, Sung Ok; Ives, Kirk L.; Wang, Xiaofu; Davey, Robert A.; Chao, Celia; Hellmich, Mark R.



Raf-1 kinase inhibitory protein (RKIP) mediates ethanol-induced sensitization of secretagogue signaling in pancreatic acinar cells.  


Excessive alcohol consumption is associated with most cases of chronic pancreatitis, a progressive necrotizing inflammatory disease that can result in pancreatic insufficiency due to acinar atrophy and fibrosis and an increased risk of pancreatic cancer. At a cellular level acute alcohol exposure can sensitize pancreatic acinar cells to secretagogue stimulation, resulting in dysregulation of intracellular Ca(2+) homeostasis and premature digestive enzyme activation; however, the molecular mechanisms by which ethanol exerts these toxic effects have remained undefined. In this study we identify Raf-1 kinase inhibitory protein as an essential mediator of ethanol-induced sensitization of cholecystokinin- and carbachol-regulated Ca(2+) signaling in pancreatic acinar cells. We show that exposure of rodent acinar cells to ethanol induces protein kinase C-dependent Raf-1 kinase inhibitory protein phosphorylation, sensitization of cholecystokinin-stimulated Ca(2+) signaling, and potentiation of both basal and cholecystokinin-stimulated extracellular signal-regulated kinase activation. Furthermore, we show that either suppression of Raf-1 kinase inhibitory protein expression using short hairpin RNA or gene ablation prevented the sensitizing effects of ethanol on cholecystokinin- and carbachol-stimulated Ca(2+) signaling and intracellular chymotrypsin activation in pancreatic acinar cells, suggesting that the modulation of Raf-1 inhibitory protein expression may have future therapeutic utility in the prevention or treatment of alcohol-associated pancreatitis. PMID:22859298

Kim, Sung Ok; Ives, Kirk L; Wang, Xiaofu; Davey, Robert A; Chao, Celia; Hellmich, Mark R



Ethanol-induced fetal dysmorphogenesis in the mouse is diminished by high antioxidative capacity of the mother.  


Intrauterine exposure to ethanol causes embryonic and fetal maldevelopment. Oxidative stress in mother and offspring has been suggested to be part of the teratogenic mechanism of ethanol. Here we aimed to assess the importance of maternal and fetal antioxidative capability for the risk of dysmorphogenesis in the offspring. We used male and female mice with different levels of superoxide dismutase (SOD) activity-wild-type (WT) mice, mice with a targeted SOD mutation (KO, decreased CuZnSOD mRNA), and mice transgenic for SOD (TG, increased CuZnSOD mRNA). Female WT, KO (heterozygous), and TG (heterozygous) mice were given drinking water containing 20% ethanol before and throughout gestation. Non-ethanol-exposed WT, KO, and TG mice served as controls. The female mice were mated with males with identical genotype, and the pregnancy was interrupted on gestational day 18 when the offspring was evaluated and genotyped. Fetal hepatic isoprostane (8-epi-PGF(2alpha)) levels were measured to assess the degree of fetal oxidative stress. Exposure to 20% ethanol decreased fetal weight by 9-13% in the three groups. Ethanol exposure roughly doubled the rates of maldeveloped WT and KO offspring but did not affect TG offspring. The fetal hepatic levels of 8-epi-PGF(2alpha) were increased in the ethanol-exposed WT and KO mice but not in ethanol-exposed TG mice. Ethanol exposure preferentially damaged WT fetuses in pregnant KO mice, whereas no such effect was found in the litters of ethanol-consuming TG mice. Administration of ethanol to pregnant mice disturbs embryogenesis by oxidative stress, and the adverse effects are more pronounced in offspring of mice with low antioxidative capacity. PMID:16731578

Wentzel, Parri; Eriksson, Ulf J



Hepatoprotective Activity of Methanolic Extract of Bauhinia purpurea Leaves against Paracetamol-Induced Hepatic Damage in Rats.  


In an attempt to further establish the pharmacological properties of Bauhinia purpurea (Fabaceae), hepatoprotective potential of methanol extract of B. purpurea leaves (MEBP) was investigated using the paracetamol- (PCM-) induced liver toxicity in rats. Five groups of rats (n = 6) were used and administered orally once daily with 10% DMSO (negative control), 200?mg/kg silymarin (positive control), or MEBP (50, 250, and 500?mg/kg) for 7 days, followed by the hepatotoxicity induction using paracetamol (PCM). The blood samples and livers were collected and subjected to biochemical and microscopical analysis. The extract was also subjected to antioxidant study using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay with the total phenolic content (TPC) also determined. From the histological observation, lymphocyte infiltration and marked necrosis were observed in PCM-treated groups (negative control), whereas maintenance of the normal hepatic structural was observed in group pretreated with silymarin and MEBP. Hepatotoxic rats pretreated with silymarin or MEBP exhibited significant decrease (P < 0.05) in ALT and AST enzyme level. Moreover, the extract also exhibited antioxidant activity and contained high TPC. In conclusion, MEBP exerts potential hepatoprotective activity that could be partly attributed to its antioxidant activity and high phenolic content and thus warrants further investigation. PMID:23853662

Yahya, F; Mamat, S S; Kamarolzaman, M F F; Seyedan, A A; Jakius, K F; Mahmood, N D; Shahril, M S; Suhaili, Z; Mohtarrudin, N; Susanti, D; Somchit, M N; Teh, L K; Salleh, M Z; Zakaria, Z A



Living With Hepatitis B  


... healthy liver is to strictly limit or avoid alcohol. Chronic hepatitis B and alcohol is a dangerous mixture. Studies have shown that even small amounts of alcohol can cause damage to an already weakened liver. ...


Ethanol-induced impairment of spatial memory and brain matrix metalloproteinases  

Microsoft Academic Search

The formation of spatial memory appears to be dependent upon an intact hippocampus capable of the specific biochemical changes associated with synaptic remodeling. Hippocampal damage results in the disruption of synaptic remodeling and the acquisition of spatial memory tasks. Ethanol also disrupts normal hippocampal functioning and spatial memory. The present investigation established a dose–response relationship between ethanol treatment and impairment

John W Wright; Alex J Masino; Jennifer R Reichert; Gary D Turner; Starla E Meighan; Peter C Meighan; Joseph W Harding



Zonal differences in ethanol-induced impairments in receptor-mediated endocytosis of asialoglycoproteins in isolated rat hepatocytes  

SciTech Connect

We have shown previously that ethanol-induced defects in receptor-mediated endocytosis of asialoorosomucoid occurred as early as 1 wk after ethanol feeding. This study was undertaken as an initial attempt to establish a possible role of defective receptor-mediated endocytosis in liver injury by investigating whether differences exist in the effects of ethanol on receptor-mediated endocytosis in hepatocytes isolated from different regions of the liver. Perivenule cells, present in the distal half of the liver, are thought to be more susceptible to ethanol-induced liver injury than are the periportal cells located in the proximal half of the liver acini. For these studies, we fed male Sprague-Dawley rats for 7 days with liquid diets containing either ethanol (36% of calories) or isocaloric carbohydrate. Perivenule and periportal hepatocytes were then isolated using a digitonin-collagenase perfusion method. In control animals, cells isolated from the perivenule region bound significantly more ligand than did cells from the periportal region. Amounts of ligand internalized and degraded were also greater in perivenule than in periportal cells in these animals. After ethanol feeding, cells isolated from both the perivenule and periportal regions bound significantly less ligand than their respective controls. This impairment in surface and total binding was more pronounced in perivenule than in periportal cells. Internalization and degradation of the ligand were also more adversely affected in the centrilobular region as shown by decreases of greater than 60% in perivenule cells and by only 20% to 30% in periportal cells of ethanol-fed animals compared with controls.

Casey, C.A.; Kragskow, S.L.; Sorrell, M.F.; Tuma, D.J. (Department of Veterans Affairs Medical Center, Omaha, NE (USA))



G9a-mediated histone methylation regulates ethanol-induced neurodegeneration in the neonatal mouse brain.  


Rodent exposure to binge-like ethanol during postnatal day 7 (P7), which is comparable to the third trimester of human pregnancy, induces neuronal cell loss. However, the molecular mechanisms underlying these neuronal losses are still poorly understood. Here, we tested the possibility of histone methylation mediated by G9a (lysine dimethyltransferase) in regulating neuronal apoptosis in P7 mice exposed to ethanol. G9a protein expression, which is higher during embryogenesis and synaptogenic period compared to adult brain, is entirely confined to the cell nuclei in the developing brain. We found that ethanol treatment at P7, which induces apoptotic neurodegeneration in neonatal mice, enhanced G9a activity followed by increased histone H3 lysine 9 (H3K9me2) and 27 (H3K27me2) dimethylation. In addition, it appears that increased dimethylation of H3K9 makes it susceptible to proteolytic degradation by caspase-3 in conditions in which ethanol induces neurodegeneration. Further, pharmacological inhibition of G9a activity prior to ethanol treatment at P7 normalized H3K9me2, H3K27me2 and total H3 proteins to basal levels and prevented neurodegeneration in neonatal mice. Together, these data demonstrate that G9a mediated histone H3K9 and K27 dimethylation critically regulates ethanol-induced neurodegeneration in the developing brain. Furthermore, these findings reveal a novel link between G9a and neurodegeneration in the developing brain exposed to postnatal ethanol and may have a role in fetal alcohol spectrum disorders. PMID:23396011

Subbanna, Shivakumar; Shivakumar, Madhu; Umapathy, Nagavedi S; Saito, Mariko; Mohan, Panaiyur S; Kumar, Asok; Nixon, Ralph A; Verin, Alexander D; Psychoyos, Delphine; Basavarajappa, Balapal S



Pyranocycloartobiloxanthone A, a novel gastroprotective compound from Artocarpus obtusus Jarret, against ethanol-induced acute gastric ulcer in vivo.  


Pyranocycloartobiloxanthone A (PA), a xanthone derived from the Artocarpus obtusus Jarret, belongs to the Moraceae family which is native to the tropical forest of Malaysia. In this study, the efficacy of PA as a gastroprotective compound was examined against ethanol-induced ulcer model in rats. The rats were pretreated with PA and subsequently exposed to acute gastric lesions induced by absolute ethanol. The ulcer index, gastric juice acidity, mucus content, histological analysis, glutathione (GSH) levels, malondialdehyde level (MDA), nitric oxide (NO) and non-protein sulfhydryl group (NP-SH) contents were evaluated in vivo. The activities of PA as anti-Helicobacter pylori, cyclooxygenase-2 (COX-2) inhibitor and free radical scavenger were also investigated in vitro. The results showed that the oral administration of PA protects gastric mucosa from ethanol-induced gastric lesions. PA pretreatment significantly (p<0.05) restored the depleted GSH, NP-SH and NO levels in the gastric homogenate. Moreover, PA significantly (p<0.05) reduced the elevated MDA level due to ethanol administration. The gastroprotective effect of PA was associated with an over expression of HSP70 and suppression of Bax proteins in the ulcerated tissue. In addition, PA exhibited a potent FRAP value and significant COX-2 inhibition. It also showed a significant minimum inhibitory concentration (MIC) against H. pylori bacterium. The efficacy of PA was accomplished safely without the presence of any toxicological parameters. The results of the present study indicate that the gastroprotective effect of PA might contribute to the antioxidant and anti-inflammatory properties as well as the anti-apoptotic mechanism and antibacterial action against Helicobacter pylori. PMID:23570997

Sidahmed, Heyam M A; Hashim, Najihah Mohd; Amir, Junaidah; Abdulla, Mahmood Ameen; Hadi, A Hamid A; Abdelwahab, Siddig Ibrahim; Taha, Manal Mohamed Elhassan; Hassandarvish, Pouya; Teh, Xinsheng; Loke, Mun Fai; Vadivelu, Jamuna; Rahmani, Mawardi; Mohan, Syam



Kolaviron, a biflavonoid complex from Garcinia kola seeds, ameliorates ethanol-induced reproductive toxicity in male wistar rats.  


In previous studies, we established that kolaviron (KV) (a biflavonoid from Garcinia kola seeds) elicited anti-oxidative and hepatoprotective effects in Wistar rats chronically treated with ethanol. The present study investigates the possible ameliorative effect of KV against ethanol-induced reproductive toxicity in male Wistar rats. Twenty-eight rats were randomly divided into four groups of seven animals each; Group 1 (control) was administered corn oil, group 2 was given 45%v/v ethanol at 3g/kg body weight, group 3 received ethanol and KV (200mg/kg) simultaneously and group 4 received KV alone. All drugs were given daily by oral gavage for 21 consecutive days. Ethanol treatment resulted in a significant (p<0.05) decrease in relative weight of testis of the animals. In the spermatozoa, ethanol intoxication resulted in 54%, 21% and 38% decreases in testicular protein content, sperm motility and count, respectively. In addition, ethanol administration enhanced lipid peroxidation (LPO) process assessed by the accumulation of malondialdehyde (MDA) in the testis. Precisely, MDA level was increased by 121% in the testis of ethanol-treated rats relative to the control. Furthermore, levels of testicular glutathione and activities of testicular antioxidant enzymes such as superoxide dismutase and catalase were significantly (p<0.05) reduced in ethanol-treated rats. Histopathology showed extensive degenerative changes in seminiferous tubules and defoliation of spermatocytes in testis of ethanol-treated rats. Interestingly, co-administration of KV with ethanol led to almost complete inhibition of testicular LPO thereby enhancing antioxidant status of the testis. Overall, KV ameliorates ethanol-induced toxic assault on testis and improves seminal qualities of the rats. PMID:23955400

Adaramoye, Oluwatosin A; Arisekola, Muritala



Cilnidipine, an L/N-type calcium channel blocker prevents acquisition and expression of ethanol-induced locomotor sensitization in mice.  


Several evidences indicated the involvement of L- and N-type calcium channels in behavioral effects of drugs of abuse, including ethanol. Calcium channels are implicated in ethanol-induced behaviors and neurochemical responses. Calcium channel antagonists block the psychostimulants induced behavioral sensitization. Recently, it is demonstrated that L-, N- and T-type calcium channel blockers attenuate the acute locomotor stimulant effects of ethanol. However, no evidence indicated the role of calcium channels in ethanol-induced psychomotor sensitization. Therefore, present study evaluated the influence of cilnidipine, an L/N-type calcium channel blocker on acquisition and expression of ethanol-induced locomotor sensitization. The results revealed that cilnidipine (0.1 and 1.0?g/mouse, i.c.v.) attenuates the expression of sensitization to locomotor stimulant effect of ethanol (2.0g/kg, i.p.), whereas pre- treatment of cilnidipine (0.1 and 1.0?g/mouse, i.c.v.) during development of sensitization blocks acquisition and attenuates expression of sensitization to locomotor stimulant effect of ethanol. Cilnidipine per se did not influence locomotor activity in tested doses. Further, cilnidipine had no influence on effect of ethanol on rotarod performance. These results support the hypothesis that neuroadaptive changes in calcium channels participate in the acquisition and the expression of ethanol-induced locomotor sensitization. PMID:22402189

Bhutada, Pravinkumar; Mundhada, Yogita; Patil, Jayshree; Rahigude, Anand; Zambare, Krushna; Deshmukh, Prashant; Tanwar, Dhanshree; Jain, Kishor



A role for ethanol-induced oxidative stress in controlling lineage commitment of mesenchymal stromal cells through inhibition of wnt/beta-catenin signaling  

Technology Transfer Automated Retrieval System (TEKTRAN)

The mechanisms by which chronic ethanol intake induces bone loss remain unclear. In females, the skeletal response to ethanol varies depending on physiologic status (viz. cycling, pregnancy, lactation). Ethanol-induced oxidative stress appears to be a key event leading to skeletal toxicity. In the c...


A crucial role for ethanol-induced oxidative stress in controlling lineage commitment of mesenchymal stromal cells through inhibition of wnt/beta-catenin signaling  

Technology Transfer Automated Retrieval System (TEKTRAN)

Female skeletal responses to ethanol may vary depending on the physiologic status (viz. cycling, pregnancy, lactation). Nonetheless, ethanol-induced oxidative stress appears to be the key event leading to skeletal toxicity. In the current study, we chronically infused EtOH-containing liquid diets ...


A crucial role for ethanol-induced oxidative stress in controlling lineage commitment of mesenchymal stromal cells through Inhibition of Wnt / Beta-catenin Signaling  

Technology Transfer Automated Retrieval System (TEKTRAN)

The mechanisms by which chronic ethanol intake induces bone loss remain largely unclear. Especially in females, skeletal response to ethanol may vary depending on the physiologic status (viz. cycling, pregnancy, lactation). Nonetheless, ethanol-induced oxidative stress appears to be the key event le...


Suppression of Ethanol-Reinforced Behavior by Naltrexone Is Associated with Attenuation of the Ethanol-Induced Increase in Dialysate Dopamine Levels in the Nucleus Accumbens  

Microsoft Academic Search

The opiate antagonist naltrexone suppresses ethanol- reinforced behavior in animals and decreases ethanol intake in humans. However, the mechanisms underlying these actions are not well understood. Experiments were designed to test the hypothesis that naltrexone attenuates the rewarding properties of ethanol by interfering with ethanol-induced stimulation of dopamine activity in the nucleus accumbens (NAcc). Simulta- neous measures of the effects

Rueben A. Gonzales; Friedbert Weiss


Characterization of ethanol-inducible human liver N-nitrosodimethylamine demethylase  

SciTech Connect

Through the use of monospecific antibodies directed against hepatic cytochrome P-450j, an enzyme induced in rats treated with ethanol or isoniazid, we have purified from human liver the related cytochrome P-450 termed HLj. HLj resembles rat P-450j and P-450 LM3a, the homologous cytochrome in rabbit liver, in its NH/sub 2/-terminal amino acid sequence, in being in highest concentration in liver microsome samples prepared from two patients intoxicated by ethanol and one patient given isoniazid, and in catalyzing the metabolic activation of the procarcinogen N-nitrosodimethylamine. Furthermore, each of nine human liver RNA samples contained a species of mRNA hybridizable to a cloned HLj cDNA. We conclude that HLj is related by structure, function, and some regulator characteristics to rat P-450j and rabbit P-450 LM3a, cytochromes critical for metabolism of several clinically relevant cytotoxic and carcinogenic agents.

Wrighton, S.A.; Thomas P.E.; Molowa, D.T.; Haniu, M.; Shively, J.E.; Maines, S.L.; Watkins, P.B.; Parker, G.; Mendez-Picon, G.; Levin, W.; Guzelian, P.S.



Inhibition of Ethanol-Induced Liver Disease in the Intragastric Feeding Rat Model by Chlormethiazole  

Microsoft Academic Search

The purpose of this investigation was to assess the effect of chlormethiazole treatment on liver damage in the experimental rat intragastric ethanol-feeding model of alcoholic liver disease. Chlormethiazole has been used in the treatment of alcoholic withdrawal and has been shown to inhibit cytochrome P4502E1. Since treatment of experimental alcoholic liver disease with CYP2E1 inhibitors had an ameliorating effect on

Z.-Q. Gouillon; D. Lucas; J. Li; A. L. Hagbjork; B. A. French; P. Fu; C. Fang; M. Ingelman-Sundberg; T. M. Donohue; S. W. French



Hepatic ischemia induced immediate oxidative stress after reperfusion and determined the severity of the reperfusion-induced damage.  


Noninvasive evaluation of organ redox states provides invaluable information in many clinical settings. We evaluated a newly developed reduction/oxidation-sensitive green fluorescent protein (roGFP) probe that reports cellular redox potentials and their dynamic changes in live cells. On hypoxia/reoxygenation (H/R) of AML12 liver cells, roGFP indicated mild reduction during hypoxia, but immediate transient oxidation after reoxygenation. The roGFP probe confirmed the antioxidative effects of N-acetylcysteine, catalase, redox factor-1, and Mn-SOD/CuZn-SOD against H/R-induced cellular oxidative stress (OS). In a mouse liver ischemia/reperfusion (I/R) model, roGFP transduced by using an adenoviral vector revealed immediate reduction of the liver under ischemia, and two distinct peaks of OS: (a) early, observed within 60 min after reperfusion, similar to the in vitro study; and (b) later, at 24 h. The early peak levels paralleled the ischemic time up to 75 min and the postischemic liver injury (sGOT/GPT/LDH) in the later phase (6 and 24 h after I/R). The roGFP probe successfully indicated postischemic OS of the liver in living mice, accurately predicting postischemic liver injury. This probe may represent an effective OS marker indicating organ redox states and also predicting the damage/function. PMID:19489709

Haga, Sanae; Remington, S James; Morita, Naoki; Terui, Keita; Ozaki, Michitaka



1H and 31P NMR Lipidome of Ethanol-Induced Fatty Liver  

PubMed Central

Background Hepatic steatosis (fatty liver), an early and reversible stage of alcoholic liver disease, is characterized by triglyceride deposition in hepatocytes, that can advance to steatohepatitis, fibrosis, cirrhosis, and ultimately to hepatocellular carcinoma. In the present work, we studied altered plasma and hepatic lipid metabolome (lipidome) to understand the mechanisms and lipid pattern of early stage alcohol induced-fatty liver. Methods Male Fischer 344 rats were fed 5% alcohol in a Lieber-DeCarli diet. Control rats were pair-fed an equivalent amount of maltose-dextrin. After one month, animals were sacrificed and plasma collected. Livers were excised for morphological, immunohistochemical, and biochemical studies. The lipids from plasma and livers were extracted with methyl-tert-butyl ether and analyzed by 750/800 MHz proton nuclear magnetic resonance (1H NMR) and phosphorus (31P) NMR spectroscopy on a 600 MHz spectrometer. The NMR data were then subjected to multivariate statistical analysis. Results Hemotoxylin & Eosin and Oil Red O stained liver sections showed significant fatty infiltration. Immunohistochemical analysis of liver sections from ethanol-fed rats showed no inflammation (absence of CD3 positive cells) or oxidative stress (absence of malondialdehyde reactivity or 4-hydroxynonenal positive straining). Cluster analysis and principal component analysis of 1H NMR data of lipid extracts of both plasma and livers showed a significant difference in the lipid metabolome of ethanol-fed vs. control rats. 31P NMR data of liver lipid extracts showed significant changes in phospholipids similar to 1H NMR data. 1H NMR data of plasma and liver reflected several changes while comparison of 1H NMR and 31P NMR data offered a correlation among the phospholipids. Conclusions Our results show that alcohol consumption alters metabolism of cholesterol, triglycerides and phospholipids that could contribute to the development of fatty liver. These studies also indicate that fatty liver precedes oxidative stress and inflammation. The similarities observed in plasma and liver lipid profiles offer a potential methodology for detecting early stage alcohol-induced fatty liver disease by analyzing the plasma lipid profile.

Fernando, Harshica; Kondraganti, Shakuntala; Bhopale, Kamlesh K.; Volk, David E.; Neerathilingam, Muniasamy; Kaphalia, Bhupendra S.; Luxon, Bruce A.; Boor, Paul J.; Ansari, G. A. Shakeel



Effects of zincl-carnosine on gastric mucosal and cell damage caused by ethanol in rats  

Microsoft Academic Search

The effects of zincl-carnosine on ethanol-induced damage and the correlation of these effects with endogenous prostaglandin E2 were evaluated in rat gastric mucosain vivo andin vivo. When given either intragastrically or intraperitoneally, zincl-carnosine (10 or 30 mg\\/kg) prevented gross visible damage to gastric mucosa caused by ethanol without affecting the mucosal prostaglandin E2 level. This protective effect of zincl-carnosine was

Tetsuo Arakawa; Hiroshi Satoh; Atsushi Nakamura; Hiroko Nebiki; Takashi Fukuda; Hiroyuki Sakuma; Hajime Nakamura; Mikio Ishikawa; Masao Seiki; Kenzo Kobayashi



?4-Containing GABAA Receptors are Required for Antagonism of Ethanol-Induced Motor Incoordination and Hypnosis by the Imidazobenzodiazepine Ro15-4513  

PubMed Central

Alcohol (ethanol) is widely consumed for its desirable effects but unfortunately has strong addiction potential. Some imidazobenzodiazepines such as Ro15-4513 are able to antagonize many ethanol-induced behaviors. Controversial biochemical and pharmacological evidence suggest that the effects of these ethanol antagonists and ethanol are mediated specifically via overlapping binding sites on ?4/?-containing GABAA-Rs. To investigate the requirement of ?4-containing GABAA-Rs in the mechanism of action of Ro15-4513 on behavior, wildtype (WT) and ?4 knockout (KO) mice were compared for antagonism of ethanol-induced motor incoordination and hypnosis. Motor effects of ethanol were tested in two different fixed speed rotarod assays. In the first experiment, mice were injected with 2.0?g/kg ethanol followed 5?min later by 10?mg/kg Ro15-4513 (or vehicle) and tested on a rotarod at 8?rpm. In the second experiment, mice received a single injection of 1.5?g/kg ethanol?±?3?mg/kg Ro15-4513 and were tested on a rotarod at 12?rpm. In both experiments, the robust Ro15-4513 antagonism of ethanol-induced motor ataxia that was observed in WT mice was absent in KO mice. A loss of righting reflex (LORR) assay was used to test Ro15-4513 (20?mg/kg) antagonism of ethanol (3.5?g/kg)-induced hypnosis. An effect of sex was observed on the LORR assay, so males and females were analyzed separately. In male mice, Ro15-4513 markedly reduced ethanol-induced LORR in WT controls, but ?4 KO mice were insensitive to this effect of Ro15-4513. In contrast, female KO mice did not differ from WT controls in the antagonistic effects of Ro15-4513 on ethanol-induced LORR. We conclude that Ro15-4513 requires ?4-containing receptors for antagonism of ethanol-induced LORR (in males) and motor ataxia.

Iyer, Sangeetha V.; Benavides, Rodrigo A.; Chandra, Dev; Cook, James M.; Rallapalli, Sundari; June, Harry L.; Homanics, Gregg E.



Urinary concentrations of ethyl glucuronide and ethyl sulfate as thresholds to determine potential ethanol-induced alteration of steroid profiles.  


The suppression of steroid biotransformation resulting in a decrease of the major urinary metabolites--androsterone and etiocholanolone--and the elevation of testosterone/epitestosterone (T/E) ratios following ethanol administration is well described. At least the latter parameter T/E represents an important indicator for endogenous steroid abuse in doping control. The quantitative correlation between ethanol consumption markers and steroid profile alteration was evaluated, aiming to differentiate between permitted ethanol administration and potential steroid abuse. Steroid profiles, ethanol, ethyl glucuronide (EtG), and sulfate (EtS) were quantified after administration of ethanol (intended maximum ethanol concentration in blood was 1 mg/g) to 21 male and 15 female volunteers. EtG concentrations in urine (corrected by either specific gravity or creatinine concentration) were found to be most suitable for quantitative evaluations. Gender specific urinary EtG concentrations of 48 ug/ml (men) and 15.5 ug/ml (women) may be considered as useful thresholds for a potential ethanol-induced suppression of steroids biotransformation. PMID:22213685

Thieme, D; Grosse, J; Keller, L; Graw, M


The effect of calorie restriction on acute ethanol-induced oxidative and nitrosative liver injury in rats.  


The aim of our study was to examine the effect of calorie restriction (CR) on oxidative and nitrosative liver injury in rats, induced by acute ethanol intoxication. Male Wistar rats were divided into groups: (1) control; (2) calorie-restricted groups with intake of 60-70% (CR60-70) and 40-50% of daily energy needs (CR40-50); (3) ethanol-treated group (E); (4) calorie-restricted, ethanol-treated groups (E+CR60-70 and E+CR40-50). Ethanol was administered in 5 doses of 2g/kg every 12h, and duration of CR was 5 weeks before ethanol treatment. Malondialdehyde and nitrite and nitrate level were significantly lower in E+CR60-70 and higher in E+CR40-50 vs. E group. Liver reduced glutathione content and activity of both superoxide dismutase izoenzymes were significantly higher in E+CR60-70 and lower in E+CR40-50 vs. E group. Oxidative stress may be a potential mechanism of hormetic effects of CR on acute ethanol-induced liver injury. PMID:23686010

Mladenovi?, Dušan; Ninkovi?, Milica; Aleksi?, Vuk; Sljivan?anin, Tamara; Vu?evi?, Danijela; Todorovi?, Vera; Stankovi?, Milena; Stanojlovi?, Olivera; Radosavljevi?, Tatjana



Dillapiole, Isolated from Peperomia pellucida, Shows Gastroprotector Activity against Ethanol-Induced Gastric Lesions in Wistar Rats.  


Peperomia pellucida is a plant used in traditional medicine to treat gastric ulcers. Although this gastroprotective activity was reported, the active compounds have not been identified. Therefore, the aim herein was to identify the most active compound in the gastroprotective activity of P. pellucida using an ethanol-induced gastric ulcer experimental rat model. A gastroprotective effect was observed when the hexane and dichloromethane extracts were tested, with the higher effect being obtained with the dichloromethane extract (82.3 ± 5.6%) at 100 mg/kg. Dillapiole was identified as the most active compound in this extract. Although there have been previous reports on dillapiole, this is the first on its gastroprotective activity. Rats treated with this compound at 3, 10, 30 and 100 mg/kg showed 23.1, 56.1, 73.2 and 85.5% gastroprotection, respectively. The effect elicited by dillapiole at 100 mg/kg was not attenuated by pretreatment with indomethacin (10 mg/kg, s.c.), a prostaglandin synthesis blocker, NG-nitro-l-arginine methyl ester (70 mg/kg, i.p.), a nitric oxide (NO) synthase inhibitor, or N-ethylmaleimide (10 mg/kg, s.c.), a blocker of sulfhydryl groups. This suggests that the gastroprotective mechanism of action of dillapiole does not involve prostaglandins, NO or sulfhydryl groups. PMID:24064453

Rojas-Martínez, Raúl; Arrieta, Jesús; Cruz-Antonio, Leticia; Arrieta-Baez, Daniel; Velázquez-Méndez, Antonio Magdiel; Sánchez-Mendoza, María Elena



Ascorbic acid is superior to silymarin in the recovery of ethanol-induced inflammatory reactions in hepatocytes of guinea pigs.  


Both oxidative stress and inflammatory reactions play a major role in alcoholic liver fibrosis. We evaluated the efficacy of ascorbic acid (AA) and silymarin in the regression of alcohol-induced inflammation in hepatocytes of guinea pigs (Cavia porcellus). Animals were administered with ethanol at a daily dose of 4 g/kg body weight (b.wt) for 90 days. On the ninety-first day, ethanol administration was stopped and animals were divided into alcohol abstention group and silymarin- (25 mg/100 g b.wt) and AA- (25 mg/100 g b.wt) supplemented groups and maintained for 30 days. There was a significant increase in the activities of alanine aminotransferase, aspartate aminotransferase, and ?-glutamyl transpeptidase in the serum of the ethanol group. The intracellular reactive oxygen species (ROS) and expressions of cytochrome P4502E1 and nuclear factor ?B1, tumor necrosis factor-?, and transforming growth factor-?1 in hepatocytes were significantly increased in ethanol group. The fibrotic markers ?-smooth muscle actin and ? 1(I) collagen and activity of cytotoxicity marker caspase-3 were significantly increased and AA content was significantly reduced in hepatocytes of alcohol-treated guinea pigs. But the AA and silymarin supplementation significantly reduced these changes in comparison with alcohol abstention group. AA could induce greater reduction of inflammatory and fibrotic markers in hepatocytes than silymarin. This indicates that AA is superior to silymarin in inhibiting intracellular ROS generation and thereby reducing the ethanol-induced inflammation in hepatocytes. PMID:23653339

Abhilash, P A; Harikrishnan, R; Indira, M



Dietary lipids affect human ethanol-inducible CYP2E1 gene expression in vivo in mononuclear cells.  


We tested the hypothesis that dietary cholesterol modulate human ethanol-inducible CYP2E1 expression in vivo in circulating mononuclear cells. Healthy volunteers (n= 10) were submitted to a low fat low cholesterol diet for 4 days (day 0-day 3, LFLC). Cholesterol (595 +/- 56 mg/day) was then reintroduced for 7 days (day 4-day 10, LFHC). In the same time, controls subjects (n=7) did not change their habitual daily diet. CYP2E1 mRNA levels, evaluated in mononuclear cells, decreased in experimental subjects during both LFLC and LFHC from 100% to 53 +/- 5%, (p<0.001) with a main decrease during LFLC period (100% to 71 +/- 16%, p=0.05). Immunoreactive CYP2E1 showed a similar pattern and decreased from 100 to 62 +/- 12% during the trial (p<0.05). No significant change occured in control subjects. Between day 0 and day 11, changes in CYP2E1 mRNA correlated positively with plasma cholesterol (r2=0.67, p<0.001) and HDL cholesterol concentrations (r2=0.61, p<0.001). In contrast, no correlation was found between plasma fatty acids concentrations and CYP2E1 expression. The present results suggest that lipid factors regulate CYP2E1 expression, in vivo, in human mononuclear cells. In particular, plasma cholesterol concentrations may play an important role in this regulation. PMID:10972199

Boucher, P; Seree, E; Vidon, C; de Souza, A C; Villard, P H; Chambon, R; Barra, Y; Vallon, J J



Post-retrieval propranolol treatment does not modulate reconsolidation or extinction of ethanol-induced conditioned place preference.  


The reconsolidation hypothesis posits that established emotional memories, when reactivated, become labile and susceptible to disruption. Post-retrieval injection of propranolol (PRO), a nonspecific ?-adrenergic receptor antagonist, impairs subsequent retention performance of a cocaine- and a morphine-induced conditioned place preference (CPP), implicating the noradrenergic system in the reconsolidation processes of drug-seeking behavior. An important question is whether post-retrieval PRO disrupts memory for the drug-cue associations, or instead interferes with extinction. In the present study, we evaluated the role of the ?-adrenergic system on the reconsolidation and extinction of ethanol-induced CPP. Male DBA/2J mice were trained using a weak or a strong conditioning procedure, achieved by varying the ethanol conditioning dose (1 or 2 g/kg) and the number of ethanol trials (2 or 4). After acquisition of ethanol CPP, animals were given a single post-retrieval injection of PRO (0, 10 or 30 mg/kg) and tested for memory reconsolidation 24 h later. Also, after the first reconsolidation test, mice received 18 additional 15-min choice extinction tests in which PRO was injected immediately after every test. Contrary to the prediction of the reconsolidation hypothesis, a single PRO injection after the retrieval test did not modify subsequent memory retention. In addition, repeated post-retrieval administration of PRO did not interfere with extinction of CPP in mice. Overall, our data suggest that the ?-adrenergic receptor does not modulate the associative processes underlying ethanol CPP. PMID:22285323

Font, Laura; Cunningham, Christopher L



Vasoprotective effect of vitamin E: rescue of ethanol-induced atherosclerosis and inflammatory stress in rat vascular wall.  


Chronic ethanol consumption increases the incidence of cardiovascular disease. The mechanisms underlying ethanol-induced susceptibility to cardiovascular disease continue to be defined. This study examines the hypothesis that chronic ethanol consumption plausibly induces vascular wall abnormalities via inflammatory reactions. In addition, it intends to find out whether vitamin E inhibits the abnormalities induced by ethanol in rats' vascular wall. Twenty four male Wistar rats were divided into three groups (n=8): Control ©, ethanol (E), and vitamin E treated ethanol (VETE) group. After 6weeks, the aortic and coronary wall changes, vascular endothelial growth factor (VEGF), alpha-1 glycoprotein and haptoglobin amounts in plasma, C-reactive protein levels(CRP), as well as the amount of aortic IL-6 were evaluated. The results revealed the elevation of polymorphonuclear (PMN) leukocyte in the vascular wall, disorganization of endothelium with ballooning of cells, proliferation of vasa-vasorum with an increase in the IL-6, CRP, as well as a decrease in VEGF and an increase in alpha-1 glycoprotein and haptoglobin in the ethanol group compared to the control group. Significant amelioration of aortic and coronary wall changes, along with the restoration of elevated level of IL6, CRP, and the decreased level of VEGF compared to that of the controls were found in vitamin E-treated animals. These findings strongly support the idea that heavy and chronic ethanol consumption initiates atherosclerosis by inflammatory stress, and that these effects can be alleviated by vitamin E as an anti-inflammatory agent. PMID:23665315

Shirpoor, Alireza; Norouzi, Leila; Khadem Ansari, Mohammad-Hasan; Ilkhanizadeh, Behrouz; Gharaaghaji, Rasool



Unique profiles of changes in cell membrane fluidity during ethanol-induced yeast-to-pseudohyphal transition in Candida tropicalis.  


A dimorphic transition from the yeast form to filamentous one in Candida tropicalis pK233 is triggered by the addition of ethanol into the glucose semi-defined liquid medium and the process of filamentation accompanies temporal depolarization of yeast cells. The transition is completely prevented by further supplementation of myo-inositol at the start of cultivation. The addition of ethanol caused an increase in membrane fluidity during the process of depolarization, and then fluidity was gradually lowered to the level equivalent with that of the stationary-phase yeast cells in accordance with filamentation. The increase in membrane fluidity of ethanol-induced cells appeared parallel with reduction in the content of membrane phosphatidylinositol, which was rich in saturated palmitic acid. Introduction of exogenous myo-inositol or 1 M sorbitol into the ethanol-supplemented culture at the start of cultivation restored yeast growth and the reduction of membrane fluidity occurred, coupled with the recovery of the phosphatidylinositol content. PMID:20953096

Suzuki, Takahito; Kono, Keita; Tawara, Shu-ichi; Fujimura, Takaji; Ito, Takuya; Omi, Kazuo; Ohbuchi, Kaoru; Komatsu, Yasuhiko; Sakaguchi, Shuichi; Kamihara, Teijiro



Reduced effect of NMDA glutamate receptor antagonist on ethanol-induced ataxia and striatal glutamate levels in mice lacking ENT1  

PubMed Central

Alcohol-sensitive type 1 equilibrative nucleotide transporter (ENT1) is known to regulate glutamate signaling in the striatum as well as ethanol intoxication. However, it was unclear whether altered extracellular glutamate levels in ENT1?/? mice contribute to ethanol-induced behavioral changes. Here we report that altered glutamate signaling in ENT1?/? mice is implicated in the ethanol-induced locomotion and ataxia by NMDA receptor antagonist, CGP37849. ENT1?/? mice appear less intoxicated following sequential treatment with CGP37849 and ethanol, compared to ENT1+/+ littermates on the rotarod. These results indicate that inhibiting NMDA glutamate receptors is critical to regulate the response and susceptibility of alcohol related behaviors. Interestingly, a microdialysis experiment showed that the ventral striatum of ENT1?/? mice is less sensitive to the glutamate-reducing effect of the NMDA receptor antagonist compared to the dorsal striatum. Our findings suggest that differential glutamate neurotransmission in the striatum regulates ethanol intoxication.

Nam, Hyung Wook; Lee, Moonnoh R.; Hinton, David J.; Choi, Doo-Sup



Ethanol Activation of Protein Kinase A Regulates GABAA Receptor Subunit Expression in the Cerebral Cortex and Contributes to Ethanol-Induced Hypnosis  

PubMed Central

Protein kinases are implicated in neuronal cell functions such as modulation of ion channel function, trafficking, and synaptic excitability. Both protein kinase C (PKC) and A (PKA) are involved in regulation of ?-aminobutyric acid type A (GABAA) receptors through phosphorylation. However, the role of PKA in regulating GABAA receptors (GABAA-R) following acute ethanol exposure is not known. The present study investigated the role of PKA in the effects of ethanol on GABAA-R ?1 subunit expression in rat cerebral cortical P2 synaptosomal fractions. Additionally, GABA-related behaviors were examined. Rats were administered ethanol (2.0–3.5?g/kg) or saline and PKC, PKA, and GABAA-R ?1 subunit levels were measured by western blot analysis. Ethanol (3.5?g/kg) transiently increased GABAA-R ?1 subunit expression and PKA RII? subunit expression at similar time points whereas PKA RII? was increased at later time points. In contrast, PKC isoform expression remained unchanged. Notably, lower ethanol doses (2.0?g/kg) had no effect on GABAA-R ?1 subunit levels, although PKA type II regulatory subunits RII? and RII? were increased at 10 and 60?min when PKC isozymes are also known to be elevated. To determine if PKA activation was responsible for the ethanol-induced elevation of GABAA-R ?1 subunits, the PKA antagonist H89 was administered to rats prior to ethanol exposure. H89 administration prevented ethanol-induced increases in GABAA-R ?1 subunit expression. Moreover, increasing PKA activity intracerebroventricularly with Sp-cAMP prior to a hypnotic dose of ethanol increased ethanol-induced loss of righting reflex (LORR) duration. This effect appears to be mediated in part by GABAA-R as increasing PKA activity also increased the duration of muscimol-induced LORR. Overall, these data suggest that PKA mediates ethanol-induced GABAA-R expression and contributes to behavioral effects of ethanol involving GABAA-R.

Kumar, Sandeep; Ren, Qinglu; Beckley, Jonathon H.; O'Buckley, Todd K.; Gigante, Eduardo D.; Santerre, Jessica L.; Werner, David F.; Morrow, A. Leslie



Ethanol-induced anesthesia in inbred strains of long-sleep and short-sleep mice: A genetic analysis of repeated measures using censored data  

Microsoft Academic Search

We present a repeated-measures, genetic analysis of ethanol-induced anesthesia (sleep time) in mice from the inbred long-sleep (ILS) and short-sleep (ISS) strains of mice and their derived F1 and F2 generations. Mice (totalN>1300) were administered a 4.1 g\\/kg intraperitoneal dose of ethanol at two times, 7 to 10 days apart. A method suggested by Cohen was used to analyze the

Paul D. Markel; John C. DeFries; Thomas E. Johnson



Physical and chemical modulation of lipid rafts by a dietary n-3 polyunsaturated fatty acid increases ethanol-induced oxidative stress  

Microsoft Academic Search

Dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to modulate lipid raft-dependent signaling, but not yet lipid raft-dependent oxidative stress. Previously, we have shown that ethanol-induced membrane remodeling, i.e., an increase in membrane fluidity and alterations in physical and biochemical properties of lipid rafts, participated in the development of oxidative stress. Thus, we decided to study n-3 PUFA

Fatiha Aliche-Djoudi; Normand Podechard; Martine Chevanne; Philippe Nourissat; Daniel Catheline; Philippe Legrand; Marie-Thérèse Dimanche-Boitrel; Dominique Lagadic-Gossmann; Odile Sergent



Ethanol toxicity: rehabilitation of hepatic antioxidant defense system with dietary ginger.  


The current investigation has been conducted to investigate the influence of ginger on hepatic antioxidant enzymes system in ethanol treated rats. Ethanol significantly decreased the superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione content while an increase of malondialdehyde (MDA) levels were estimated in the hepatic tissue. This effect was reversed by a treatment with 1% dietary ginger for 4 weeks in rats by improved antioxidant status which suggest that treatment of ginger may have protective role against the ethanol induced hepatotoxicity. PMID:18182172

Mallikarjuna, K; Sahitya Chetan, P; Sathyavelu Reddy, K; Rajendra, W



A diagnostic approach to different types of nonA non-B acute hepatitis through the evaluation of the lobular distribution of hepatocytic damage  

Microsoft Academic Search

Summary  The activity in the serum of three hepatic mitochondrial enzymes, glutamate dehydrogenase (GDH), ornithine carbamyl transferase\\u000a (OCT) and mitochondrial glutamic oxaloacetic transaminase (m-GOT), all of which show different lobular distribution in the\\u000a liver, was investigated in order to clarify the usefulness of determinations of these enzymes for the diagnosis of different\\u000a types of acute non-A non-B (NANB) hepatitis. In NANB

Shujiro Takase; Akira Takada; Hiroyuki Sato



Is Antiretroviral Therapy Causing Long-Term Liver Damage? A Comparative Analysis of HIV-Mono-Infected and HIV\\/Hepatitis C Co-Infected Cohorts  

Microsoft Academic Search

The effects of highly active antiretroviral therapy (HAART) on progression of hepatic fibrosis in HIV-hepatitis C virus (HCV) co-infection are not well understood. Deaths from liver diseases have risen in the post-HAART era, yet some cross-sectional studies have suggested that HAART use is associated with improved fibrosis rates. In a retrospective cohort of 533 HIV mono-infected and 127 HIV\\/HCV co-infected

Erica E. M. Moodie; Nitika Pant Pai; Marina B. Klein; Srikanth Tripathy



Hepatitis C Virus Infection Activates the Immunologic (Type II) Isoform of Nitric Oxide Synthase and Thereby Enhances DNA Damage and Mutations of Cellular Genes  

Microsoft Academic Search

Hepatitis C virus (HCV) infection causes hepatitis, hepatocellular carcinoma, and B-cell lymphomas in a significant number of patients. Previously we have shown that HCV infection causes double-stranded DNA breaks and enhances the mutation frequency of cellular genes, including proto-oncogenes and immunoglobulin genes. To determine the mechanisms, we studied in vitro HCV infection of cell culture. Here we report that HCV

Keigo Machida; Kevin T.-H. Cheng; Vicky M.-H. Sung; Ki Jeong Lee; Alexandra M. Levine; Michael M. C. Lai



Microwave attenuation of ethanol-induced hypothermia: ethanol tolerance, time course, exposure duration, and dose response studies  

SciTech Connect

Four experiments were conducted to quantify the reported attenuation by microwave (MW) irradiation of ethanol-induced hypothermia. In one experiment rats were irradiated (continuous wave 2.45 GHz, specific absorption rate = 0.3 W/kg) or sham irradiated for 45 min, injected with 3.6 g/kg, 20% (v/v) ethanol (EtOH) or saline (NaCl) i.p.. Colonic temperature was monitored at 20-min intervals for 2 h. This procedure was repeated for 8 days to determine the rate of tolerance development to the hypothermic effect of ethanol. While MW irradiation did significantly attenuate EtOH-induced hypothermia, it did not enhance or retard the rate of tolerance development. To determine the duration of irradiation necessary to attenuate EtOH-induced hypothermia, groups of rats were irradiated or sham irradiated for 5, 15, 30, or 60 min prior to EtOH injection and subsequent temperature measurements. The attenuation was apparent only after 60 min of irradiation. To determine the duration of the attenuation effect after irradiation, rats were injected with EtOH or NaCl at 0, 30, 60, 120, or 480 min after 45 min of irradiation or sham irradiation. The attenuation effect was apparent among rats injected 0 to 30 min after irradiation and for the first 40 min for groups injected at 120 min. Additional rats were injected with NaCl or 0.9, 1.8, or 2.7 g/kg of EtOH i.p. following 45 min of irradiation or sham irradiation to determine if the attenuation effect depends on the dose of EtOH administered. Attenuation of EtOH-induced hypothermia was more apparent at lower doses of EtOH than at higher doses. These results indicate that the effect is an acute response to irradiation, and rule out several other potential explanations.

Hjeresen, D.L.; Francendese, A.; O'Donnell, J.M.




PubMed Central

Organotypic cultures of rat cortex were used to test the hypotheses that nerve growth factor (NGF) is neuroprotective for immature cortical neurons and that ethanol abolishes this neuroprotection in a developmental stage-dependent manner. Samples were obtained on gestational day (G) 16 or postnatal day (P) 3 and cultured with ethanol (0 or 400 mg/dl) and NGF (0 or 30 ng/ml) for 72 hours. Dying neurons were identified as exhibiting terminal nick-end labeling, immunoreactivity for activated caspase 3, or condensed nuclear chromatin. Two cortical compartments were examined in fetal tissue; a superficial, cell-sparse marginal zone (MZ) and a cell-dense cortical plate (CP). At P3, the CP was subdivided into a cell-dense upper cortical plate (UCP) and a less densely packed lower cortical plate (LCP). Neuronal death in the MZ was affected by neither NGF nor ethanol at both ages. In the fetal CP, NGF did not affect the incidence of cell death, but ethanol increased it. Treatment with NGF caused an upregulation of the expression of Neg, a gene known to be affected by NGF and ethanol. NGF did not ameliorate the ethanol-induced death. In pups, ethanol increased the amount of death in the LCP. NGF did protect against this death. Neither ethanol nor NGF altered the incidence of cell death in the UCP. The laminar-dependent neuroprotection did not correlate with expression of NGF receptors or Neg. Thus, NGF can be protective against the neurotoxic effect of ethanol in the neonatal brain. This effect is site-selective and time-dependent and it targets post-migratory, differentiating neurons.

Mooney, Sandra M.; Miller, Michael W.



Anandamide-CB1 Receptor Signaling Contributes to Postnatal Ethanol-Induced Neonatal Neurodegeneration, Adult Synaptic and Memory Deficits  

PubMed Central

The transient exposure of immature rodents to ethanol during postnatal day 7 (P7), which is comparable to the third trimester human pregnancy, induces synaptic dysfunctions. However, the molecular mechanisms underlying these dysfunctions are still poorly understood. Although the endocannabinoid system has been shown to be an important modulator of ethanol sensitivity in adult mice, its potential role in synaptic dysfunctions in mice exposed to ethanol during early brain development is not examined. In this study, we investigated the potential role of endocannabinoids and the cannabinoid receptor type 1 (CB1R) in neonatal neurodegeneration and adult synaptic dysfunctions in mice exposed to ethanol at P7. Ethanol treatment at P7, which induces neurodegeneration, increased anandamide (AEA) but not 2-arachidonylglycerol biosynthesis and CB1R protein expression in the hippocampus and cortex, two brain areas that are important for memory formation and storage, respectively. N-arachidonoyl phosphatidylethanolamine-phospholipase D (NAPE-PLD), glycerophosphodiesterase (GDE1) and CB1Rs protein expression were enhanced by transcriptional activation of the genes encoding NAPE-PLD, GDE1 and CB1R proteins respectively. In addition, ethanol inhibited ERK1/2 and AKT phosphorylation. The blockade of CB1Rs prior to ethanol treatment at P7 relieved ERK1/2 but not AKT phosphorylation and prevented neurodegeneration. CB1R knockout mice exhibited no ethanol-induced neurodegeneration and inhibition of ERK1/2-phosphorylation. The protective effects of CB1R blockade through pharmacological or genetic deletion resulted in normal adult synaptic plasticity and novel object recognition memory in mice exposed to ethanol at P7. The AEA/CB1R/pERK1/2 signaling pathway may be directly responsible for the synaptic and memory deficits associated with fetal alcohol spectrum disorders.

Subbanna, Shivakumar; Shivakumar, Madhu; Psychoyos, Delphine; Xie, Shan; Basavarajappa, Balapal S.



Antioxidant Mechanism is Involved in the Gastroprotective Effects of Ozonized Sunflower Oil in Ethanol-Induced Ulcers in Rats  

PubMed Central

This research was performed in order to determine the potential protective effects of ozonized sunflower oil (OSO) in the injury of rat gastric mucosa induced by absolute ethanol and as well as to elucidate the role of reactive oxygen species (ROS), lipid peroxidation, and some important constituents of antioxidant defense such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in these effects. OSO was administered to rats intragastrically by a cannula and it was applied during four days to animals. The doses of OSO administered daily to each group of rats were 4, 12, and 24 mg/kg, respectively, and one hour after the last treatment, absolute ethanol (1 mL/200 mg body weight) was administered. Our results showed that gastric ulcer index was significantly reduced in rats pretreated with OSO as compared with ethanol-treated controls. However, in rats pretreated with OSO, no significant reduction of TBARS content in gastric mucosa was found as compared to those rats treated with ethanol alone. In contrast, SOD and GSH-Px activities were significantly increased in gastric mucosa of OSO-pretreated rats with respect to those treated with ethanol alone. In summary, our results demonstrate that OSO pretreatment exerts protective effects in ethanol-induced gastric ulcers in rats. Furthermore, these results provide evidence that these protective effects of OSO are mediated at least partially by stimulation of some important antioxidant enzymes such as SOD and GSH-Px, which are scavengers of ROS and therefore prevent gastric injury induced by them.

Rodriguez, Zullyt B. Zamora; Alvarez, Ricardo Gonzalez; Guanche, Dailen; Merino, Nelson; Rosales, Frank Hernandez; Cepero, Silvia Menendez; Gonzalez, Yaima Alonso; Schulz, Siegfried



Hepatitis C virus infection and liver steatosis  

Microsoft Academic Search

The mechanism by which the hepatitis C virus (HCV) causes chronic, progressive liver damage is unknown. Factors other than the virus itself have been implicated. The role of liver steatosis has been recently studied. Hepatic steatosis is a common histological finding occurring in more 50% of patients with chronic hepatitis C. Both host and viral factors have been demonstrated to

Fernando Ramalho



Hepatoprotective Activity of Elephantopus scaber on Alcohol-Induced Liver Damage in Mice  

PubMed Central

Elephantopus scaber has been traditionally used as liver tonic. However, the protective effect of E. scaber on ethanol-induced liver damage is still unclear. In this study, we have compared the in vivo hepatoprotective effect of E. scaber with Phyllanthus niruri on the ethanol-induced liver damage in mice. The total phenolic and total flavanoid content of E. scaber ethanol extract were determined in this study. Accelerating serum biochemical profiles (including AST, ALT, ALP, triglyceride, and total bilirubin) associated with fat drop and necrotic body in the liver section were observed in the mice treated with ethanol. Low concentration of E. scaber was able to reduce serum biochemical profiles and the fat accumulation in the liver. Furthermore, high concentration of E. scaber and positive control P. niruri were able to revert the liver damage, which is comparable to the normal control. Added to this, E. scaber did not possess any oral acute toxicity on mice. These results suggest the potential effect of this extract as a hepatoprotective agent towards-ethanol induced liver damage without any oral acute toxicity effect. These activities might be contributed, or at least in part, by its high total phenolic and flavonoid contents.

Ho, Wan Yong; Yeap, Swee Keong; Ho, Chai Ling; Abdul Rahim, Raha; Alitheen, Noorjahan Banu



Ethanol-induced analgesia  

SciTech Connect

The effect of ethanol (ET) on nociceptive sensitivity was evaluated using a new tail deflection response (TDR) method. The IP injection of ET (0.5 - 1.5 g/kg) produced raid dose-dependent analgesia. Near maximal effect (97% decrease in TDR) was produced with the 1.5 g/kg dose of ET ten minutes after injection. At ninety minutes post-injection there was still significant analgesia. Depression of ET-induced nociceptive sensitivity was partially reversed by a 1 mg/kg dose of naloxone. On the other hand, morphine (0.5 or 5.0 mg/kg IP) did not modify ET-induced analgesia, while 3.0 minutes of cold water swim (known to produce non-opioid mediated analgesia) potentiated ET-induced analgesic effect. The 0.5 g/kg dose of ET by itself did not depress motor activity in an open field test, but prevented partially the depression in motor activity produced by cold water swim (CWS). Thus, the potentiation by ET of the depression of the TDR produced by CWS cannot be ascribed to the depressant effects of ET on motor activity. 21 references, 4 figures, 1 table.

Pohorecky, L.A.; Shah, P.



Resveratrol Restores Nrf2 Level and Prevents Ethanol-Induced Toxic Effects in the Cerebellum of a Rodent Model of Fetal Alcohol Spectrum Disorders  

PubMed Central

In humans, ethanol exposure during pregnancy produces a wide range of abnormalities in infants collectively known as fetal alcohol spectrum disorders (FASD). Neuronal malformations in FASD manifest as postnatal behavioral and functional disturbances. The cerebellum is particularly sensitive to ethanol during development. In a rodent model of FASD, high doses of ethanol (blood ethanol concentration 80 mM) induces neuronal cell death in the cerebellum. However, information on potential agent(s) that may protect the cerebellum against the toxic effects of ethanol is lacking. Growing evidence suggests that a polyphenolic compound, resveratrol, has antioxidant and neuroprotective properties. Here we studied whether resveratrol (3,5,4?-trihydroxy-trans-stilbene), a phytoalexin found in red grapes and blueberries, protects the cerebellar granule neurons against ethanol-induced cell death. In the present study, we showed that administration of resveratrol (100 mg/kg) to postnatal day 7 rat pups prevents ethanol-induced apoptosis by scavenging reactive oxygen species in the external granule layer of the cerebellum and increases the survival of cerebellar granule cells. It restores ethanol-induced changes in the level of transcription factor nuclear factor-erythroid derived 2-like 2 (nfe2l2, also known as Nrf2) in the nucleus. This in turn retains the expression and activity of its downstream gene targets such as NADPH quinine oxidoreductase 1 and superoxide dismutase in cerebellum of ethanol-exposed pups. These studies indicate that resveratrol exhibits neuroprotective effects in cerebellum by acting at redox regulating proteins in a rodent model of FASD.

Kumar, Ambrish; Singh, Chandra K.; LaVoie, Holly A.; DiPette, Donald J.



Screening, diagnosis, and monitoring of hepatic injury.  


Although prophylactic vaccines and a better screened blood supply have contributed to a decreased incidence of viral hepatitis, liver injury remains a common problem. It is important that nurse practitioners know which patients are at risk for hepatic injury, when and how to screen for hepatic injury, and how to monitor patients diagnosed with hepatic damage. The National Academy of Clinical Biochemistry guidelines related to hepatic injury provide a framework for the screening, diagnosis, and monitoring of hepatic injury resulting from a variety of causes. PMID:14606131

Goolsby, Mary Jo



[Viral hepatitis].  


Viral hepatitis is associated with significant morbidity and mortality worldwide. Hepatitis A and E viruses are enterally transmitted and lead to usually self-limited acute hepatitis. Hepatitis B, C and D viruses are transmitted by parenteral routes and can lead to chronic hepatitis with progression to liver cirrhosis and hepatocellular carcinoma. Here, we briefly review current understanding and new developments in the virology and epidemiology, diagnosis, natural history, therapy and prevention of viral hepatitis. PMID:21452137

Moradpour, Darius; Blum, Hubert E



miR-497 and miR-302b regulate ethanol-induced neuronal cell death through BCL2 protein and cyclin D2.  


In chronic alcoholism, brain shrinkage and cognitive defects because of neuronal death are well established, although the sequence of molecular events has not been fully explored yet. We explored the role of microRNAs (miRNAs) in ethanol-induced apoptosis of neuronal cells. Ethanol-sensitive miRNAs in SH-SY5Y, a human neuroblastoma cell line, were identified using real-time PCR-based TaqMan low-density arrays. Long-term exposure to ethanol (0.5% v/v for 72 h) produced a maximum increase in expression of miR-497 (474-fold) and miR-302b (322-fold). Similar to SH-SY5Y, long-term exposure to ethanol induced miR-497 and miR-302b in IMR-32, another human neuroblastoma cell line. Using in silico approaches, BCL2 and cyclin D2 (CCND2) were identified as probable target genes of these miRNAs. Cotransfection studies with 3'-UTR of these genes and miRNA mimics have demonstrated that BCL2 is a direct target of miR-497 and that CCND2 is regulated negatively by either miR-302b or miR-497. Overexpression of either miR-497 or miR-302b reduced expression of their identified target genes and increased caspase 3-mediated apoptosis of SH-SY5Y cells. However, overexpression of only miR-497 increased reactive oxygen species formation, disrupted mitochondrial membrane potential, and induced cytochrome c release (mitochondria-related events of apoptosis). Moreover, ethanol induced changes in miRNAs, and their target genes were substantially prevented by pre-exposure to GSK-3B inhibitors. In conclusion, our studies have shown that ethanol-induced neuronal apoptosis follows both the mitochondria-mediated (miR-497- and BCL2-mediated) and non-mitochondria-mediated (miR-302b- and CCND2-mediated) pathway. PMID:21878650

Yadav, Sanjay; Pandey, Ankita; Shukla, Aruna; Talwelkar, Sarang S; Kumar, Ashutosh; Pant, Aditya B; Parmar, Devendra




Technology Transfer Automated Retrieval System (TEKTRAN)

We have previously reported that chronic feeding of alcohol-containing diets (via intragastric infusion) to Sprague-Dawley rats induces hepatic alcohol dehydrogenase (ADH) Class 1 by interfering with signaling via the sterol regulatory element binding protein (SREBP-1). We have studied the effects ...


Hepatitis C virus core protein induces hepatic steatosis in transgenic mice  

Microsoft Academic Search

Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide, which finally leads to develop- ment of hepatocellular carcinoma. Chronic hepa- titis C is characterized by several histological features in the liver which discriminate it from other forms of hepatitis: bile duct damage, lymphoid follicles and steatosis (fatty change). Little is known, however, about the role of HCV

Kyoji Moriya; Hiroshi Yotsuyanagi; Yoshizumi Shintani; Hajime Fujie; Kotaro Ishibashi; Yoshiharu Matsuura; Tatsuo Miyamura; Kazuhiko Koike


Serum Iron Levels and Hepatic Iron Overload in Nonalcoholic Steatohepatitis and Chronic Viral Hepatitis  

Microsoft Academic Search

Our objective was to determine the effect of serum iron levels and hepatic iron overload on hepatocellular damage in nonalcoholic steatohepatitis (NASH) and to compare this with chronic viral hepatitis. Twenty-five patients who had elevated transaminase levels on at least two occasions, without any evidence of viral and autoimmune hepatitis and diabetes, without a history of significant alcohol use, and

Suleyman Uraz; Cem Aygun; Abdullah Sonsuz; Gulsen Ozbay



Decreased V?2 ?? T Cells Associated With Liver Damage by Regulation of Th17 Response in Patients With Chronic Hepatitis B.  


Background.??? T cells comprise a small subset of T cells and play a protective role against cancer and viral infections; however, their precise role in patients with chronic hepatitis B remains unclear. Methods.?Flow cytometry and immunofunctional assays were performed to analyze the impact of V?2 ?? (V?2) T cells in 64 immune-activated patients, 22 immune-tolerant carriers, and 30 healthy controls. Results.?The frequencies of peripheral and hepatic V?2 T cells decreased with disease progression from immune tolerant to immune activated. In the latter group of patients, the decreases in peripheral and intrahepatic frequencies of V?2 T cells reversely correlated with alanine aminotransferase levels and histological activity index. These activated terminally differentiated memory phenotypic V?2 T cells exhibited impaired abilities in proliferation and chemotaxis, while maintained a relative intact interferon (IFN) ? production. Importantly, V?2 T cells, in vitro, significantly suppressed the production of cytokines associated with interleukin 17-producing CD4(+) T (Th17) cells through both cell contact-dependent and IFN-?-dependent mechanisms. Conclusions.?Inflammatory microenvironment in IA patients result in decreased numbers of V?2 T cells, which play a novel role by regulating the pathogenic Th17 response to protect the liver in patients with chronic hepatitis B. PMID:23847059

Wu, Xiaoli; Zhang, Ji-Yuan; Huang, Ang; Li, Yuan-Yuan; Zhang, Song; Wei, Jun; Xia, Siyuan; Wan, Yajuan; Chen, Weiwei; Zhang, Zheng; Li, Yangguang; Wen, Ti; Chen, Yan; Tanaka, Yoshimasa; Cao, Youjia; Wang, Puyue; Zhao, Liqing; Wu, Zhenzhou; Wang, Fu-Sheng; Yin, Zhinan



Contrasting dose-effects of multi-glycoside of Tripterygium wilfordii HOOK. f. on glomerular inflammation and hepatic damage in two types of anti-Thy1.1 glomerulonephritis.  


Multi-glycoside, one of the extracted compounds from Tripterygium wilfordii HOOK. f. (GTW), has been shown to be clinically effective in suppressing glomerular inflammation in chronic kidney disease. However, its clinical application is often limited by its cytotoxic actions on the liver. This study was performed to contrast the dose-effects of GTW on glomerular inflammation and hepatic damage in two types of anti-Thy1.1 glomerulonephritis (GN). Rats with acute or chronic anti-Thy1.1 GN were either left untreated (the Vehicle group) or treated with a high or low dose of GTW and sacrificed on day 7 or day 45. GTW was administrated 3 days before or at the same time as the antibody injection and lasted until sacrifice. GTW at high dose ameliorated glomerular macrophage accumulation, mesangial proliferation, proteinuria, and interleukin-2 expression in the acute anti-Thy1.1 GN model, but caused structural and functional lesions in the liver. In contrast, GTW at low dose improved activated macrophage and T lymphocyte infiltration, mesangial injury, proteinuria, and interleukin-2 and interferon-? expressions without hepatic toxicity in the chronic model of GN induced by anti-Thy1.1 antibody. In conclusion, GTW at low dose not only effectively inhibits glomerular inflammation but also avoids severe injuries to the liver. PMID:22447300

Wan, Yi-Gang; Zhao, Qing; Sun, Wei; Zhang, Hui-Lan; Li, Min; Wei, Qing-Xue; Wu, Wei; Yue, Li-Jun; Wang, Qing




PubMed Central

Sex- and age-typical responses to ethanol and novel stimuli tend to emerge postpubertally, suggesting a potential organizational or activational role for pubertal hormones in these behaviors. To test this possibility, male and female rats were gonadectomized (GX) or received sham gonadectomy (SH) either prepubertally on postnatal day (P) 23 (early) or in adulthood on P70 (late). Animals were tested as adults for response to novelty and, on the following day, challenged with either saline or ethanol (1g/kg) prior to social interaction testing with an unfamiliar partner in a familiar setting under low light conditions. Gonadectomy did not influence ethanol-induced social inhibition in either sex, but instead altered the microstructure of social behavior, with GX animals exhibiting proportionally less time in social investigation and proportionally more time in contact behavior than SH animals, regardless of age of gonadectomy. The early sham surgical manipulation process itself influenced social motivation, with early SH surgery eliminating ethanol-induced decreases in social preference in both sexes. Response to novelty was unaffected by gonadectomy, but was suppressed in early compared to late SH manipulated animals. These results suggest that adult-typical responses to ethanol and novelty-directed behaviors are little influenced by gonadal hormones during puberty or in adulthood. However, the experience of surgical manipulation itself during development exerts behavioral and pharmacological consequences that last into adulthood.

Vetter-O'Hagen, Courtney S.; Spear, Linda P.



Sex differences in the effects of ethanol pre-exposure during adolescence on ethanol-induced conditioned taste aversion in adult rats  

PubMed Central

Alcohol use, which typically begins during adolescence and differs between males and females, is influenced by both the rewarding and aversive properties of the drug. One way adolescent alcohol use may modulate later consumption is by reducing alcohol s aversive properties. Here, we used a conditioned taste aversion (CTA) paradigm to determine if pre-exposure to alcohol (ethanol) during adolescence would attenuate ethanol-induced CTA assessed in adulthood in a sex-dependent manner. Male and female Long-Evans rats were given intraperitoneal (i.p.) injections of saline or 3.0 g/kg ethanol in a binge-like pattern during postnatal days (PD) 35–45. In adulthood (> PD 100), rats were given access to 0.1% saccharin, followed by saline or ethanol (1.0 or 1.5 g/kg, i.p.), over four conditioning sessions. We found sex differences in ethanol-induced CTA, with males developing a more robust aversion earlier in conditioning. Sex differences in the effects of pre-exposure were also evident: males, but not females, showed an attenuated CTA in adulthood following ethanol pre-exposure, which occurred approximately nine weeks earlier. Taken together, these findings indicate that males are more sensitive to the aversive properties of ethanol than females. In addition, the ability of pre-exposure to the ethanol US to attenuate CTA is enhanced in males compared to females.

Sherrill, Luke K.; Berthold, Claire; Koss, Wendy A.; Juraska, Janice M.; Gulley, Joshua M.



Occult hepatitis B virus infection.  


Many studies have shown that hepatitis B virus infection may also occur in hepatitis B surface antigen-negative patients. This occult infection has been identified both in patients with cryptogenic liver disease and in patients with hepatitis C virus-related chronic hepatitis, and much evidence suggests that it may be a risk factor of hepatocellular carcinoma development. However several aspects of this occult infection remain unclear such as its prevalence and the factor(s) involved in the lack of circulating hepatitis B surface antigen. Moreover, it is uncertain whether the occult hepatitis B virus infection may contribute to chronic liver damage, considering that it is usually associated with a suppressed viral replication. Evidence and hypotheses concerning this fascinating field of bio-medical research are reviewed. PMID:11215565

Raimondo, G; Balsano, C; Craxì, A; Farinati, F; Levrero, M; Mondelli, M; Pollicino, T; Squadrito, G; Tiribelli, C



Liver ultrastructural morphology and mitochondrial DNA levels in HIV/hepatitis C virus coinfection: no evidence of mitochondrial damage with highly active antiretroviral therapy.  


Liver mitochondrial toxicity is a concern, particularly in HIV/hepatitis C virus (HCV) coinfection. Liver biopsies from HIV/HCV co-infected patients, 14 ON-highly active antiretroviral therapy (HAART) and nine OFF-HAART, were assessed by electron microscopy quantitative morphometric analyses. Hepatocytes tended to be larger ON-HAART than OFF-HAART (P = 0.05), but mitochondrial volume, cristae density, lipid volume, mitochondrial DNA and RNA levels were similar. We found no evidence of increased mitochondrial toxicity in individuals currently on HAART, suggesting that concomitant HAART should not delay HCV therapy. PMID:18525271

Matsukura, Motoi; Chu, Fanny F S; Au, May; Lu, Helen; Chen, Jennifer; Rietkerk, Sonja; Barrios, Rolando; Farley, John D; Montaner, Julio S; Montessori, Valentina C; Walker, David C; Côté, Hélène C F



Treatment with oligonol, a low-molecular polyphenol derived from lychee fruit, attenuates diabetes-induced hepatic damage through regulation of oxidative stress and lipid metabolism.  


We have identified the effects of oligonol, a low-molecular polyphenol derived from lychee fruit, on oxidative stress and lipid metabolism in a type 2 diabetic model. Oligonol was orally administered at 10 or 20 mg per kg body weight per d for 8 weeks to db/db mice, and its effects were compared with those of the vehicle in db/db and m/m mice. Serum and hepatic biochemical factors, and protein and mRNA expression related to lipid metabolism were measured. In the oligonol-administered group, there were significant reductions of reactive oxygen species (ROS), lipid peroxidation, and the TAG and total cholesterol concentrations in both the serum and liver. Additionally, oligonol attenuated oxidative stress through the inhibition of advanced glycation endproduct formation and its receptor expression. Furthermore, augmented expressions of NF-?Bp65 and inducible NO synthase were down-regulated to the levels of m/m mice in the group treated with oligonol at 20 mg/kg. Regarding lipid metabolism, lower hepatic lipid resulted from the down-regulation of sterol regulatory element-binding protein-1 and its target gene of lipogenic enzymes in the liver of db/db mice. The present results suggest that oligonol has protective effects against ROS-related inflammation and excess lipid deposition in the type 2 diabetic liver. PMID:21477406

Noh, Jeong Sook; Park, Chan Hum; Yokozawa, Takako




PubMed Central

Background Adolescent rats have been observed to be less sensitive than adults to a number of acute ethanol effects, including ethanol-induced motor impairment. These adolescent insensitivities may be related in part to the more rapid emergence of within session (acute) tolerance in adolescents than adults. Adolescent-related alterations in neural systems that serve as ethanol target sites, including changes in NMDA receptor subunit expression, may influence the responsiveness of adolescents to acute ethanol effects. The present study explored the role of NMDA NR2B receptors in the development of acute tolerance to ethanol-induced motor impairment in male adolescent (postnatal day [P]28–30), and adult (P68-70) Sprague-Dawley rats. Methods Motor impairing effects of ethanol on the stationary inclined plane and blood ethanol concentrations (BECs) were examined following challenge at each age with a functionally equivalent ethanol dose (adolescents: 2.25 g/kg; adults: 1.5 g/kg). Data were collected at two post-injection intervals (10 or 60 min) to compare rate of recovery from ethanol intoxication with BEC declines using the Radlow approach (Radlow, 1994) and changes in motor impairment/BEC ratios over time for assessing acute tolerance. Results Both vehicle-treated adolescent and adult animals showed similar acute tolerance development to the motor-impairing effects of ethanol at these functionally equivalent doses on the stationary inclined plane, as indexed by an increasing time-dependent dissociation between BECs and ethanol-induced motor impairment, with motor impairment declining faster than BECs, as well as by significant declines in motor impairment/BEC ratios over time. Acute tolerance development was reliably blocked by administration of the NR2B antagonist, ifenprodil, (5.0 mg/kg), in adult rats, whereas adolescents were affected by a higher dose (10.0 mg/kg). Conclusions These data support the suggestion that alterations in NMDA receptor systems occurring during adolescence may contribute to reduced sensitivity to ethanol by enhancing the expression of acute tolerance development in adolescents relative to adults.

Ramirez, R. Liane; Varlinskaya, Elena I.; Spear, Linda P.




Technology Transfer Automated Retrieval System (TEKTRAN)

It has been suggested that alcohol-induced liver damage is dependent on development of oxidative stress resulting from ethanol metabolism by CYP2E1 to the hydroxyethyl radical (HER). In the current study we examined the effects of treatment with the dietary antioxidants N-acetyl cysteine (NAC) and ...


Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver.  


Alcohol-induced fatty liver, a major cause of morbidity, has been attributed to enhanced hepatic lipogenesis and decreased fat clearance of unknown mechanism. Here we report that the steatosis induced in mice by a low-fat, liquid ethanol diet is attenuated by concurrent blockade of cannabinoid CB1 receptors. Global or hepatocyte-specific CB1 knockout mice are resistant to ethanol-induced steatosis and increases in lipogenic gene expression and have increased carnitine palmitoyltransferase 1 activity, which, unlike in controls, is not reduced by ethanol treatment. Ethanol feeding increases the hepatic expression of CB1 receptors and upregulates the endocannabinoid 2-arachidonoylglycerol (2-AG) and its biosynthetic enzyme diacylglycerol lipase beta selectively in hepatic stellate cells. In control but not CB1 receptor-deficient hepatocytes, coculture with stellate cells from ethanol-fed mice results in upregulation of CB1 receptors and lipogenic gene expression. We conclude that paracrine activation of hepatic CB1 receptors by stellate cell-derived 2-AG mediates ethanol-induced steatosis through increasing lipogenesis and decreasing fatty acid oxidation. PMID:18316028

Jeong, Won-il; Osei-Hyiaman, Douglas; Park, Ogyi; Liu, Jie; Bátkai, Sándor; Mukhopadhyay, Partha; Horiguchi, Norio; Harvey-White, Judith; Marsicano, Giovanni; Lutz, Beat; Gao, Bin; Kunos, George



Hepatitis A  


... has hepatitis A Receive clotting-factor concentrates for hemophilia or another medical condition Complications Continuing signs and ... and symptoms as part of making a diagnosis. Treatments and drugs No specific treatment exists for hepatitis ...


Toxic Hepatitis  


... may be reprinted for personal, noncommercial use only. Toxic hepatitis By Mayo Clinic staff Original Article: Definition Symptoms Causes Risk factors Complications ...


Serum Apoptosis Markers Related to Liver Damage in Chronic Hepatitis C: sFas as a Marker of Advanced Fibrosis in Children and Adults While M30 of Severe Steatosis Only in Children  

PubMed Central

Background Liver biopsy represents the gold standard for evaluating damage and progression in patients with chronic hepatitis C (CHC); however, developing noninvasive tests that can predict liver injury represents a growing medical need. Considering that hepatocyte apoptosis plays a role in CHC pathogenesis; the aim of our study was to evaluate the presence of different apoptosis markers that correlate with liver injury in a cohort of pediatric and adult patients with CHC. Methods Liver biopsies and concomitant serum samples from 22 pediatric and 22 adult patients with CHC were analyzed. Histological parameters were evaluated. In serum samples soluble Fas (sFas), caspase activity and caspase-generated neoepitope of the CK-18 proteolytic fragment (M30) were measured. Results sFas was associated with fibrosis severity in pediatric (significant fibrosis p?=?0.03, advanced fibrosis p?=?0.01) and adult patients (advanced fibrosis p?=?0.02). M30 levels were elevated in pediatric patients with severe steatosis (p?=?0.01) while in adults no relation with any histological variable was observed. Caspase activity levels were higher in pediatric samples with significant fibrosis (p?=?0.03) and they were associated with hepatitis severity (p?=?0.04) in adult patients. The diagnostic accuracy evaluation demonstrated only a good performance for sFas to evaluate advanced fibrosis both in children (AUROC: 0.812) and adults (AUROC: 0.800) as well as for M30 to determine steatosis severity in children (AUROC: 0.833). Conclusions Serum sFas could be considered a possible marker of advanced fibrosis both in pediatric and adult patient with CHC as well as M30 might be a good predictor of steatosis severity in children.

Valva, Pamela; Casciato, Paola; Lezama, Carol; Galoppo, Marcela; Gadano, Adrian; Galdame, Omar; Galoppo, Maria Cristina; Mullen, Eduardo; De Matteo, Elena; Preciado, Maria Victoria



Hepatic mRNA, microRNA, and miR-34a-Target responses in mice after 28 days exposure to doses of benzo(a)pyrene that elicit DNA damage and mutation  

PubMed Central

Benzo(a)pyrene (BaP) is a mutagenic carcinogen that is ubiquitous in our environment. To better understand the toxic effects of BaP and to explore the relationship between toxicity and toxicogenomics profiles, we assessed global mRNA and microRNA (miRNA) expression in Muta™Mouse. Adult male mice were exposed by oral gavage to 25, 50, and 75 mg/kg/day BaP for 28 days. Liver tissue was collected 3 days following the last treatment. Initially, we established that exposure to BaP led to the formation of hepatic DNA adducts and mutations in the lacZ transgene of the Muta™Mouse. We then analyzed hepatic gene expression profiles. Microarray analysis of liver samples revealed 134 differentially expressed transcripts (adjusted P < 0.05; fold changes > 1.5). The mRNAs most affected were involved in xenobiotic metabolism, immune response, and the downstream targets of p53. In this study, we found a significant 2.0 and 3.6-fold increase following exposure to 50 and 75 mg/kg/day BaP, respectively, relative to controls for miR-34a. This miRNA is involved in p53 response. No other significant changes in miRNAs were observed. The protein levels of five experimentally confirmed miR-34a targets were examined, and no major down-regulation was present. The results suggest that liver miRNAs are largely unresponsive to BaP doses that cause both DNA adducts and mutations. In summary, the validated miRNA and mRNA expression profiles following 28 day BaP exposure reflect a DNA damage response and effects on the cell cycle, consistent with the observed increases in DNA adducts and mutations. Environ. Mol. Mutagen., 2012. © 2011 Crown in the right of Canada

Malik, Amal I; Williams, Andrew; Lemieux, Christine L; White, Paul A; Yauk, Carole L



Viral Hepatitis  

Microsoft Academic Search

Various forms of viral hepatitis have been identified as being sexually transmitted infections (STIs), whereas other forms\\u000a are transmitted primarily via oralfecal routes. The most common forms of viral hepatitis are hepatitis A, B, and C. Hepatitis\\u000a A virus (HAV) infection is most often a benign self-limiting disease; however, it can progress to fulminant liver failure.\\u000a Fecal-oral transmission though contact

Michelle L. Geller; Jeremy R. Herman


Hepatitis A  


... of hepatitis - a liver disease - caused by the hepatitis A virus (HAV). The disease is spread primarily through food or water contaminated by stool from an infected person. You can get HAV ... several weeks. The hepatitis A vaccine can prevent HAV. Healthy habits also ...


Hepatoprotective Effect of Platycodon grandiflorum against Chronic Ethanol-Induced Oxidative Stress in C57BL\\/6 Mice  

Microsoft Academic Search

Aims: This study was carried out to evaluate the hepatoprotective effect of Platycodon grandiflorum (PG) in ethanol (EtOH)-induced liver damage. Methods and Results: PG treatment (both the total extract and saponin fraction) significantly blocked EtOH-induced oxidative stress through the preservation of activities of antioxidant enzymes in HepG2 cells. Furthermore, while the administration of EtOH to C57BL\\/6 mice for 6 weeks

Jung-Ran Noh; Yong-Hoon Kim; Gil-Tae Gang; Jung-Hwan Hwang; Sang-Kyum Kim; Shi-Yong Ryu; Young-Sup Kim; Hyun-Sun Lee; Chul-Ho Lee



Scrub typhus hepatitis confirmed by immunohistochemical staining  

PubMed Central

Scrub typhus is an acute febrile disease caused by Orientia tsutsugamushi (O. tsutsugamushi). We report herein the case of a woman who presented with fever and elevated serum levels of liver enzymes and who was definitively diagnosed with scrub typhus by histopathological examination of liver biopsy specimens, serological tests and nested polymerase chain reaction. Immunohistochemical staining using a monoclonal anti-O. tsutsugamushi antibody showed focally scattered positive immunoreactions in the cytoplasm of some hepatocytes. This case suggests that scrub typhus hepatitis causes mild focal inflammation due to direct liver damage without causing piecemeal necrosis or interface hepatitis. Thus, scrub typhus hepatitis differs from acute viral hepatitis secondary to liver damage due to host immune responses, which causes severe lobular disarray with diffuse hepatocytic degeneration, necrosis and apoptosis as well as findings indicative of hepatic cholestasis, such as hepatic bile plugs or brown pigmentation of hepatocytes.

Chung, Jong-Hoon; Lim, Sung-Chul; Yun, Na-Ra; Shin, Sung-Heui; Kim, Choon-Mee; Kim, Dong-Min



Hepatic vein obstruction (Budd-Chiari)  


Hepatic vein obstruction prevents blood from flowing out of the liver and back to the heart. This blockage can cause liver damage. Obstruction of this vein can be caused by a tumor or growth pressing on the vessel, or ...


Autoimmune hepatitis, HLA and extended haplotypes  

Microsoft Academic Search

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease. Characteristic liver-infiltrating immune cells in portal and periportal areas, hypergammaglobulinemia and typical autoantibodies indicate an ongoing autoimmune reaction against liver self antigens, which lead to irreversible cellular damage and ultimately to severe hepatic failure. A significant part of adult, but not pediatric AIH patients, exhibit concurrent autoimmune diseases, further strengthening the

Lea Campos Oliveira; Gilda Porta; Maria Lucia C. Marin; Paulo Lisboa Bittencourt; Jorge Kalil; Anna Carla Goldberg



Hepato-protective potential of carotenoid meso-zeaxanthin against paracetamol, CCl4 and ethanol induced toxicity.  


Hepato-protective potential of carotenoid meso-zeaxanthin [(3R, 3'S)-beta, beta-carotene-3, 3'-diol] was studied using in vivo rat models. Paracetamol (3 g/kg body wt, orally), 20% ethanol (7.5 g/kg body wt, orally) and CCl4 (2.5 ml /kg, ip) were used as hepato toxins. Levels of marker enzymes of hepatic injury such as serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase and alkaline phosphatase, and serum bilirubin, which were drastically elevated by these hepato toxins were significantly decreased by meso-zeaxanthin pretreatment in a dose-dependent manner. Oxidative stress markers, tissue lipid peroxidation, conjugated dienes and tissue hydroperoxides, were high in the paracetamol treated control group animals, which were lowered by meso-zeaxanthin administration. Level of glutathione and antioxidant enzymes, superoxide dismutase, catalase and glutathione peroxidase, in liver tissue was increased by meso-zeaxanthin pretreatment compared to control group during alcohol and CCl4 induced hepatotoxicity. Hydroxyproline, an indicator of fibrosis in liver tissue, decreased remarkably by meso-zeaxanthin administration despite its notable elevation in ethanol treated rats. Histopathological analysis of liver tissue showed the hepatoprotective potential of meso-zeaxanthin. PMID:21365995

Firdous, Alikunjhi P; Sindhu, Edakkadath R; Kuttan, Ramadasan



Coenzyme Q10 rescues ethanol-induced corneal fibroblast apoptosis through the inhibition of caspase-2 activation.  


Recent studies indicate that caspase-2 is involved in the early stages of apoptosis, particularly before the occurrence of mitochondrial damage. Here we report the important role of the coenzyme Q10 (CoQ10) on the activity of caspase-2 upstream of mitochondria in ethanol (EtOH)-treated corneal fibroblasts. After EtOH exposure, cells produce excessive reactive oxygen species formation, p53 expression, and most importantly, caspase-2 activation. After the activation of the caspase-2, the cells exhibited hallmarks of apoptotic pathway, such as mitochondrial damage and translocation of Bax and cytochrome c, which were then followed by caspase-3 activation. By pretreating the cells with a cell-permeable, biotinylated pan-caspase inhibitor, we identified caspase-2 as an initiator caspase in EtOH-treated corneal fibroblasts. Loss of caspase-2 inhibited EtOH-induced apoptosis. We further found that caspase-2 acts upstream of mitochondria to mediate EtOH-induced apoptosis. The loss of caspase-2 significantly inhibited EtOH-induced mitochondrial dysfunction, Bax translocation, and cytochrome c release from mitochondria. The pretreatment of CoQ10 prevented EtOH-induced caspase-2 activation and mitochondria-mediated apoptosis. Our data demonstrated that by blocking caspase-2 activity, CoQ10 can protect the cells from mitochondrial membrane change, apoptotic protein translocation, and apoptosis. Taken together, EtOH-induced mitochondria-mediated apoptosis is initiated by caspase-2 activation, which is regulated by CoQ10. PMID:23430247

Chen, Chun-Chen; Liou, Shiow-Wen; Chen, Chi-Chih; Chen, Wen-Chung; Hu, Fung-Rong; Wang, I-Jong; Lin, Shing-Jong



Viral hepatitis*  

PubMed Central

Three forms of viral hepatitis can be recognized: hepatitis A, hepatitis B, and hepatitis non-A, non-B. Hepatitis A is caused by a picornavirus, is transmitted by the faceal—oral route, does not become chronic, and no chronic virus carriers exist. The virus can be grown in cell cultures, and killed as well as live attenuated virus vaccines are under development. Hepatitis B is caused by an enveloped virus containing a circular, double-stranded form of DNA. The disease is transmitted parenterally through inoculation of blood or blood products containing virus or through close personal contact with a virus-positive person. Hepatitis B becomes chronic in a certain number of cases and can lead to cirrhosis and primary liver cell carcinoma. The blood and certain body secretions of individuals with a persistent or chronic infection may remain infectious for many years. The hepatitis B virus cannot be grown in cell cultures but the entire genome has been sequenced and cloned in bacterial and eukaryotic cells. An inactivated virus vaccine has been prepared from hepatitis B surface antigen present in the plasma of hepatitis B virus carriers and further vaccines are under development. The agents of hepatitis non-A, non-B have not been identified. It is possible to distinguish between a predominantly parenterally transmitted and an orally transmitted form of hepatitis non-A, non-B. The latter is reported to be caused by a picornavirus that does not, however, have any antigenic relationship with hepatitis A virus.

Deinhardt, F.; Gust, I. D.



Collateral Damage.  

National Technical Information Service (NTIS)

Collateral damage is undesirable civilian materiel damage or personnel injuries produced by the effects of friendly nuclear weapons. For a nation on whose soil a nuclear weapon is detonated, any damage, other than damage to enemy military resources, may w...

F. W. Thornhill



Ethanol-induced impairments in receptor-mediated endocytosis of asialoorosomucoid in isolated rat hepatocytes: Time course of impairments and recovery after ethanol withdrawal  

SciTech Connect

Chronic ethanol administration markedly impairs the process of receptor-mediated endocytosis (RME) of a representative asialoglycoprotein, asialoorosomucoid (ASOR), by the liver. In this study, we further characterized these impairments by identifying the time of onset for ethanol-induced changes in RME as well as establishing the time course for recovery to normal endocytotic values after ethanol withdrawal. Ethanol administration for 3 days did not alter any aspect of endocytosis examined in this study. After feeding ethanol to rats for 7 days, however, significant decreases in amounts of ligand bound, internalized, and degraded were apparent. These impairments persisted throughout the 5-week feeding study although the effects were somewhat attenuated with more prolonged ethanol feeding. In addition, an accumulation of intracellular receptors was observed in ethanol-fed animals relative to controls after 7 days of ethanol feeding. In all cases, recovery of endocytotic values to control levels was partially completed after 2 to 3 days of refeeding control diet and was fully completed after 7 days of refeeding. These results indicate that ethanol feeding for as little as 7 days profoundly impairs the process of RME by the liver. These impairments can be reversed after refeeding control diet for 7 days.

Casey, C.A.; Kragskow, S.L.; Sorrell, M.F.; Tuma, D.J.



Gastroprotection of suaveolol, isolated from Hyptis suaveolens, against ethanol-induced gastric lesions in Wistar rats: role of prostaglandins, nitric oxide and sulfhydryls.  


Hyptis suaveolens is a medicinal plant that is, according to traditional medicine, considered useful in the treatment of gastric ulcers. Although its gastroprotective activity was reported, the active compounds have not been identified. Therefore, the aim of the present study was to identify at least one active compound potentially responsible for the gastroprotective activity of H. suaveolens by using a bioassay guided study with an ethanol-induced gastric ulcer experimental model in rats. The results show that the hexane extract had protective activity (close to 70% when using doses between 10 and 100 mg/kg), and that the compound suaveolol, isolated from this extract, was one of the active gastroprotective agents. This is the first report about the gastroprotective activity of suaveolol. Rats treated with this compound at 3, 10, 30 and 100 mg/kg showed 12.6, 21.3, 39.6 and 70.2% gastroprotection respectively. The effect elicited by suaveolol (at 100 mg/kg) was attenuated by pretreatment with either N(G)-nitro-L-arginine methyl ester (70 mg/kg, i.p.), a nitric oxide (NO) synthase inhibitor, indomethacin (10 mg/kg, s.c.), a blocker of prostaglandin synthesis, or N-ethylmaleimide (10 mg/kg, s.c.), a blocker of sulfhydryl groups. This suggests that the gastroprotective mechanism of action of this compound involves NO, prostaglandins and sulfhydryl groups. PMID:22836211

Vera-Arzave, Carlos; Antonio, Leticia Cruz; Arrieta, Jesús; Cruz-Hernández, Gerardo; Velasquez-Mendez, Antonio Magdiel; Reyes-Ramírez, Adelfo; Sánchez-Mendoza, María Elena



Mechanisms of Gastroprotective Effects of Ethanolic Leaf Extract of Jasminum sambac against HCl/Ethanol-Induced Gastric Mucosal Injury in Rats  

PubMed Central

Jasminum sambac is used in folk medicine as the treatment of many diseases. The aim of the present investigation is to evaluate the gastroprotective effects of ethanolic extracts of J. sambac leaves against acidified ethanol-induced gastric ulcers in rats. Seven groups of rats were orally pre-treated with carboxymethylcellulose (CMC) as normal group, CMC as ulcer group, 20?mg/kg of omeprazole as positive group, 62.5, 125, 250, and 500?mg/kg of extract as the experimental groups, respectively. An hour later, CMC was given orally to normal group and acidified ethanol solution was given orally to the ulcer control, positive control, and the experimental groups. The rats were sacrificed after an hour later. Acidity of gastric content, the gastric wall mucus, ulcer areas, and histology and immunohistochemistry of the gastric wall were assessed. Gastric homogenates were determined for prostaglandin E2 (PGE2), superoxide dismutase (SOD), andmalondialdehyde (MDA) content. Ulcer group exhibited significantly severe mucosal injury as compared with omeprazole or extract which shows significant protection towards gastric mucosal injury the plant promotes ulcer protection as it shows significant reduction of ulcer area grossly, and histology showed marked reduction of edema and leucocytes infiltration of submucosal layer compared with ulcer group. Immunohistochemistry showed overexpression of Hsp70 protein and downexpression of Bax protein in rats pretreated with extract. Significant increased in the pH, mucus of gastric content and high levels of PGE2, SOD and reduced amount of MDA was observed.

AlRashdi, Ahmed S.; Salama, Suzy M.; Alkiyumi, Salim S.; Abdulla, Mahmood A.; Hadi, A. Hamid A.; Abdelwahab, Siddig I.; Taha, Manal M.; Hussiani, Jamal; Asykin, Nur



Mechanisms of Gastroprotective Effects of Ethanolic Leaf Extract of Jasminum sambac against HCl/Ethanol-Induced Gastric Mucosal Injury in Rats.  


Jasminum sambac is used in folk medicine as the treatment of many diseases. The aim of the present investigation is to evaluate the gastroprotective effects of ethanolic extracts of J. sambac leaves against acidified ethanol-induced gastric ulcers in rats. Seven groups of rats were orally pre-treated with carboxymethylcellulose (CMC) as normal group, CMC as ulcer group, 20?mg/kg of omeprazole as positive group, 62.5, 125, 250, and 500?mg/kg of extract as the experimental groups, respectively. An hour later, CMC was given orally to normal group and acidified ethanol solution was given orally to the ulcer control, positive control, and the experimental groups. The rats were sacrificed after an hour later. Acidity of gastric content, the gastric wall mucus, ulcer areas, and histology and immunohistochemistry of the gastric wall were assessed. Gastric homogenates were determined for prostaglandin E(2) (PGE(2)), superoxide dismutase (SOD), andmalondialdehyde (MDA) content. Ulcer group exhibited significantly severe mucosal injury as compared with omeprazole or extract which shows significant protection towards gastric mucosal injury the plant promotes ulcer protection as it shows significant reduction of ulcer area grossly, and histology showed marked reduction of edema and leucocytes infiltration of submucosal layer compared with ulcer group. Immunohistochemistry showed overexpression of Hsp70 protein and downexpression of Bax protein in rats pretreated with extract. Significant increased in the pH, mucus of gastric content and high levels of PGE(2), SOD and reduced amount of MDA was observed. PMID:22550543

Alrashdi, Ahmed S; Salama, Suzy M; Alkiyumi, Salim S; Abdulla, Mahmood A; Hadi, A Hamid A; Abdelwahab, Siddig I; Taha, Manal M; Hussiani, Jamal; Asykin, Nur



Tonic modulatory role of mouse cerebellar ?- and ?-adrenergic receptors in the expression of ethanol-induced ataxia: role of AC-cAMP.  


To further study neurochemical basis of ethanol-induced ataxia (EIA), we investigated role of cerebellar ? and ?-adrenergic receptors. Male CD-1 mice received intracerebellar microinfusion of adrenergic drugs to evaluate their effect on EIA (2g/kg; ip) by Rotorod. Isoproterenol, phenylephrine (4, 8, 16 ng each), methoxamine (8 ng), and atenolol (2, 4, 8 ng), propranolol (4, 8, 16 ng), markedly attenuated and accentuated, respectively, EIA indicating the tonic nature of modulation. The attenuation of EIA by isoproterenol is ?(1)-receptor mediated because it is blocked by atenolol. Tonic ?(1) modulation is functionally correlated with EIA potentiation by atenolol and propranolol. The prazosin-induced attenuation of EIA, initially thought of ?(1)-receptor mediated, appeared instead ?(1)-receptor modulated because of: (i) blockade by atenolol; and (ii) phosphodiesterase inhibition by prazosin. The phenylephrine/methoxamine-induced attenuation of EIA seems paradoxical as the response is similar to antagonist prazosin. However, functionally the attenuation seems ?(1) receptor-mediated since atenolol blocked it but prazosin did not. Also norepinephrine (NE) attenuated EIA that was inhibited by atenolol suggesting role of ?(1) receptors. Similarly yohimbine and rauwolscine attenuated EIA that indicates ?(2)-receptor modulation associated with stimulation of AC-cAMP pathway. The results of study support the hypothesis that attenuation and potentiation of EIA is mediated by activation and inhibition of AC-cAMP pathway, respectively, in agreement with our previous reports, via direct and/or indirect activation of ?-receptor. PMID:23246526

Dar, M Saeed; Al-Rejaie, Salim



Glutathione Content as a Potential Mediator of the Vulnerability of Cultured Fetal Cortical Neurons to Ethanol-Induced Apoptosis  

PubMed Central

Ethanol ingestion during pregnancy elicits damage to the developing brain, some of which appears to result from enhanced apoptotic death of neurons. A consistent characteristic of this phenomenon is a highly differing sensitivity to ethanol within specific neuron populations. One possible explanation for this “selective vulnerability” could be cellular variations in glutathione (GSH) homeostasis. Prior studies have illustrated that ethanol elicits apoptotic death of neurons in the developing brain, that oxidative stress may be an underlying mechanism, and that GSH can be neuroprotective. In the present study, both multiphoton microscopy and flow cytometry demonstrate a striking heterogeneity in GSH content within cortical neuron populations. Ethanol differentially elicits apoptotic death and oxidative stress in these neurons. When neuron GSH content is reduced by treatment with butathione sulfoxamine, the ethanol-mediated enhancement of reactive oxygen species is exacerbated. Sorting of cells into high- and low-GSH populations further exemplifies ethanol-mediated oxidative stress whereby apoptotic indices are preferentially elevated in the low-GSH population. Western blot analysis of the low-GSH subpopulations shows higher ethanol-mediated expression of active caspase 3 and 24-kDa PARP-1 fragments compared with the high-GSH subpopulation. In addition, neuronal content of 4-hydroxynonenal adducts is higher in low-GSH neurons in response to ethanol. These studies suggest that GSH content is an important predictor of neuronal sensitivity to ethanol-mediated oxidative stress and subsequent cell death. The data support the proposition that the differences in proapoptotic responses to ethanol within specific neuron populations reflect a heterogeneity of neuron GSH content.

Maffi, Shivani Kaushal; Rathinam, Mary Latha; Cherian, Priscilla P.; Pate, William; Hamby-Mason, Rhoda; Schenker, Steven; Henderson, George I.



Hepatitis E  

Microsoft Academic Search

Hepatitis E has a world-wide distribution and causes substantial morbidity and mortality in some developing countries, particularly among pregnant women. Hepatitis E virus (HEV) has recently been cloned and sequenced, and new diagnostic tests have been developed. These tests have been used to begin to characterize the natural history and epidemiological features of HEV infection. Experimental vaccines have also been

Eric E. Mast; Michael A. Purdy; Krzysztof Krawczynski



Hepatitis Information for the Public  


... hepatitis. Hepatitis A Hepatitis A is an acute liver disease caused by the Hepatitis A virus (HAV), lasting ... More Information Hepatitis B Hepatitis B is a liver disease caused by the Hepatitis B virus (HBV). It ...


[Forgotten hepatitis: the hepatitis E].  


Hepatitis E is caused by the Hepatitis E Virus (HEV), entericaly transmitted. In areas with poor sanitation, HEV is responsible for high endemicity and major outbreaks. In countries with high sanitary conditions, HEV is a zoonosis responsible for sporadic cases, and is encountered in travellers returning from endemic areas. The clinical manifestations are not distinguishable from that caused by other causes of acute viral hepatitis. Fulminant hepatitis are encountered in 1 to 4% of acute hepatitis E. Remarquably, mortality among pregnant women is very high. Diagnosis can be made by serological testing and eventually viral detection by PCR. HEV can cause chronic infection in immunocompromised patients. There is no specific therapy. There is no vaccine currently available. PMID:22662626

Bru, J-P



Biochemical laboratory tests in viral hepatitis and other hepatic diseases  

PubMed Central

The differential diagnosis between viral hepatitis and other liver diseases (particularly obstructive jaundice) is often difficult on purely clinical grounds. Damage to the liver causes changes in the pattern of the serum enzymes and this has led to the development in recent years of a number of enzyme tests. The authors have amassed evidence to show that the most useful of these is determination of the levels of serum glutamic oxalacetic and serum glutamic pyruvic transaminase (SGOT and SGPT), coupled with calculation of the SGOT/SGPT ratio. It is characteristic of viral hepatitis that both levels are greatly increased, but the SGOT/SGPT ratio, normally greater than one, falls considerably below his figure. In a few cases of obstructive jaundice, the serum transaminase picture may initially resemble that in viral hepatitis, but the differential diagnosis can be established by repeating the determinations at intervals. Other enzyme tests, such as determination of alkaline phosphatase and leucylaminopeptidase, may be used to confirm the biliary obstruction. Flocculation tests and electrophoretic determination of the plasma protein picture, while of limited value in the diagnosis of acute viral hepatitis, are useful in conjunction with the serum transaminase test for assessing the activity of the disease and any tendency to progress towards “active” chronic hepatitis or post-hepatic cirrhosis.

De Ritis, Fernando; Giusti, Giuseppe; Piccinino, Felice; Cacciatore, Luigi



Hepatitis A  


... You can also get infected by eating contaminated food or drinking contaminated water. The virus can live on hands, in water and in soil. Hepatitis A is common in developing countries. Diagnosis & ...


Hepatitis B  

MedlinePLUS Videos and Cool Tools

... who need blood for medical conditions such as hemophilia • People who received a blood transfusion before 1992 • ... results of these tests and the patient’s health. Treatment For an acute hepatitis B infection, there is ...


Autoimmune hepatitis  

Microsoft Academic Search

Autoimmune hepatitis (AIH) is an inflammatory liver disease affecting mainly females and characterised histologically by interface\\u000a hepatitis, biochemically by elevated transaminase levels and serologically by the presence of autoantibodies and increased\\u000a levels of immunoglobulin G. AIH responds to immunosuppressive treatment, which should be instituted as soon as diagnosis is\\u000a made. Seropositivity for smooth muscle and\\/or anti-nuclear antibody defines type 1

Diego Vergani; Maria Serena Longhi; Dimitrios P. Bogdanos; Yun Ma; Giorgina Mieli-Vergani



[Autoimmune hepatitis].  


Autoimmune hepatitis is a systemic disease, difficult to diagnose due the high variability of the clinical presentation and some non specific histological features. The recent identification of additional autoantibodies used as serological markers, as well as simplified diagnostic criteria should help the primary care physician to advance with the diagnostic process. These progresses are crucial as undiagnosed and therefore untreated autoimmune hepatitis has a poor prognosis, whereas immunosuppressive therapy leads to remission in a majority of cases. PMID:23667973

Luong Ba, Kim; Juillerat, Pascal; Ducommun, Julien



BBB - Hepatitis A Virus  

Center for Food Safety and Applied Nutrition (CFSAN)

... The term hepatitis A (HA) or type A viral hepatitis has replaced all previous designations: infectious hepatitis, epidemic hepatitis, epidemic jaundice ... More results from


Feature Hepatitis: Hepatitis Symptoms, Diagnosis, Treatment & Prevention  


... Navigation Bar Home Current Issue Past Issues Feature Hepatitis Hepatitis: Symptoms, Diagnosis, Treatment & Prevention Past Issues / Spring 2009 ... No appetite Fever Headaches Diagnosis To check for hepatitis viruses, your doctor will test your blood. You ...


Mapping ethanol-induced deletions  

Microsoft Academic Search

Chromosomal rearrangements, uniformly represented by very large deletions, were stimulated upon transiently exposing Escherichia coli cells with a defective lambda prophage to about 18% (v\\/v) ethanol. It was shown that the ethanol treatment induced deletion formation rather than enriching for ethanol-tolerant cells. The deletions in 435 mutants were mapped to 26 groups. Ethanol treatment changed the spectrum of deletions relative

Sidney Hayes



An experimental study on the disorders of hepatic hemodynamics and changes of plasma histamine in dogs with fulminant hepatic failure.  


The model of fulminant hepatic failure induced by acetaminophen was established in dogs to observe the changes of hepatic hemodynamics and plasma histamine levels in portal vein (PV), hepatic vein (HV), abdominal aorta (AA) and inferior vena cava (ICV). The results showed that the portal vein resistance (PVR) was elevated and portal venous blood flow (PVF) was decreased; hepatic artery resistance (HAR) was decreased and the hepatic artery blood flow (HAF), portal venous pressure (PVP), wedged hepatic venous pressure (WHVP) and inferior vena cava pressure (ICVP) had no changes. The histamine of the PV, HV, ICV and AA were all elevated after formation of fulminant hepatic failure. And the increasing wave of the HV was the highest. The increased histamine in HV may be mediated by H1 receptor causing the contraction of hepatic venulae, resulting liver sinusoid congestion, increasing PVR and decreasing PVF which exacerbate the liver cell damage. Moreover, the more severe liver damage, the more histamine was released, and a vicious circle may ensue. Our results also suggest the possibility of using H1 receptor antagonist to treat the disturbance of liver hemodynamics in severe acute liver damage. The increased histamine in systematic circulation as a vasodilator may lower blood pressure and accelerate heart beats. The increase of plasma histamine may play an important role in the changes of hepatic and systemic hemodynamics in fulminant hepatic failure. PMID:10806799

Zhang, L; Zhao, Q



Hepatitis C and pregnancy  

PubMed Central

Acute hepatitis C is a rare event in pregnancy. The most common scenario is chronic hepatitis C virus (HCV) infection in pregnancy. During pregnancy in women with chronic HCV infection a significant reduction in mean alanine aminotransferase levels has been reported, with a rebound during the postpartum period. In few cases exacerbation of chronic hepatitis C has been reported in pregnancy. A cofactor that might play a role in the reduction of liver damage is the release of endogenous interferon from the placenta. Observations regarding serum HCV-RNA concentration have been variable. In some women HCV-RNA levels rise toward the end of pregnancy. In general, pregnancy does not have a negative effect on HCV infection. Conversely, chronic hepatitis does not appear to have an adverse effect on the course of pregnancy, or the birth weight of the newborn infant. The role of spontaneous abortion is approximately the same as in the general population. The overall rate of mother-to-child transmission for HCV is 3%-5% if the mother is known to be anti-HCV positive. Co-infection with human immunodeficiency virus (HIV) increases the rate of mother-to-child transmission up to 19.4%. Numerous risk factors for vertical transmission have been studied. In general, high viral load defined as at least 2.5 × 106 viral RNA copies/mL, HIV co-infection, and invasive procedures are the most important factors. Both interferon and ribavirin are contraindicated during pregnancy. Viral clearance prior to pregnancy increases the likelihood that a woman remains non-viremic in pregnancy with a consequent reduced risk of vertical transmission.

Floreani, Annarosa



Punitive Damages  

Microsoft Academic Search

This entry concerns punitive damages. In considering the rationale for the award of punitive damages, we refer to two broad social goals: deterrence and punishment. In section 2 of the entry, we review the basic theory of deterrence, and in sections 3 through 6, we discuss the main deterrence-related justifications for punitive damages: the possibility of escaping sanctions; underestimation of

A. Mitchell Polinsky; Steven Shavell


Punitive Damages  

Microsoft Academic Search

Punitive damages is a controversial topic in American law. Defenders of punitive damages see these awards as a useful mechanism for sanctioning and deterring egregious conduct, particularly the conduct of corporations not subject to the sanctions of the criminal law but still harmful to society. Opponents of punitive damages argue that they are capriciously and unfairly awarded by juries and

Neil Vidmar; Matthew W. Wolfe



Tornado Damage!  

NSDL National Science Digital Library

Students will learn about tornadoes, the damage they cause, and how to rate tornadoes. Specifically, students will investigate the Fujita Damage Scale of tornado intensity, and use it to complete a mock engineering analysis of damage caused by a tornado. Lastly, students will learn some basic tornado safety procedures.

Integrated Teaching And Learning Program


Hepatitis C: progress and problems.  

PubMed Central

The hepatitis C virus (HCV), a single-stranded RNA virus, is the major cause of posttransfusion hepatitis. HCV isolates differ in nucleotide and amino acid sequences. Nucleotide changes are concentrated in hypervariable regions and may be related to immune selection. In most immunocompetent persons, HCV infection is diagnosed serologically, using antigens from conserved regions. Amplification of RNA may be necessary to detect infection in immunosuppressed patients. Transmission by known parenteral routes is frequent; other means of spread are less common and may represent inapparent, percutaneous dissemination. Infection can lead to classical acute hepatitis, but most infected persons have no history of acute disease. Once infected, most individuals apparently remain carriers of the virus, with varying degrees of hepatocyte damage and fibrosis ensuing. Chronic hepatitis may lead to cirrhosis and hepatocellular carcinoma. However, disease progression varies widely, from less than 2 years to cirrhosis in some patients to more than 30 years with only chronic hepatitis in others. Determinants important in deciding outcome are unknown. Alpha interferon, which results in sustained remission in selected patients, is the only available therapy. Long-term benefits from such therapy have not been demonstrated. Prevention of HCV infection by vaccination is likely to be challenging if ongoing viral mutation results in escape from neutralization and clearance.

Cuthbert, J A



Antioxidant liposoluble vitamins and carotenoids in chronic hepatitis  

Microsoft Academic Search

Background: It is known that antioxidant liposoluble vitamins and carotenoids are reduced in liver cirrhosis, but little is known about chronic viral hepatitis, where oxidative damage has to be taken into account. Methods: Fifty-five patients with chronic hepatitis, mainly C virus-related, were matched with 16 patients with biliary stones and 20 healthy controls. Plasma and liver analyses were carried out

E. Rocchi; G. Casalgrandi; A. Ronzoni; M. C. Rosa; G. Cioni; A. Marazzi; A. Manenti; S. Marchini; E. Ventura



Autoimmune hepatitis  

Microsoft Academic Search

Autoimmune hepatitis (AIH) is a distinct form of acute and chronic inflammatory liver disease in which immune reactions against host antigens are found to be the major pathological mechanism. If left untreated it carries an unfavourable prognosis, and the diagnosis should be made as soon as possible. The diagnostic approach has been greatly facilitated by the establishment of a panel

Karl-Hermann Meyer zum Büschenfelde; Hans-Peter Dienes



Hepatic failure  

Microsoft Academic Search

Acute liver failure is a rare multisystem disease that is characterised by the development of encephalopathy and coagulopathy within 26 weeks of the onset of symptoms in a patient with previously normal liver function. The commonest causes are viral hepatitis and acetaminophen overdose. The prognosis depends on the aetiology and the grade of encephalopathy at presentation. Because of the rapid

Kevin EJ Gunning



Tolerability of a Recombinant DNA Hepatitis B Vaccine Results of Post-Marketing Surveillance  

Microsoft Academic Search

Hepatitis B virus (HBV) is the most important cause of hepatitis both in children and adults. Hepatitis B virus is distributed alt over the world with a much marked infection level (5 - 20%) in Asia specially South East Asia, Person to person HBV transmission occurs through contact of slightly damaged skin or mucosa, infected body fluids like blood, semen

Sanjay Singh; R. Sharma


Hepatic phosphatidylethanolamine methyltransferase activity is decreased by ethanol and increased by phosphatidylcholine.  


Phosphatidylethanolamine N-methyltransferase participates in the synthesis of membrane phosphatidylcholine. Its activity was reported to be decreased in patients with alcoholic cirrhosis, but it is not known whether this is a consequence of the cirrhosis or precedes it. This question was studied in a baboon model of alcohol-induced fibrosis. Phosphatidylethanolamine N-methyltransferase activity was measured in sequential percutaneous needle liver biopsies by the conversion of phosphatidylethanolamine to phosphatidylcholine, using radioactive S-adenosylmethionine as a methyl donor. Chronic alcohol consumption (1-6 years) significantly decreased hepatic phospholipid and phosphatidylcholine levels and reduced phosphatidyl-ethanolamine N-methyltransferase activity even before the development of fibrosis. These effects were prevented or attenuated by supplementing the diet with 2.8 g/1000 kcal of a preparation rich in dilinoleoyl phosphatidylcholine, a highly bioavailable phosphatidylcholine species. There were significant (p < 0.001) correlations between phosphatidylethanolamine N-methyltransferase activity and both hepatic phosphatidylcholine (r = 0.678) and total phospholipid (r = 0.662). Conclusions: 1. Alcohol consumption diminishes phosphatidylethanolamine N-methyltransferase activity prior to the development of cirrhosis and decreases the hepatic content of its product, namely phosphatidylcholine, a key component of cell membranes. This may promote hepatic injury and possibly trigger fibrosis. 2. Phosphatidylcholine administration ameliorates the ethanol-induced decrease in phosphatidylethanolamine N-methyltransferase activity and corrects phospholipid and phosphatidylcholine depletions, thereby possibly contributing to the protection against alcoholic liver injury. PMID:7943660

Lieber, C S; Robins, S J; Leo, M A



Hepatitis A FAQs  


... or not Have clotting-factor disorders, such as hemophilia Live with someone who has Hepatitis A Have ... diseases, such as Hepatitis B or C. Diagnosis / Treatment How will I know if I have Hepatitis ...


Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis  

Microsoft Academic Search

Background\\/Aims: Little is known about the pathogenesis of liver damage related to hepatitis C virus. The presence of steatosis or increased ferritin levels, and preliminary data on the relevance of iron as a prognostic factor prompted us to ascertain whether hepatitis C virus-related liver damage might be mediated by iron accumulation.Methods: We evaluated the degree of hepatic inflammation and steatosis,

Fabio Farinati; Romilda Cardin; Nicola De Maria; Gianni Della Libera; Cinzia Marafin; Enrico Lecis; Patrizia Burra; Annarosa Floreani; Attilio Cecchetto; Remo Naccarato



Diabetes and Hepatitis B Vaccination  


Diabetes and Hepatitis B Vaccination Information for Diabetes Educators What is hepatitis B? Hepatitis B is a contagious liver disease that ... as liver failure or liver cancer. How is hepatitis B spread? The hepatitis B virus is usually ...


Autoimmune hepatitis  

Microsoft Academic Search

Autoimmune hepatitis (AIH) is a rare disease, characterized by female predominance, hypergammaglobulinemia, autoantibodies, association with HLA DR3 and HLA DR4 and a good response to immunosuppression. Different subtypes of AIH may be distinguished, based on differences in the autoantibody patterns. AIH type 1 is characterized by anti-nuclear (ANA) and\\/or anti-smooth muscular (SMA) autoantibodies. AIH type 2 is characterized by liver\\/kidney

Petra Obermayer-Straub; Christian P. Strassburg; Michael P. Manns



Immediate Postoperative Angiographic Embolization After Damage Control Surgery for Liver Injury: Report of a Case  

Microsoft Academic Search

A multimodality strategy, including damage control and angioembolization techniques, has been reported to reduce the mortality\\u000a associated with surgery for complex blunt hepatic injuries. However, the indications for angiographic evaluation and embolization\\u000a in patients who require surgery for hepatic injury remain unclear. We report a case of blunt hepatic injury requiring emergency\\u000a laparotomy, which we treated by damage control surgery

Shigeki Kushimoto; Yuichi Koido; Kenichiro Omoto; Junichi Aiboshi; Futoshi Ogawa; Ryusuke Yoshida; Yasuhiro Yamamoto



Damage Control  

Microsoft Academic Search

Damage control is an approach that has gained widespread popularity and acceptance in the management of severely injured patients. Although initially popularized in the trauma literature, this technique is being expanded to the management of a broad range of serious, often desperate surgical circumstances that may be encountered, including scenarios confronted by the colon and rectal surgeon. Damage-control surgery is

Kenneth J. McPartland; Neil H. Hyman



Coculturing embryonic stem cells with damaged hepatocytes leads to restoration of damage and high frequency of fusion.  


Controversy surrounds issue of cell fusion as a repair mechanism whereby stem cells regenerate. To identify the ratio of fusion happens between stem cells and damaged cells, hepatic cells were damaged with 200microM H2O2 for 2 hr. Then, mouse ESCs were cocultured with damaged human hepatocytes. Fusion was detected directly by karyotyping after 48hr coculture as well as by Oct4 promoter drove GFP signal. Results showed that average ratio of fusion in undamaged control group was 0.031 per thousand while ratio of fusion in damaged group was 0.357 per thousand, which was 10 times higher than fusion happened in the control group. Meanwhile, GFP signal indicated that fusion induced hepatic cells' Oct-4 reactivation. Fusion derived hybrid cells contained chromosomes from both parental cells. Most of the chromosomes were from damaged human hepatic cells. Activity of damage-related enzymes LDH, SGOT and SGPT were significantly lower at 48hr coculture than at 12hr coculture. Expression of albumin in co-culture system was up-regulated after coculture, which indicated the reparation of damage after coculturing. Also, by applying RT-PCR and immunocytochemistry differentiation status of ES cells were evaluated. It was shown that ES cells differentiated to hepatic lineage cells and expressed hepatic genes and proteins. PMID:20003813

Xu, D; Wang, F; Pan, Z; Guo, Q



Ethanol-induced changes in the expression of proteins related to neurotransmission and metabolism in different regions of the rat brain  

Microsoft Academic Search

Despite extensive description of the damaging effects of chronic alcohol exposure on brain structure, mechanistic explanations for the observed changes are just emerging. To investigate regional brain changes in protein expression levels following chronic ethanol treatment, one rat per sibling pair of male Wistar rats was exposed to intermittent (14h\\/day) vaporized ethanol, the other to air for 26weeks. At the

Natalie M. Zahr; Richard L. Bell; Heather N. Ringham; Edith V. Sullivan; Frank A. Witzmann; Adolf Pfefferbaum



The roles of the hepatocellular redox state and the hepatic acetaldehyde concentration in determining the ethanol elimination rate in fasted rats.  


Ethanol administration (2 g/kg i.p.) to fasted male Wistar rats caused, on average, a 64% decrease in the cytosolic free NAD+:NADH ratio and a 41% decrease in the mitochondrial free NAD+:NADH ratio measured 90 min after ethanol was injected. Treatment of animals with either Naloxone (2 mg/kg i.p.) 1 hr after ethanol or 3-palmitoyl-(+)-catechin (100 mg/kg p.o. 1 hr before ethanol) prevented these ethanol induced redox state changes, without affecting the ethanol elimination rate or the hepatic acetaldehyde concentration measured at 90 min after ethanol administration. The thiol compounds cysteine and malotilate (diisopropyl-1,3-dithiol-2-ylidene malonic acid) significantly lowered the hepatic acetaldehyde concentrations measured at 0.75, 1.5 and 6.0 hr after ethanol, and caused a 29% and 12% increase respectively in the ethanol elimination rate, without affecting the ethanol induced alterations in the NAD+:NADH ratio. Pretreatment of animals with the aldehyde dehydrogenase inhibitor, cyanamide (1 mg/kg or 15 mg/kg p.o. one hour before ethanol), caused increases of up to 23-fold in the hepatic acetaldehyde level, without influencing the cytosolic NAD+:NADH ratio in ethanol dosed rats, while significantly reducing the ethanol elimination rate by up to 44%, compared with controls. These results suggest that ethanol oxidation by cytosolic alcohol dehydrogenase may be regulated in part by the hepatic acetaldehyde concentration achieved during ethanol metabolism rather than NADH reoxidation, either to supply NAD for the dehydrogenase, or to reduce inhibition of the enzyme by NADH, being a rate-limiting factor in ethanol metabolism in fasted rats. PMID:2932116

Ryle, P R; Chakraborty, J; Thomson, A D



Damaged Goods  

Microsoft Academic Search

Manufacturers may intentionally damage a portion of their goods in order to price discriminate. Many instances of this phenomenon are observed. It may result in a Pareto improvement. Copyright 1996 The Massachusetts Institute of Technology.

Raymond J. Deneckere; R. Preston McAfee



Ethanol-Induced Expression of ET-1 and ET-BR in Liver Sinusoidal Endothelial Cells and Human Endothelial Cells Involves Hypoxia-Inducible Factor-1? and MicroRNA-1991  

PubMed Central

Chronic alcohol consumption leads to inflammation and cirrhosis of the liver. In this study, we observed that liver sinusoidal endothelial cells (LSEC) derived from ethanol-fed rats showed several fold increases in the mRNA expression of endothelin-1 (ET-1), hypoxia-inducible factor-1? (HIF-1?), and inflammatory cytochemokines compared with control rat LSEC. We also observed the same results in acute ethanol-treated LSEC from control rats and human dermal microvascular endothelial cells. Ethanol-mediated ET-1 expression involved NADPH oxidase and HIF-1? activation. Furthermore, ethanol increased the expression of the ET-1 cognate receptor ET-BR in Kupffer cells and THP-1 monocytic cells, which also involved HIF-1? activation. Promoter analysis and chromatin immunoprecipitation showed that hypoxia response element sites in the proximal promoter of ET-1 and ET-BR were required for the binding of HIF-1? to up-regulate their expression. We showed that microRNAs, miR-199 among several microRNAs, attenuated HIF-1? and ET-1 expression, while anti-miR-199 reversed the effects, suggesting that ethanol-induced miR-199 down-regulation may contribute to augmented HIF-1? and ET-1 expression. Our studies, for the first time to our knowledge, show that ethanol-mediated ET-1 and ET-BR expression involve HIF-1?, independent of hypoxia. Additionally, ethanol-induced ET-1 expression in rat LSEC is regulated by miR-199, while in human endothelial cells, ET-1 expression is regulated by miR-199 and miR-155, indicating that these microRNAs may function as novel negative regulators to control ET-1 transcription and, thus, homeostatic levels of ET-1 to maintain microcirculatory tone.

Yeligar, Samantha; Tsukamoto, Hidekazu; Kalra, Vijay K.



[Toxic hepatitis induced by Polygonum multiflorum].  


Toxic liver injury is a common cause of acute hepatitis. Here we report a case of 33-year old female with toxic hepatitis caused by unusual agent- extract of chinese plant Polygonum multiflorum. The patient presented with clinical signs of nausea and icterus and laboratory signs of hepatocellular damage following 2 months of readministration of Polygonum mulltiflorum pills. All other causes of hepatocellular damage were excluded. The causality between hepatocellular damage and Polygonum multiflorum ingestion was supported by early recovery after discontinuation, by international scoring system of causality between drug and hepatotoxicity as well as by similarities with other reports from the literature. Considering the growing popularity of herbal products as nutrition supplements we appeal to caution in using these preparations. PMID:23691566

Banarova, A; Koller, T; Payer, J



Prevalence of Hepatitis E Virus Antibodies in Patients with Chronic Hepatitis B and Chronic Hepatitis C  

Microsoft Academic Search

Objectives: To investigate the prevalence of hepatitis E virus (HEV) among patients with chronic hepatitis B and chronic hepatitis C, serum samples were collected between January and December 2004 from patients with chronic hepatitis B and chronic hepatitis C. Methods: There were 190 adult patients with chronic hepatitis B virus (HBV) and 174 with chronic hepatitis C virus (HCV) infection

A. Bayram; F. Eksi; M. Mehli; E. Sözen



Effect of cimetidine and ranitidine on drug induced damage to gastric epithelial cell monolayers in vitro.  

PubMed Central

The effect of the H2 blockers cimetidine and ranitidine on drug induced damage to gastric cell monolayers has been evaluated in conditions independent of systemic factors and their anti-acid properties. Monolayers of mucous cells from a human cell line MKN 28, obtained from a human gastric adenocarcinoma, have been studied. Cell damage has been assessed qualitatively by trypan blue dye exclusion test and quantitatively by 51Cr release assay. Cimetidine and ranitidine significantly protected cultured cells against damage induced by sodium taurocholate decreasing taurocholate induced 51Cr release by 36% (p less than 0.001) and 28% (p less than 0.01), respectively. Cimetidine was also protective in concentrations lower than ranitidine. This protection was not prevented by the prostaglandin synthesis inhibitor indomethacin nor by the sulph-hydryl blocker N-ethylmaleimide. Incubation with cimetidine and ranitidine did not increase the production of PGE2 by cultured cells nor did it affect the cellular level of sulph-hydryl compounds. Cimetidine and ranitidine did not afford protection against damage induced by indomethacin and ethanol. Cimetidine in a concentration of 10 4M increased ethanol induced damage significantly. In conclusion (1) cimetidine and ranitidine protect gastric cells against taurocholate induced damage in vitro, independently of their anti-acid effect; (2) this protection is not mediated by prostaglandin E2 or sulph-hydryl compounds; (3) cimetidine and ranitidine do not protect gastric cells against damage induced by indomethacin and ethanol. Images Fig. 1

Romano, M; Razandi, M; Ivey, K J



Congenital Hepatic Vascular Malformations  

Microsoft Academic Search

\\u000a Congenital hepatic vascular malformations are rare entities that result in abnormal shunting of blood through the liver. Three\\u000a different types of shunting can occur: arteriovenous (hepatic artery to hepatic vein), arterioportal (hepatic artery to portal\\u000a vein) and portovenous (portal vein to hepatic vein). Malformations result from alterations in the formation of blood vessels\\u000a during fetal development and can occur as

Guadalupe Garcia-Tsao


Halothane hepatitis  

PubMed Central

This report describes five cases of hepatocellular injury following halothane anesthesia. Four patients had multiple exposures to the anesthetic. Three of the five died from submassive to massive liver cell necrosis. The two survivors developed jaundice and/or dark urine following each exposure to halothane; liver biopsy in one showed centrilobular and linear areas of necrosis. Fever, anorexia, nausea, vomiting, abdominal pain and jaundice were present in all cases. In the two survivors the prothrombin time was less than 20 seconds throughout the course of the disease, whereas in the three who died the prothrombin time was more than 20 seconds from the onset. The English literature to the end of 1971 is reviewed. Approximately 600 cases of halothane-related hepatitis have been reported ImagesFIG. 1FIG. 2FIG. 3FIG. 4FIG. 5

Qizilbash, Ali H.



Acute and chronic ethanol consumption differentially impact pathways limiting hepatic protein synthesis.  


This review identifies the various pathways responsible for modulating hepatic protein synthesis following acute and chronic alcohol intoxication and describes the mechanism(s) responsible for these changes. Alcohol intoxication induces a defect in global protein synthetic rates that is localized to impaired translation of mRNA at the level of peptide-chain initiation. Translation initiation is regulated at two steps: formation of the 43S preinitiation complex [controlled by eukaryotic initiation factors 2 (eIF2) and 2B (eIF2B)] and the binding of mRNA to the 40S ribosome (controlled by the eIF4F complex). To date, alcohol-induced alterations in eIF2 and eIF2B content and activity are best investigated. Ethanol decreases eIF2B activity when ingested either acutely or chronically. The reduced eIF2B activity most likely is a consequence of twofold increased phosphorylation of the alpha-subunit of eIF2 on Ser(51) following acute intoxication. The increase in eIF2alpha phosphorylation after chronic alcohol consumption is the same as that induced by acute ethanol intoxication, and protein synthesis is not further reduced by long-term alcohol ingestion despite additional reduced expression of initiation factors and elongation factors. eIF2alpha phosphorylation alone appears sufficient to maximally inhibit hepatic protein synthesis. Indeed, pretreatment with Salubrinal, an inhibitor of eIF2alpha(P) phosphatase, before ethanol treatment does not further inhibit protein synthesis or increase eIF2alpha phosphorylation, suggesting that acute ethanol intoxication causes maximal eIF2alpha phosphorylation elevation and hepatic protein synthesis inhibition. Ethanol-induced inhibition of hepatic protein synthesis is not rapidly reversed by cessation of ethanol consumption. In conclusion, sustained eIF2alpha phosphorylation is a hallmark of excessive alcohol intake leading to inhibition of protein synthesis. Enhanced phosphorylation of eIF2alpha represents a unique response of liver to alcohol intoxication, because the ethanol-induced elevation of eIF2alpha(P) is not observed in skeletal muscle or heart. PMID:18334613

Karinch, Anne M; Martin, Jonathan H; Vary, Thomas C



Multiplication of hepatitis B virus in fulminant hepatitis B  

Microsoft Academic Search

The presence in serum of hepatitis B e antigen (HBeAg) and hepatitis B virus DNA, which are each regarded as reflecting multiplication of hepatitis B virus, were looked for one to five days after the onset of hepatic encephalopathy in 64 patients with fulminant hepatitis B. HBeAg and hepatitis B virus DNA were found in the serum of only 24

C Brechot; J Bernuau; V Thiers; F Dubois; A Goudeau; B Rueff; P Tiollais; J P Benhamou



What Is Hepatitis?  


... WHO .int site Submit Advanced search What is hepatitis? Online Q&A Updated June 2013 Q: What ... cause liver disease, they vary in important ways. Hepatitis A virus (HAV) is present in the faeces ...


Literacy Measure B - Hepatitis  

Center for Drug Evaluation (CDER)

... Literacy Measure B - Hepatitis. HEPATITIS. Frequency. Percent. Valid Percent. Cumulative Percent. Valid, Correct, 838, 92.7, 92.7, 92.7. ... More results from


Viral Hepatitis Therapies  


... Cancer Liaison Program Cardiovascular Information Diabetes Information - Viral Hepatitis Therapies Click on drug brand name for additional information. Approved Treatments for Hepatitis B Brand Name Generic Names Manufacturer Name Indication ...


Ammonia: Key factor in the pathogenesis of hepatic encephalopathy  

Microsoft Academic Search

There is substantial clinical and experimental evidence to suggest that ammonia toxicity is a major factor in the pathogenesis\\u000a of hepatic encephalopathy associated with subacute and chronic liver disease. Ammonia levels in patients with severe liver\\u000a disease are frequently found to be elevated both in blood and cerebrospinal fluid (csf). Hepatic encephalopathy results in\\u000a neuropathological damage of a similar nature

Roger F. Butterworth; Jean-François Giguère; Jean Michaud; Joël Lavoie; Gilles Pomier Layrargues



Prevention of viral hepatitis  

Microsoft Academic Search

Opinion statement  Despite the availability of vaccines against hepatitis A and B, acute viral hepatitis due to these agents continues to be\\u000a among the most commonly reported notifiable infectious diseases in the United States. Currently available hepatitis A and\\u000a B vaccines are highly immunogenic and well tolerated, but vaccine coverage needs to be expanded. Use of the hepatitis A vaccine\\u000a in

Raymond S. Koff



Hepatitis C in pregnancy.  


Hepatitis C is a worldwide health problem affecting men and women of all ages. In young pregnant women, however, the existence of hepatitis C presents a set of unique issues for the mother and the child. For the mother, therapeutic and medical decisions for hepatitis C are affected by pregnancy. For the child, transmission of hepatitis C from the mother can occur. Identification of risk factors for mother-to-child transmission and prevention of this transmission are the foremost concerns. PMID:15701298

Su, Grace L



Hepatitis C in pregnancy  

Microsoft Academic Search

Hepatitis C is a worldwide health problem affecting men and women of all ages. In young pregnant women, however, the existence\\u000a of hepatitis C presents a set of unique issues for the mother and the child. For the mother, therapeutic and medical decisions\\u000a for hepatitis C are affected by pregnancy. For the child, transmission of hepatitis C from the mother

Grace L. Su



Hepatocarcinogenesis in the LEC rat with hereditary hepatitis.  


A new mutant developing spontaneous hepatitis and hepatocellular carcinoma has been discovered among Long Evans rats. Hepatitis appears suddenly in the mutant, Long Evans Cinnamon (LEC) rats, three to four months after birth. Characteristic clinical signs of the hepatitis are jaundice, bilirubinuria, subcutaneous bleeding and loss of body weight. The affected rats showed a high mortality and histological changes with focal necrosis of hepatocytes and infiltration of a few inflammatory cells. Genetic studies indicate that a single autosomal recessive gene is responsible for the hepatitis. Long-surviving rats show chronic hepatitis, and subsequently develop hepatocellular carcinoma at one and a half years of age. We recently found an abnormal copper accumulation in the liver of LEC rats prior to development of the hepatitis. Copper concentration in the liver is over 40 times more than that of normal Long Evans Agouti (LEA) rats, whereas the serum ceruloplasmin and copper levels are lower. An excess of toxic-form copper, free copper, will cause DNA damage in the presence of free radicals and oxygen radicals. Such DNA damage by the radicals is considered to be responsible for hepatic necrosis and hepatocellular carcinoma in LEC rats. PMID:1844250

Takeichi, N



Pathogenesis of Hepatic Encephalopathy  

PubMed Central

Hepatic encephalopathy can be a serious complication of acute liver failure and chronic liver diseases, predominantly liver cirrhosis. Hyperammonemia plays the most important role in the pathogenesis of hepatic encephalopathy. The brain-blood barrier disturbances, changes in neurotransmission, neuroinflammation, oxidative stress, GABA-ergic or benzodiazepine pathway abnormalities, manganese neurotoxicity, brain energetic disturbances, and brain blood flow abnormalities are considered to be involved in the development of hepatic encephalopathy. The influence of small intestine bacterial overgrowth (SIBO) on the induction of minimal hepatic encephalopathy is recently emphasized. The aim of this paper is to present the current views on the pathogenesis of hepatic encephalopathy.

Ciecko-Michalska, Irena; Szczepanek, Malgorzata; Slowik, Agnieszka; Mach, Tomasz



Role of viral factors in the natural course and therapy of chronic hepatitis B  

Microsoft Academic Search

Hepatitis B virus (HBV) infection is a global health problem that causes a wide spectrum of liver disease, including acute\\u000a or fulminant hepatitis, inactive carrier state, chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The pathogenesis\\u000a of hepatocyte damage associated with HBV is mainly through immune-mediated mechanisms. On the basis of the virus and host\\u000a interactions, the natural history of HBV

Jia-Horng Kao



Potential in vitro Protective Effect of Quercetin, Catechin, Caffeic Acid and Phytic Acid against Ethanol-Induced Oxidative Stress in SK-Hep-1 Cells  

PubMed Central

Phytochemicals have been known to exhibit potent antioxidant activity. This study examined cytoprotective effects of phytochemicals including quercetin, catechin, caffeic acid, and phytic acid against oxidative damage in SK-Hep-1 cells induced by the oxidative and non-oxidative metabolism of ethanol. Exposure of the cells to excess ethanol resulted in a significant increase in cytotoxicity, reactive oxygen species (ROS) production, lipid hydroperoxide (LPO), and antioxidant enzyme activity. Excess ethanol also caused a reduction in mitochondrial membrane potential (MMP) and the quantity of reduced glutathione (GSH). Co-treatment of cells with ethanol and quercetin, catechin, caffeic acid and phytic acid significantly inhibited oxidative ethanol metabolism-induced cytotoxicity by blocking ROS production. When the cells were treated with ethanol after pretreatment of 4-methylpyrazole (4-MP), increased cytotoxicity, ROS production, antioxidant enzyme activity, and loss of MMP were observed. The addition of quercetin, catechin, caffeic acid and phytic acid to these cells showed suppression of non-oxidative ethanol metabolism-induced cytotoxicity, similar to oxidative ethanol metabolism. These results suggest that quercetin, catechin, caffeic acid and phytic acid have protective effects against ethanol metabolism-induced oxidative insult in SK-Hep-1 cells by blocking ROS production and elevating antioxidant potentials.

Lee, Ki-Mo; Kang, Hyung-Sik; Yun, Chul-Ho; Kwak, Hahn-Shik



Neuronal cell death in hepatic encephalopathy  

Microsoft Academic Search

It is generally assumed that neuronal cell death is minimal in liver failure and is insufficient to account for the neuropsychiatric\\u000a symptoms characteristic of hepatic encephalopathy. However, contrary to this assumption, neuronal cell damage and death are\\u000a well documented in liver failure patients, taking the form of several distinct clinical entities namely acquired (non-Wilsonian)\\u000a hepatocerebral degeneration, cirrhosis-related Parkinsonism, post-shunt myelopathy

Roger F. Butterworth



Hepatic Microcirculatory Changes in Acute and Chronic Carbon Tetrachloride Poisoning in Rats.  

National Technical Information Service (NTIS)

A study of the hepatic microvasculature was carried out in the course of prolonged carbon tetrachloride poisoning, utilizing a silicone rubber perfusion technique. Consistent and rather selective damage was confined to central veins and centrilobular sinu...

T. Hase



Long-lasting reductions of ethanol drinking, enhanced ethanol-induced sedation, and decreased c-fos expression in the Edinger-Westphal nucleus in Wistar rats exposed to the organophosphate chlorpyrifos.  


Intermittent or continuous exposure to a wide variety of chemically unrelated environmental pollutants might result in the development of multiple chemical intolerance and increased sensitivity to drugs of abuse. Interestingly, clinical evidence suggests that exposure to organophosphates might be linked to increased ethanol sensitivity and reduced voluntary consumption of ethanol-containing beverages in humans. The growing body of clinical and experimental evidence emerging in this new scientific field that bridges environmental health sciences, toxicology, and drug research calls for well-controlled studies aimed to analyze the nature of the neurobiological interactions of drugs and pollutants. Present study specifically evaluated neurobiological and behavioral responses to ethanol in Wistar rats that were previously exposed to the pesticide organophosphate chlorpyrifos (CPF). In agreement with clinical data, animals pretreated with a single injection of CPF showed long-lasting ethanol avoidance that was not secondary to altered gustatory processing or enhancement of the aversive properties of ethanol. Furthermore, CPF pretreatment increased ethanol-induced sedation without altering blood ethanol levels. An immunocytochemical assay revealed reduced c-fos expression in the Edinger-Westphal nucleus following CPF treatment, a critical brain area that has been implicated in ethanol intake and sedation. We hypothesize that CPF might modulate cellular mechanisms (decreased intracellular cAMP signaling, alpha-7-nicotinic receptors, and/or cerebral acetylcholinesterase inhibition) in neuronal pathways critically involved in neurobiological responses to ethanol. PMID:17190973

Carvajal, Francisca; López-Grancha, Matilde; Navarro, Montserrat; Sánchez-Amate, Maria del Carmen; Cubero, Inmaculada



A Case of Renal Amyloidosis Associated with Hepatic Adenoma: The Pathogenetic Role of Tumor Necrosis Factor-?  

Microsoft Academic Search

We report a case of a 35-year-old man with secondary amyloidosis chiefly involving the kidney and heart. The patient showed severe proteinuria and ischemic heart damage and had hepatic adenoma at the age of 33. Biopsy specimens from the kidney, heart, stomach and rectum showed extensive deposition of amyloid. After the surgical resection of a 300-gram hepatic adenoma, highly elevated

Toshiaki Shibasaki; Hiroshi Matsumoto; Kazuhiko Watabe; Kensuke Joh; Hirofumi Nakano; Hiroyuki Matsuda; Hideho Gomi; Iwao Ohno; Fumio Ishimoto; Osamu Sakai



Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis  

Microsoft Academic Search

Background & Aims: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that occasionally progresses to cirrhosis but usually has a benign course. The aim of this study was to investigate the role of the hemochromatosis mutation Cys282Tyr in development of the mild hepatic iron overload found in some patients with NASH and its association with hepatic damage in these patients.

D. Keith George; Stefano Goldwurm; Graeme A. Macdonald; Lex L. Cowley; Neal I. Walker; Patrick J. Ward; Elizabeth C. Jazwinska; Lawrie W. Powell



[Liver damage caused by drugs].  


The liver has a central role in the metabolism of many drugs, since this organ is the main site of biotransformation of endo- and xenobiotics. Water-soluble drugs have a small volume of distribution and can be eliminated unchanged in the urine. By contrast, lipid-soluble drugs have a larger volume of distribution and require conversion to water-soluble metabolites for their elimination in urine or bile. The liver with its specific receptors, transporters and enzymes is responsible for the uptake, transformation and excretion of the lipophilic drugs. While most of the drugs are transformed into stable metabolites, other drugs form reactive, potentially toxic, metabolites producing liver cell damage. Liver injury caused by drugs may mimic almost any kind of liver disease. Clinical findings are gastrointestinal symptoms with nausea, vomiting and abdominal pain, cholestatic liver injury with jaundice and pruritus of severe inflammatory and cirrhotic liver damage with signs of liver failure, encephalopathy and cerebral edema. The morphological changes vary from hepatitis, cholestasis, fatty liver, granulomatous hepatitis, peri-/portal inflammation, to fibrosis with cirrhotic alterations and vascular lesions and tumors. The most commonly used drugs causing severe liver injury are discussed in detail. These are anabolics, oral contraceptives, antituberculous and antifungal agents, nonsteroidal anti-inflammatory drugs, ring substituted amphetamins ("designer drugs"), antiarrhythmics and antibiotics. PMID:10413844

Strohmeyer, G; Weik, C



Feline hepatic disease.  


Species differences in anatomy, physiology, and biochemistry lead to many dissimilarities between the canine and feline liver. Major differences exist in the interpretation of liver function tests, the significance of biochemical jaundice, the consequences of anorexia, and the efficiency of hepatic metabolic systems. Biochemical alterations in total bilirubin, ALT, and SAP may indicate the presence of disease in the feline liver. It is, however, impossible to make accurate diagnoses without liver biopsy. A liver biopsy can provide a diagnosis and prognosis and can guide the therapeutic plan. The feline hepatic diseases most frequently seen in our hospital are hepatic lipidosis, cholangiohepatitis complex, toxic hepatopathy, and hepatic neoplasia. Less common diseases of the feline liver include extrahepatic biliary obstruction, portacaval vascular anomalies, hepatic parasites, hepatic cysts, and diaphragmatic hernia. Systemic diseases that can effect the liver of cats are feline infectious peritonitis, multicentric lymphosarcoma, myeloproliferative diseases, hemolytic anemia, infectious panleukopenia, and systemic fungal infections. PMID:6393553

Zawie, D A; Garvey, M S



Hepatitis B Frequently Asked Questions  


... Hepatitis B were infected at birth or during early childhood. How is Hepatitis B spread? Hepatitis B is ... it. However, some people, especially those infected during early childhood, remain infected for life because they never clear ...


Hepatite E Hepatitis E  

Microsoft Academic Search

Hepatitis E virus (HEV) is the second most frequent hepatotropic virus transmitted via fecal-oral route, following closely behind hepatitis A virus. The great epidemics of hepatitis described during the 50s and 60s, in India, were caused by this virus. Epidemic bursts have also been described in Central Africa, Latin America, Middle East and in the independent Republics of the ex-Soviet

Raymundo Paraná; Maria Isabel Schinoni


Hepatitis E infection  

Microsoft Academic Search

Hepatitis E — formerly called ‘enterically transmitted non-A non-B hepatitis’ — is transmitted by the faecal-oral route. The\\u000a Hepatitis E Virus (HEV) is a positive-sense single-stranded RNA virus and has great similarities to the caliciviruses. Virus\\u000a replication appears to be limited to the hepatocyte. The disease is especially endemic and\\/or epidemic on the Indian sub-continent.\\u000a Epidemics are mostly waterborne infections.

Axel Schmidt; Manfred H. Wolff


Mononeuritis multiplex and painful ulcers as the initial manifestation of hepatitis B infection.  


Hepatitis B virus infection leads to multisystem manifestations owing to involvement of kidney, skin, vasculature, haematopoietic and nervous system. The hepatitis B infection can cause neuropathy either to vasculitis associated with polyarteritis nodosa or immune-mediated neural damage. In this submission, we report a young woman, who presented with mononeuritis multiplex and painful ulcerations as the first manifestation of chronic hepatitis B virus infection. The antiviral therapy along with steroids led to remarkable recovery. The clinical settings of hepatitis B virus infection should not be ignored in the presentation of mononeuritis multiplex with ulcers, although the commonest cause is leprosy in the Indian sub-continent. PMID:23645658

Verma, Rajesh; Lalla, Rakesh; Babu, Suresh



Hepatic stellate cells and astrocytes  

PubMed Central

Scar formation inhibits tissue repair and regeneration in the liver and central nervous system. Activation of hepatic stellate cells (HSCs) after liver injury or of astrocytes after nervous system damage is considered to drive scar formation. HSCs are the fibrotic cells of the liver, as they undergo activation and acquire fibrogenic properties after liver injury. HSC activation has been compared to reactive gliosis of astrocytes, which acquire a reactive phenotype and contribute to scar formation after nervous system injury, much like HSCs after liver injury. It is intriguing that a wide range of neuroglia-related molecules are expressed by HSCs. We identified an unexpected role for the p75 neurotrophin receptor in regulating HSC activation and liver repair. Here we discuss the molecular mechanisms that regulate HSC activation and reactive gliosis and their contributions to scar formation and tissue repair. Juxtaposing key mechanistic and functional similarities in HSC and astrocyte activation might provide novel insight into liver regeneration and nervous system repair.

Schachtrup, Christian; Le Moan, Natacha; Passino, Melissa A



Recent experiences with a multidisciplinary approach to complex hepatic trauma  

Microsoft Academic Search

Background: The selection of an appropriate time to terminate damage control efforts when faced with haemorrhagic shock from severe hepatic trauma can be challenging. At our centre, trauma surgeons have increasingly been favouring an operative approach simply involving early perihepatic packing (without extensive use of intraoperative measures aimed at achieving definitive haemostasis) and temporary abdominal closure. This is often followed

Shawn MacKenzie; John B. Kortbeek; Robert Mulloy; S. Morad Hameed



Hepatitis C Virus-Induced Steatosis: An Overview  

Microsoft Academic Search

The pathogenesis of liver damage associated with the chronic hepatitis C virus (HCV) infection is largely immunomediated. However, some frequent histopathological features, such as fatty liver, suggest a direct cytopathic effect of HCV. The direct responsibility of HCV in the pathogenesis of steatosis is shown by: (1) the association with HCV genotype 3 infection, suggesting that some viral sequences are

Francesco Negro




EPA Science Inventory

Allylisopropylacetamide (AIA) did not cause DNA damage in rat liver. The porphyrinogenic research drug did strongly induce the activity (25-fold) of rat hepatic enzyme ornithine decarboxylase (ODC). By either the oral or the subcutaneous route AIA produced a long lasting inductio...


Prognosis of histological cirrhosis in type 1 autoimmune hepatitis  

Microsoft Academic Search

BACKGROUND & AIMS: Cirrhosis connotes irreversible damage to the liver and shortened life expectancy. The aim of this study was to evaluate the impact of cirrhosis on treatment response and survival in type 1 autoimmune hepatitis. METHODS: One hundred twenty-eight patients were evaluated for histological cirrhosis. Response to treatment, predictors for cirrhosis, and outcomes were determined. RESULTS: Thirty-seven patients (29%)

SK Roberts; TM Therneau; AJ Czaja



Management of viral hepatitis B.  


Hepatitis B virus (HBV) infection is a major global health concern and is the most common cause of chronic liver disease worldwide. The natural history and clinical outcomes of chronic HBV infection are determined by the viral replication cycle and the host immune responses. Treatment of chronic hepatitis B is directed at interrupting the natural history by suppressing HBV replication before development of any significant irreversible liver cell damage. Effective antiviral therapies should be followed by sustained suppression of HBV-DNA, normalization of transaminases levels and a stable stage of HBeAg seroconversion with persistence of circulating anti-HBeAg antibodies. Two major classes of antiviral therapeutic agents that have been approved for treatment of chronic hepatitis B are immunomodulating agents (i.e. interferon) and the nucleoside analogs (i.e. lamivudine). A 4-6 month course of interferon-alpha has resulted in improvement of survival in 20%-30% of patients with chronic hepatitis B who had elevated serum ALT levels without hepatic decompensation. Interferon-alpha therapy is associated with HBeAg seroconversion; normalization of ALT levels, reduced hepatic inflammation, and possibly reduced disease progression to cirrhosis and hepatocellular carcinoma. Interferon can also be used with caution in patients with early compensated cirrhosis. A 12-month course of lamivudine has been shown to be well tolerated and effective. Lamivudine can be used in decompensated cirrhosis and immunosuppressed patients and for prevention of recurrent HBV infection after liver transplantation. The response rates after 3 years of lamivudine therapy account for 40-65%. A major problem of antiviral treatment is the emergence of drug resistance conferred by mutations in the YMDD motif of HBV reverse transcriptase. The prevalence of YMDD mutations increases with longer durations of antiviral therapies and this has been detected in 20% of immunocompetent patients receiving lamivudine per year. Contentious issues remain when to stop the treatment if HBeAg seroconversion does not occur. Many new immunomodulatory therapies and antiviral agents are in various stages of clinical development and have shown some promise. Among newer HBV antivirals, adefovir dipivoxil, entecavir, emtricitabine, DAPD and clevudine appear to be at least as potent as lamivudine in suppressing HBV replication. In vitro studies have shown that YMDD mutations confer cross-resistance between lamivudine and emtricitabine. However, adefovir, dipivoxil, lobucavir, DAPD and possibly clevudine suppress replications of both YMDD mutants and wild types of HBV. Immunomodulatory approaches for treatment of chronic hepatitis B are conceptually attractive, but newer agents used to date (thymosin-alpha, interleukin-12, therapeutic vaccines) have not demonstrated sufficient efficacy for widespread use. Combinations of an immunomodulatory agent and nucleoside analog may improve the therapeutic efficacy and reduce the emergence of drug resistance. Nevertheless, combinations of interferon and lamivudine therapies do not confer such additional benefits. The next challenge for HBV treatment is to use antivirals in combination and/or in cyclical therapy to minimize the emergence of drug resistance and increase efficacy, particularly to achieve sustainable post-treatment suppression of HBV. Randomized prospective control trials of combined antiviral therapies given simultaneously or sequentially are needed to establish safe and effective combined regimens that can be recommended for future treatment strategies. PMID:12000599

Pramoolsinsup, Chutima



Morphologic Studies of Hepatitis.  

National Technical Information Service (NTIS)

Particles were found in cases of chronic hepatitis in hepatocellular nuclei, and these were identified as Australia antigen (HB Ag) by its ability to combine with ferritin labelled HB antibody. The relation of HB Ag to hepatitis has been postulated to be ...

F. Schaffner



Oxidative Damage to Nuclear DNA in Hyperthyroid Rat Liver: Inability of Vitamin C to Prevent the Damage  

Microsoft Academic Search

The effects of hyperthyroidism on oxidative DNA damage in liver tissue and modification by vitamin C supplementation were investigated in rats. Animals were rendered hyperthyroid by administration of l-thyroxine (0.4 mg\\/100 g food) for 25 d. In the plasma samples, T3, T4, and thyroid-stimulating hormone (TSH) were measured by radioimmunoassay and ascorbate spectrophotometrically. Oxidative damage to hepatic nuclear DNA was

Gülnur Andican; Remise Geli?gen; Sabiha Civelek; Arzu Seven; Oktay Seymen; Tuncay Altu?; Günnur Yi?it; Gülden Burçak



[Viral hepatitis during pregnancy].  


Viral hepatitis is one of the most common liver diseases appearing during pregnancy. Prevention against hepatotropic viruses is restricted due to lack of vaccines being effective in induction of efficient immunization in the majority of these microorganisms. In general, there is no possibility of active immunization against hepatotropic viruses except type A and B viral hepatitis. An issue of viral hepatitis in pregnancy as an aspect of potential risk factor connected with infection of pregnant women and a fetus has been described in this paper. Furthermore, the most important topics in the field of the epidemiology, prophylaxis and possible treatment options of viral hepatitis A, B, C, D, E and G have been discussed. The newest reports of pregnant women lamivudine therapy as a preventive treatment against vertical transmission during delivery have been reviewed. Rarly diagnosed viral hepatitis caused by herpes simplex virus, cytomegalovirus, Epstein-Barr virus and adenoviruses have been characterized as well. PMID:17219815

Gutkowski, Krzysztof; Gutkowska, Dorota; Lepiech, Jacek



Hepatitis A in Children  

Microsoft Academic Search

\\u000a \\u000a \\u000a \\u000a \\u000a \\u000a • \\u000a \\u000a \\u000a \\u000a Hepatitis A virus is the most common viral hepatitis globally.\\u000a \\u000a \\u000a \\u000a \\u000a • \\u000a \\u000a \\u000a \\u000a Hepatitis A virus is a serious public health concern, and causes significant morbidity and mortality.\\u000a \\u000a \\u000a \\u000a \\u000a • \\u000a \\u000a \\u000a \\u000a The changing epidemiological features of hepatitis A are associated with the inception of vaccine programs.\\u000a \\u000a \\u000a \\u000a \\u000a • \\u000a \\u000a \\u000a \\u000a Hepatitis A infection has numerous clinical presentations.

Michelle Rook; Philip Rosenthal


Hepatic Steatosis in Chronic Hepatitis C: Risk factors and role in the development of hepatic fibrosis  

Microsoft Academic Search

3. To identify viral and non-viral risk factors for hepatic steatosis in patients with chronic hepatitis C. 4. To identify metabolic predictors of week 20 and sustained virologic response 5. To determine the effects of long-term interferon therapy on hepatic steatosis in patients with chronic hepatitis C. 6. To determine the effects of virologic clearance on insulin resistance in patients

Anna S. F. Lok; Zachary Goodman; Joel Greenson; James Everhart


Therapy of viral hepatitis.  


Worldwide viral hepatitis is the most common cause of jaundice, chronic liver disease cirrhosis and hepatocellular carcinoma. While important advances have been made in prevention of viral hepatitis, therapy of this disease remains unsatisfactory. There are no specific therapies of proven benefit for acute hepatitis, although use of alpha-interferon during the acute phase of hepatitis C may result in a decrease in the rate of chronicity. For chronic viral hepatitis, alpha-interferon has been widely used, but is expensive, poorly tolerated and limited in effectiveness. New antiviral agents and use of combinations of antivirals are now being evaluated and promise to provide a therapy that is effective in the majority of patients. The currently recommended therapy of chronic hepatitis B is a 4- to 6-month course of alpha-interferon in doses of 5-10 million units three times a week; a regimen that results in sustained clearance of hepatitis B virus (HBV) DNA and hepatitis B e antigen (HBeAg) from serum in approximately one-third and a loss of hepatitis B surface antigen (HBsAg) in one-tenth of patients. Long-term follow-up of patients who respond to interferon treatment with clearance of HBeAg indicate that the majority ultimately clear HBsAg as well and have continued remission in the liver disease, although low levels of HBV DNA can commonly be detected in liver tissue. Better therapies of hepatitis B are needed. Recently, several oral 'second-generation' nucleoside analogues have been developed that have potent activity against HBV. The best studied is lamivudine (3-thiacytidine) which results in marked inhibition of HBV DNA levels and improvement in serum aminotransferases and hepatic histology in the majority of patients. When stopped, however, most patients relapse and the shortcomings of long-term therapy have been the development of viral resistance in up to one-quarter of patients within a year and a higher percentage with more prolonged therapy. Future approaches of therapy of promise for hepatitis B are combinations of lamivudine with interferon and other antiviral nucleoside analogues. The currently recommended therapy of chronic hepatitis C is a 12- to 18-month course of alpha interferon in doses of 3 million units three times a week: a regimen that results in sustained clearance of hepatitis C virus (HCV) RNA in approximately 20% of patients. Sustained responses have been associated with marked improvements in hepatic histology and long-term studies indicate that the majority of patients remain free of virus in serum and liver, suggesting a 'cure' of infection. Responses to interferon correlate to some degree with clinical and virological features, including young age, absence of hepatic fibrosis, low levels of HCV RNA in serum and HCV genotypes 2 and 3. (ABSTRACT TRUNCATED) PMID:9705540

Hoofnagle, J H



Aggressive hepatitis (image)  


Chronic active hepatitis is a liver disease caused by infection, drug ingestion, metabolic or autoimmune disorders. Necrosis (death) of liver cells, inflammation and fibrosis may lead to liver failure. Death within 5 years ...


Hepatitis B Vaccine (Recombinant)  

Center for Biologics Evaluation and Research (CBER)

... Hepatitis B Vaccine (Recombinant). -. Products. Engerix-B; Recombivax HB. -. Contact FDA. (800) 835-4709. (301) 827-1800. ... More results from


Children with hepatitis C  

Microsoft Academic Search

Hepatitis C affects thousands of children throughout the world. Most children acquire the virus through vertical transmission,\\u000a although parenteral routes of acquisition are also common. Hepatitis C progresses slowly, with mild biopsy findings and no\\u000a symptoms in most children and in many adults. However, significant liver inflammation and fibrosis can occur in childhood.\\u000a Trials of antiviral therapy with interferon and

Girish Subba Rao; Jean Pappas Molleston



Laparoscopic anatomical hepatic resection  

Microsoft Academic Search

.   Four patients underwent a laparoscopic left hepatic resection for solid tumor, two for metastasis from colonic cancer, and\\u000a two for focal nodular hyperplasia (final diagnosis). The procedure was performed according to the rules of conventional hepatic\\u000a surgery and cancer surgery. No blood transfusion was necessary. No surgical complication occurred. In malignant disease, laparoscopy\\u000a allows a good staging and the

G. Samama; L. Chiche; J. L. Bréfort; Y. Le Roux



Sex Differences in Hepatic Gluconeogenic Capacity After Chronic Alcohol Consumption  

PubMed Central

Alcohol-induced hypoglycemia has traditionally been attributed to the amount of ethanol consumed rather than any inherent decline in glucose output capacity by the gluconeogenic organs and/or an increase in skeletal muscle glucose uptake. Further, while the potential for sex differences that might impact glucose homeostasis following chronic alcohol consumption has been recognized, direct evidence has been noticeably absent. This paper will provide a brief review of past and present reports of the potential for sex differences in glucose homeostasis following chronic ethanol consumption. This paper will also provide direct evidence from our laboratory demonstrating sex differences from chronic alcohol consumption resulting in a decrement in glucose appearance and more importantly, a specific decline in hepatic gluconeogenic (HGN) capacity in the absence and presence of ethanol. All our studies involved 8 weeks of chronic alcohol consumption in male and female Wistar rats, as well as a 24 to 48 hour fast to deplete hepatic glycogen stores. Under the conditions of chronic alcohol consumption and an acute dose of ethanol, we provide in vivo evidence of an early decline in whole body glucose appearance in females fed an ethanol diet compared to controls. While the decline was also observed in males fed the alcohol diet, it occurred much later compared to ethanol fed females. The site for the decline in whole body glucose production (i.e., either the kidneys or the liver) was beyond the scope of our prior in vivo study. In a follow-up study using the in situ perfused liver preparation, we provide additional evidence for a specific reduction in HGN capacity from lactate in ethanol fed females compared to ethanol fed males in the absence of alcohol in the perfusion medium. Finally, employing the isolated hepatocyte technique, we report decrements in HGN from lactate in ethanol fed females compared to ethanol fed males in the presence of ethanol in the incubation medium. The mechanism for the specific decline in HGN within the liver of ethanol fed females remains to be determined. To the extent that our observations in animals can be extrapolated to humans, we conclude that alcoholic women are more susceptible to ethanol-induced hypoglycemia compared to alcoholic men.

Sumida, Ken D.; Hill, Janeen M.; Matveyenko, Aleksey V.



Mechanisms of Hepatic Fibrogenesis  

PubMed Central

Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5–10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow– derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, post-transcriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.

Friedman, Scott L.



Hepatitis B Guidelines for Pregnant Women  


Hepatitis B Foundation Cause for a Cure Hepatitis B Foundation · 3805 Old Easton Road, ... PA 18902 · 215-489-4900 · Hepatitis B Guidelines for Pregnant Women What is hepatitis ...


Effects of 2-butoxyethanol on hepatic oxidative damage  

Microsoft Academic Search

2-Butoxyethanol has been reported to induce an increase in liver tumors in male B6C3F1 mice following chronic inhalation while rats, similarly treated, showed no increase in liver tumors. The mechanism for the selective induction of cancer in mouse liver is unknown, however, 2-butoxyethanol has been shown to induce hemolysis in mice, resulting in an accumulation of hemosiderin (iron) in the

Lisa M Kamendulis; James E Klaunig



Antibody to hepatitis B core antigen in chronic active hepatitis  

Microsoft Academic Search

Antibody to hepatitis B core antigen (anti-HBc), which has been assumed to be a more sensitive indicator of hepatitis B virus replication than hepatitis B surface antigen (HBsAg), was detected in the sera of 26 of our 65 patients with HBsAg-negative chronic active hepatitis. Thus despite the absence of HBsAg the liver disease could be the consequence of chronic infection

P Bories; P Coursaget; A Goudeau; C Degott; P Maupas; J P Benhamou



Advances in prevention and treatment of hepatic disorders following hematopoietic cell transplantation.  


Development of jaundice is an ominous prognostic sign, whether it occurs early or late in the months following hematopoietic cell transplant. In the first weeks after transplant, the dominant causes of liver injury are Sinusoidal Obstruction Syndrome (toxic damage resulting from myeloablative conditioning regimens) and cholangitis lenta (cholestasis of sepsis). Later after transplant, cholestasis is more commonly caused by acute graft-vs.-host disease and drugs. Hepatic infections have become uncommon because of the use of prophylactic anti-fungal and anti-viral drugs. Treatment of severe liver dysfunction is often futile in this setting, but prevention of liver injury is feasible. Hepatic sinusoidal injury can be prevented by avoiding sinusoidal toxins as part of conditioning therapy in patients at high-risk. Cholestatic liver damage can be minimized by prophylactic use of ursodiol and by careful drug monitoring. Anti-microbial drugs will prevent most fungal liver infections and viral hepatitis caused by herpesviruses and hepatitis B virus. PMID:16516132

McDonald, George B



Detection of Hepatitis in Blood.  

National Technical Information Service (NTIS)

A retrospective study of post transfusion hepatitis (PTH) revealed that 24% of PTH was associated with transfusion of hepatitis B antigen (HBAg) as assayed by radioimmunoassay (RIA) or red cell agglutination (RCA). Asubsequent prospective study revealed t...

G. L. Gitnick



Infected hepatic cyst.  


We describe an unusual case involving an infected hepatic cyst. An 88-year-old woman presented with acute onset of right upper quadrant abdominal pain, mild left lower abdominal pain, diarrhea, and fever. On admission, computed tomography revealed multiple hepatic cysts including an 8-cm cyst located in the left medial segment of the liver, which demonstrated a thickened wall enhanced with contrast media. Ultrasonography showed an 8-cm hypoechoic lesion which differed in appearance from the other, anechoic hepatic cysts. The serum concentration of C-reactive protein was 29.8 mg/dL; white blood cell count, 12,800/microL; CA19-9, 96 U/mL; and CEA, 2.2 ng/mL. Diagnosis of infected hepatic cyst was made by percutaneous transhepatic drainage of the cyst. Milky fluid was obtained and the patient's right upper quadrant abdominal pain resolved after drainage. The cyst fluid CA19-9 concentration was 18,000 U/mL. Cytology of the cyst fluid was negative. Serum CA19-9 (41 U/mL) and CEA (1.8 ng/mL) concentrations were improved 1 week after drainage. Escherichia coli was cultured from the drainage fluid. The patient was discharged 27 days after admission. Percutaneous transhepatic drainage is effective in the treatment of infected hepatic cysts. PMID:12749258

Yoshida, Hiroshi; Onda, Masahiko; Tajiri, Takashi; Mamada, Yasuhiro; Taniai, Nobuhiko; Mineta, Sho; Hirakata, Atsushi; Futami, Ryohei; Arima, Yasuo; Inoue, Matsuoh; Hatta, Shigeo; Kishimoto, Akio


Activation of Tubuloglomerular Feedback in Rat Nephrons by Sera from Rabbits with Fulminant Hepatic Failure  

Microsoft Academic Search

Experiments were designed to determine whether substance(s) other than electrolytes might activate tubuloglomerular feedback in experimental fulminant hepatic failure. Severe hepatic damage and renal dysfunction were induced by intravenous administration of D-galactosamine. Sera from normal or D-galactosamine-treated rabbits were dialyzed against glucose solution to reduce electrolyte concentrations. Tubuloglomerular feedback response was evaluated in rat nephrons by measuring the early proximal

Toshikazu Takabatake; Hiromichí Ohta; Hiromoto Hara; Yoh-ichi Ishida; Yatsugi Noda; Nobu Hattori



The protective mechanism of Yisheng Injection against hepatic ischemia reperfusion injury in mice  

Microsoft Academic Search

AIM: Hepatic ischemia\\/reperfusion injury may cause acute inflammatory, significant organ damage or dysfunction, and remains an important problem for liver transplantation. Our previous in vivo and in vitro studies demonstrated that Yisheng injection (YS), a traditional Chinese medicine, had protective effect on ischemia\\/reperfusion injury. In this study, we examined whether YS had protective effect for hepatic ischemia\\/reperfusion injury and explored

Feng Cheng; You-Ping Li; Jing-Qiu Cheng; Li Feng; Sheng-Fu Li



Alpha-Lipoic Acid Protects against Hepatic Ischemia-Reperfusion Injury in Rats  

Microsoft Academic Search

Background and Aim: To evaluate the protective effect of alpha-lipoic acid in reducing oxidative damage after severe hepatic ischemia\\/reperfusion (IR) injury. Methods: Wistar albino rats were subjected to 45 min of hepatic ischemia, followed by 60 min reperfusion period. Lipoic acid (100 mg\\/kg i.p.) was administered 15 min prior to ischemia and immediately before reperfusion period. At the end of

Ender Dulundu; Yahya Ozel; Umit Topalaoglu; Özer Sehirli; Feriha Ercan; Nursal Gedik



Hepatobiliary excretion of cysteinyl leukotrienes in three experimental models of acute hepatic injury  

Microsoft Academic Search

The acute phase response to chemically-induced organ damage involves inflammation and the production of leukotrienes. The\\u000a liver ordinarily takes up, metabolizes and excretes into bile cysteinyl leukotrienes, but the effect of hepatic injury on\\u000a these processes is unknown. The hepatic uptake and biliary excretion of LTC4 was studied in male Sprague-Dawley rats after exposure to either streptozotocin (45 mg\\/kg iv

H. M. Omar; R. A. Sanders; J. B. Watkins



Hepatic antigen-presenting cells and regulation of liver transplant outcome  

Microsoft Academic Search

In the steady state, hepatic antigen (Ag)-presenting cells (APC) generally dampen systemic inflammatory responses to gut-derived\\u000a Ags. Our studies focus on the role of specific liver APC populations, both non-parenchymal cells (dendritic cells [DC], Kupffer\\u000a cells, and hepatic stellate cells [HSC]) and parenchymal cells, in the molecular regulation of tissue damage (ischemia and\\u000a reperfusion [I\\/R] injury) and immunity following liver

Angus W. ThomsonDavid; David A. Geller; Chandrashekhar Gandhi; Noriko Murase; A. Jake Demetris; Donna Beer-Stolz



Hepatoprotective activity of Tridax procumbens against d-galactosamine\\/lipopolysaccharide-induced hepatitis in rats  

Microsoft Academic Search

The hepatoprotective activity of aerial parts of Tridax procumbens was investigated against d-Galactosamine\\/Lipopolysaccharide (d-GalN\\/LPS) induced hepatitis in rats. d-GalN\\/LPS (300mg\\/kg body weight\\/30?g\\/kg body weight)-induced hepatic damage was manifested by a significant increase in the activities of marker enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase and gamma glutamyl transferase) and bilirubin level in serum and lipids both in serum

Vilwanathan Ravikumar; Kanchi Subramanian Shivashangari; Thiruvengadam Devaki



Inhibitory effect of tetrahydroswertianolin on tumor necrosis factor-?-dependent hepatic apoptosis in mice  

Microsoft Academic Search

We investigated the effect of tetrahydroswertianolin (THS), a hepatoprotective agent from Swertia japonica, on tumor necrosis factor-? (TNF-?)-dependent hepatic apoptosis induced by d-galactosamine (d-GalN) (700 mg\\/kg, i.p.) and lipopolysaccharide (LPS) (10 ?g\\/kg, i.p.) in mice. Apoptotic symptoms were observed at the initial stage of liver damage. By 5 hr after intoxication, hepatic DNA fragmentation had risen to 2123%, with the

Koji Hase; Quanbo Xiong; Purusotam Basnet; Tsuneo Namba; Shigetoshi Kadota



Acute hepatic failure in children.  

PubMed Central

Many diseases may present as acute hepatic failure in the pediatric age group, including viral hepatitis A and B, adverse drug reactions, both toxic and "hepatitic," and inherited metabolic disorders such as tyrosinemia, alpha 1 antitrypsin deficiency, and Wilson's disease. Management is primarily supportive, with care taken to anticipate the known complications of hepatic failure. Few "curative" therapies are known, although attempts at stimulating hepatic regeneration may be helpful. Images FIG. 1 FIG. 3 FIG. 4

Riely, C. A.



New aspects of hepatic fibrosis  

Microsoft Academic Search

Hepatic stellate cells are the major source of extracellular matrix proteins in hepatic fibrosis, including Type I collagen. In response to liver injury, the hepatic stellate cells change from a quiescent to an activated phenotype. This activation process includes a phenotypic change to a myofibroblast-like cell, increased proliferation rate, loss of retinoid stores, increased production of extracellular matrix proteins, chemokines,

David A. Brenner; Tim Waterboer; Sung Kyu Choi; Jeffrey N. Lindquist; Branko Stefanovic; Elmar Burchardt; Mitsui Yamauchi; Andrea Gillan; Richard A. Rippe



Viral hepatitis in the Arctic  

Microsoft Academic Search

Objectives. Summarize research on viral hepatitis in indigenous populations in the Arctic. Study De- sign. Literature review. Methods. Medline search from 1966-2003. Results. High prevalence rates of total hepatitis A antibody of > 50% and of hepatitis B of between 22% in Alaska and 42% in Greenland for total infection and between 3% in Canada and 12% in Siberia for

Brian J McMahon


Natural history of hepatitis C  

Microsoft Academic Search

Ten years after the discovery of the hepatitis C virus (HCV) and its association with NANB hepatitis as a major cause of chronic liver disease worldwide, our knowledge of the natural history of hepatitis C is still limited. The asymptomatic course of the disease in most patients, its slow and silent progression and heterogeneous outcome and the widespread use of

Alfredo Alberti; Liliana Chemello; Luisa Benvegnù



Natural history of hepatitis C  

Microsoft Academic Search

It is now widely accepted that 85% or more of individuals with acute hepatitis C virus (HCV) infection progress to chronic hepatitis, and chronic hepatitis C is a known risk factor for cirrhosis and hepatocellular carcinoma (HCC). However, there has been much controversy about the inevitability of developing cirrhosis and HCC and the time frames in which they are likely

Leonard B Seeff



[Minimal hepatic encephalopathy].  


Minimal hepatic encephalopathy (MHE) is defined by the presence of neurophysiological alterations,with an important impact in the quality of life, in the risk of performing dangerous tasks as leading cars and heavy machinery and increases risk of overt hepatic encephalopathy. MHE is present in a third of cirrhotic depending on liver function. Psychometric and neurophysiologic test are used in the diagnosis of MHE, mainly PHES (Psychometric Hepatic Encephalopathy Score) battery, electroencephalogram, evoked potentials and measurement of the critical flicker frequency. Oral glutamine challenge (OGC) measures intestinal ammonia production after glutamine intake and indirectly intestinal glutaminase activity. Altered OGC in patients with MHE predicts short-time survival. In conclusion,MHE is the first stage in HE syndrome, affect to a third of cirrhotic and worsen quality of life. There are useful and easy-to-use diagnostic tests and new therapeutic options are warranted. PMID:19666316

Jover, M; Hoyas, E; Grande, L; Romero-Gómez, M



Treatments for hepatitis B.  


New optimism surrounds treatments for chronic hepatitis B (CHB). Interferon- alpha , lamivudine, and adefovir dipivoxil are currently approved by the United States Food and Drug Administration for the treatment of CHB. All 3 treatments possess unique characteristics with respect to their side effect profiles, potencies, and treatment niches within the spectrum of CHB. New agents, which are in various stages of clinical development, represent potential improvements within existing, as well as novel, classes of antiviral therapy, and they offer significant promise of a cure for the many patients with chronic and progressive hepatitis B. However, there remain many