Enhanced cyclooxygenase-2 gene expression in alcoholic liver disease in the rat

BACKGROUND & AIMS: Inflammatory stimuli and lipid peroxidation up-regulate cyclooxygenase (COX)-2. This study evaluated the relationship between inflammatory mediators, COX expression, and pathological changes in experimental alcoholic liver disease. METHODS: Rats (5 per group) were fed ethanol and a diet containing saturated fat, corn oil, or fish oil by intragastric infusion. Dextrose isocalorically replaced ethanol in controls. In the first set of experiments, whole livers were analyzed. In the second set of experiments, Kupffer cells, endothelial cells, and hepatocytes were isolated from rats in each group. Pathological analyses and measurements of lipid peroxidation, tumor necrosis factor (TNF)-alpha, COX-1 and COX-2 messenger RNA (mRNA), endotoxin, and liver and plasma thromboxane were performed. RESULTS: Increased expression of COX-2 mRNA was detected in the livers of rats showing necroinflammatory changes. The Kupffer cell was the cell primarily responsible for the increase in COX-2 mRNA level. Increased expression of COX-2 was associated with increased levels of endotoxin, TNF-alpha mRNA, lipid peroxidation, and synthesis of thromboxane. COX-1 mRNA was decreased in Kupffer cells in rats with the most severe liver injury. CONCLUSIONS: Up-regulation of COX-2 in alcoholic liver injury occurred in the presence of proinflammatory stimuli and resulted in increased synthesis of inflammatory and vasoactive eicosanoids. Down-regulation of COX-1 may result in decreased synthesis of cytoprotective eicosanoids and additionally exacerbate liver injury.     

The 21-aminosteroid 16-desmethyl tirilazad mesylate prevents necroinflammatory changes in experimental alcoholic liver disease

Previous studies have shown that the room temperature photocycle of the photoactive yellow protein (PYP) from Ectothiorhodospira halophila involves at least two intermediate species: I1, which forms in <10 ns and decays with a 200-micros lifetime to I2, which itself subsequently returns to the ground state with a 140-ms time constant at pH 7 (Genick et al. 1997. Biochemistry. 36:8-14). Picosecond transient absorption spectroscopy has been used here to reveal a photophysical relaxation process (stimulated emission) and photochemical intermediates in the PYP photocycle that have not been reported previously. The first new intermediate (I0) exhibits maximum absorption at approximately 510 nm and appears in 相似文献   

Ethanol-induced changes in membrane ATPases: inhibition by iron chelation

The authors present the case of a 49-year-old man with an isolated malformation of the left cervical facet joint at C5-6, with secondary spondylarthrotic hypertrophy of the joint leading to involvement of the C-6 nerve root. The etiology of this cervical joint malformation is discussed.     

Free radical formation during ketamine anesthesia in rats: a cautionary note

The small subunit ribosomal RNA (SSU rRNA) genes of hippoboscid (Ornithoica vicina Walker) and tabanid (Chrysops niger Macquart) Diptera were sequenced to determine their phylogenetic position within the order and to determine whether or not extensive hypervariable regions in this gene are widespread in the Diptera. A parsimony analysis of an alignment containing 8 dipteran sequences produced a single most parsimonious tree that placed O. vicina as sister group to Drosophila melanogaster Meigen. The tabanid Chrysops niger was sister group to the asilomorphan taxa, and the sister group to the Brachycera was a Tipula sp. although this relationship was not supported by bootstrap analysis. The hippoboscid and tabanid sequences contain extensive hypervariable regions in the V2, V4, V6, and V7 regions as do other Diptera. When these regions of the alignment were excluded from the phylogenetic analysis, a single most parsimonious tree was found. This tree had an identical overall topology to the tree obtained from the total data set. The hypervariable regions in parts of the dipteran SSU rRNA genes were more extensive in the nematocerous dipteran sequences used in this study than in the other dipteran representatives; these hypervariable regions may be of more utility in inferring relationship among species and subspecies than at the suprageneric level.     

Genetic mapping of the copper toxicosis locus in Bedlington terriers to dog chromosome 10, in a region syntenic to human chromosome region 2p13-p16

Abnormal hepatic copper accumulation is recognized as an inherited disorder in man, mouse, rat and dog. The major cause of hepatic copper accumulation in man is a dysfunctional ATP7B gene, causing Wilson disease (WD). Mutations in the ATP7B genes have also been demonstrated in mouse and rat. The ATP7B gene has been excluded in the much rarer human copper overload disease non-Indian childhood cirrhosis, indicating genetic heterogeneity. By investigating the common autosomal recessive copper toxicosis (CT) in Bedlington terriers, we have identified a new locus involved in progressive liver disease. We examined whether the WD gene ATP7B was also causative for CT by investigating the chromosomal co-localization of ATP7B and C04107, using fluorescence in situ hybridization (FISH). C04107 is an anonymous microsatellite marker closely linked to CT. However, BAC clones containing ATP7B and C04107 mapped to the canine chromosome regions CFA22q11 and CFA10q26, respectively, demonstrating that WD cannot be homologous to CT. The copper transport genes CTR1 and CTR2 were also excluded as candidate genes for CT since they both mapped to canine chromosome region CFA11q22. 2-22.5. A transcribed sequence identified from the C04107-containing BAC was found to be homologous to a gene expressed from human chromosome 2p13-p16, a region devoid of any positional candidate genes.     

Fatty acid omega- and (omega-1)-hydroxylation in experimental alcoholic liver disease: relationship to different dietary fatty acids

Arachidonic acid concentrations in liver are decreased in response to ethanol administration. In addition, the oxygenated products of arachidonic acid metabolites could affect the severity of alcoholic liver injury. Selective utilization of arachidonic acid by the cytochrome P-450 system could, in part, account for the decrease in arachidonic acid. To evaluate this pathway further, male Wistar rats were fed different dietary fats: medium chain triglycerides, palm oil, and corn oil or fish oil with either ethanol or isocaloric amounts of dextrose. Histopathology, cytochrome P-4502E1 (CYP2E1) and cytochrome P-4504A (CYP4A), and omega- and (omega-1)-hydroxylation products of lauric and arachidonic acids were evaluated. Ethanol induction of CYP2E1 was related to the concentration of polyunsaturated fatty acids in the diet; induction of CYP4A by ethanol was seen in all groups. The highest levels of 11-hydroxy-lauric acid and 19-hydroxyarachidonic acid (omega-1) were seen in rats fed ethanol with palm oil and corn oil. Highly significant correlations were seen between the (omega-1)-hydroxylation products and CYP2E1 activity. No correlation was seen between the omega-hydroxylation products and CYP2E1 activity. In contrast, the levels of omega-hydroxylation products correlated with CYP4A. The overall results showed a significant increase in (omega-1)-hydroxylation products in rats fed diets containing significant amounts of linoleic acid (i.e., palm oil and corn oil).     

High-dose vitamin E supplementation has no effect on ethanol-induced pathological liver injury

The effect of alpha-tocopherol (alpha-T) supplementation on ethanol-induced liver damage was studied. The intragastric feeding rat model was used in this study. Both normal and alpha-T supplemented animals (3125 IU/kg body weight) were fed liquid diet and ethanol for 1 mo. In pair-fed animals, ethanol was isocalorically replaced by dextrose. The blood ethanol level in the ethanol-fed groups was between 150 to 350 mg/dl. Lipid peroxidation was assessed by measuring liver thiobarbituric acid reactive substances (TBARS) and conjugated dienes. Liver damage was assessed by light microscopy. Overall, chronic ethanol treatment resulted in increase in TBARS and conjugated dienes in both normal (60% and 35%, P < .01, respectively) and alpha-T-supplemented groups (50% and 47%, P < .01, respectively). In animals receiving either dextrose or ethanol and regular diet, there was a significant inverse correlation between liver alpha-T and TBARS (r = 0.88, P < 0.01) and conjugated dienes (r = -0.75, P < .05). In contrast, in the vitamin E-supplemented rats, a significant positive correlation was observed between liver alpha-T, TBARS (r = 0.78, P < .01) and conjugated dienes (r = 0.87, P < .01). Of major significance is that alpha-T supplementation had no effect on ethanol-induced pathological changes in the liver. In conclusion, these results show that in the intragastric feeding model, alpha-T supplementation had no protective effect on ethanol-induced liver damage.