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Ethanol-fed Rats (ethanol-fed + rat)
Selected AbstractsDown-regulation of reduced folate carrier may result in folate malabsorption across intestinal brush border membrane during experimental alcoholismFEBS JOURNAL, Issue 24 2007Abid Hamid Folate plays a critical role in maintaining normal metabolic, energy, differentiation and growth status of all mammalian cells. The intestinal folate uptake is tightly and diversely regulated, and disturbances in folate homeostasis are observed in alcoholism, attributable, in part, to intestinal malabsorption of folate. The aim of this study was to delineate the regulatory mechanisms of folate transport in intestinal absorptive epithelia in order to obtain insights into folate malabsorption in a rat model of alcoholism. The rats were fed 1 g·kg,1 body weight of ethanol daily for 3 months. A reduced uptake of [3H]folic acid in intestinal brush border membrane was observed over the course of ethanol administration for 3 months. Folate transport exhibited saturable kinetics and the decreased intestinal brush border membrane folate transport in chronic alcoholism was associated with an increased Km value and a low Vmax value. Importantly, the lower intestinal [3H]folic acid uptake in ethanol-fed rats was observed in all cell fractions corresponding to villus tip, mid-villus and crypt base. RT-PCR analysis for reduced folate carrier, the major folate transporter, revealed that reduced folate carrier mRNA levels were decreased in jejunal tissue derived from ethanol-fed rats. Parallel changes were observed in reduced folate carrier protein levels in brush border membrane along the entire crypt,villus axis. In addition, immunohistochemical staining for reduced folate carrier protein showed that, in alcoholic conditions, deranged reduced folate carrier localization was observed along the entire crypt,villus axis, with a more prominent effect in differentiating crypt base stem cells. These changes in functional activity of the membrane transport system were not caused by a general loss of intestinal architecture, and hence can be attributed to the specific effect of ethanol ingestion on the folate transport system. The low folate uptake activity observed in ethanol-fed rats was found to be associated with decreased serum and red blood cell folate levels, which might explain the observed jejunal genomic hypomethylation. These findings offer possible mechanistic insights into folate malabsorption during alcoholism. [source] Role of endothelin in endotoxin-induced hepatic microvascular dysfunction in rats fed chronically with ethanolJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 8 2001Yoshinori Horie Abstract Background: We examined the role of endothelin in endotoxin-induced hepatic microcirculatory disturbance in pair-fed rats given a liquid diet containing ethanol or isocaloric control. Methods and Results: One lobe of the liver was observed with the use of an intravital microscope. Erythrocytes (RBCs) labeled with fluorescein isothiocyanate (FITC) were injected, and the flow velocity of the FITC-RBCs in the sinusoids was measured with an off-line velocimeter. The flow velocity decreased 30 min after 1 mg/kg of lipopolysaccharide (LPS) was administered to the controls, and portal pressure (PP) was increased at 60 min. In ethanol-fed rats, however, both the flow velocity and PP increased in the early phase (at 10 min), and in the late phase, flow velocity decreased and PP increased more than in the controls. The LPS-induced decrease in flow velocity was blunted, when BQ-123, an antagonist of endothelin receptor subtype A, was infused into ethanol-fed rats, and BQ-123 also attenuated the change in PP. The plasma endothelin levels in both systemic and portal blood of the ethanol-fed rats were higher than in the controls. Conclusions: These results suggest that endothelin plays a role in the LPS-induced hepatic microcirculatory disturbance, especially in alcohol-fed animals. [source] Cholinergic Mediation of Alcohol-Induced Experimental PancreatitisALCOHOLISM, Issue 10 2010Aurelia Lugea Objectives:, The mechanisms initiating pancreatitis in patients with chronic alcohol abuse are poorly understood. Although alcohol feeding has been previously suggested to alter cholinergic pathways, the effects of these cholinergic alterations in promoting pancreatitis have not been characterized. For this study, we determined the role of the cholinergic system in ethanol-induced sensitizing effects on cerulein pancreatitis. Methods:, Rats were pair-fed control and ethanol-containing Lieber-DeCarli diets for 6 weeks followed by parenteral administration of 4 hourly intraperitoneal injections of the cholecystokinin analog, cerulein at 0.5 ,g/kg. This dose of cerulein was selected because it caused pancreatic injury in ethanol-fed but not in control-fed rats. Pancreatitis was preceded by treatment with the muscarinic receptor antagonist atropine or by bilateral subdiaphragmatic vagotomy. Measurement of pancreatic pathology included serum lipase activity, pancreatic trypsin, and caspase-3 activities, and markers of pancreatic necrosis, apoptosis, and autophagy. In addition, we measured the effects of ethanol feeding on pancreatic acetylcholinesterase activity and pancreatic levels of the muscarinic acetylcholine receptors m1 and m3. Finally, we examined the synergistic effects of ethanol and carbachol on inducing acinar cell damage. Results:, We found that atropine blocked almost completely pancreatic pathology caused by cerulein administration in ethanol-fed rats, while vagotomy was less effective. Ethanol feeding did not alter expression levels of cholinergic muscarinic receptors in the pancreas but significantly decreased pancreatic acetylcholinesterase activity, suggesting that acetylcholine levels and cholinergic input within the pancreas can be higher in ethanol-fed rats. We further found that ethanol treatment of pancreatic acinar cells augmented pancreatic injury responses caused by the cholinergic agonist, carbachol. Conclusion:, These results demonstrate key roles for the cholinergic system in the mechanisms of alcoholic pancreatitis. [source] Antioxidant effect of 2-hydroxy-4-methoxy benzoic acid on ethanol-induced hepatotoxicity in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2007Nadana Saravanan Alcoholic liver disease (ALD) is one of the most common diseases in society. A large number of studies are in progress to identify natural substances that are effective in reducing the severity of ALD. 2-Hydroxy-4-methoxy benzoic acid (HMBA), the active principle of Hemidesmus indicus, an indigenous Ayurvedic medicinal plant in India, is expected to significantly inhibit the development of liver injury in ethanol administration. It is expected to reduce the severity of liver damage in terms of body weight, hepatic marker enzymes, oxidative stress, antioxidant status and histological changes in ethanol-induced hepatotoxic rats. Hepatotoxicity was induced by administering 20% ethanol (5 g kg,1 daily) for 60 days to male Wistar rats, which resulted in significantly decreased body weight and an increase in liver-body weight ratio. The liver marker enzymes aspartate transaminase, alanine transaminase, alkaline phosphatase, ,-glutamyl transpeptidase and lactate dehydrogenase were elevated. In addition, the levels of plasma, erythrocyte and hepatic thiobarbituric acid reactive substances, hydroperoxides and conjugated dienes were also elevated in ethanol-fed rats as compared with those of the experimental control rats. Decreased activity of superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, vitamin C and ,-tocopherol was also observed on alcohol administration as compared with experimental control rats. HMBA was co-administered at a dose of 200 ,gkg,1 daily for the last 30 days of the experiment to rats with alcohol-induced liver injury, which significantly increased body weight, significantly decreased the liver-body weight ratio, transaminases, alkaline phosphatase, ,-glutamyl transpeptidase and lactate dehydrogenase, significantly decreased the levels of lipid peroxidative markers, significantly elevated the activity of enzymic and non-enzymic antioxidants in plasma, erythrocytes and liver and also increased levels of plasma and liver vitamin C and ,-tocopherol at the end of the experimental period as compared with untreated ethanol-administered rats. The histological changes were also in correlation with the biochemical findings. The results suggest that HMBA administration may afford protection against ethanol-induced liver injury in rats. [source] Defective Translocation of PKC, in EtOH-Induced Inhibition of Mg2+ Accumulation in Rat HepatocytesALCOHOLISM, Issue 9 2010Lisa M. Torres Background:, Rats chronically fed ethanol for 3 weeks presented a marked decreased in total hepatic Mg2+ content and required approximately 12 days to restore Mg2+ homeostasis upon ethanol withdrawal. This study was aimed at investigating the mechanisms responsible for the EtOH-induced delay. Methods:, Hepatocytes from rats fed ethanol for 3 weeks (Lieber-De Carli diet,chronic model), rats re-fed a control diet for varying periods of time following ethanol withdrawal, and age-matched control rats fed a liquid or a pellet diet were used. As acute models, hepatocytes from control animals or HepG2 cells were exposed to varying doses of ethanol in vitro for 8 minutes. Results:, Hepatocytes from ethanol-fed rats presented a marked inhibition of Mg2+ accumulation and a defective translocation of PKC, to the cell membrane. Upon ethanol withdrawal, 12 days were necessary for PKC, translocation and Mg2+ accumulation to return to normal levels. Exposure of control hepatocytes or HepG2 cells to a dose of ethanol as low as 0.01% for 8 minutes was already sufficient to inhibit Mg2+ accumulation and PKC, translocation for more than 60 minutes. Also in this model, recovery of Mg2+ accumulation was associated with restoration of PKC, translocation. The use of specific antisense in HepG2 cells confirmed the involvement of PKC, in modulating Mg2+ accumulation. Conclusions:, Translocation of PKC, isoform to the hepatocyte membrane is essential for Mg2+ accumulation to occur. Both acute and chronic ethanol administrations inhibit Mg2+ accumulation by specifically altering PKC, translocation to the cell membrane. [source] Decreased Proteasome Activity Is Associated With Increased Severity of Liver Pathology and Oxidative Stress in Experimental Alcoholic Liver DiseaseALCOHOLISM, Issue 8 2004Terrence M. Donohue Jr Background: Because of its role in degrading the bulk of intracellular proteins and eliminating damaged proteins, the proteasome is important in maintaining cell viability. Previously, we showed a 35,40% decrease in proteasome peptidase activity when ethanol was administered to rats by intragastric infusion. We hypothesized that this reduction was caused by ethanol-elicited oxidative stress, the degree of which varies depending on the method of ethanol administration. This study examined the relationship of proteasome activity and content with ethanol-induced oxidative stress and the degree of liver injury. Methods: Rats were given ethanol or isocaloric dextrose-containing liquid diets by intragastric infusion for 1 month. The diets contained medium-chain triglycerides (MCT), palm oil (PO), corn oil (CO), or fish oil (FO) as the principal source of fat. Results: Rats given ethanol and MCT exhibited no significant liver pathology, whereas cumulative pathology scores in ethanol-fed rats given PO, CO, or FO were 2.5, 5.4 and 7.0, respectively, indicating that ethanol and FO caused the greatest liver damage. The severity of liver pathology in the last three groups of animals correlated with levels of lipid peroxides and serum 8-isoprostanes. Alpha smooth muscle actin, an indicator of stellate cell activation, was increased relative to controls in the livers of all ethanol-fed rats except FO-fed animals, in which both control and ethanol-fed rats had similar levels of this protein. In livers of CO and FO ethanol-fed rats, proteasome chymotrypsin-like activity was decreased by 55,60%, but there was no quantitative alteration in 20S proteasome subunit content. In contrast, ethanol affected neither proteasome activity nor its content in MCT- and PO-treated animals. Conclusions: Our findings indicate that the severity of liver injury and ethanol-induced oxidative stress is associated with a reduction in proteasome catalysis. [source] | ||||||||||