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Abstracts

Liver Cirrhosis

ABSTRACTS

Hepatoprotective activity of polyphenolic compounds from Cynara scolymnus against CCl4 toxicity in isolated rat hepatocytes.

Adzet T, Camarasa J, Laguna JC. Departamento de Farmacognosia y Farmacodinamia, Facultad de Farmacia, Nucleo Universitario de Pedralbes, Barcelona, Spain.

J Nat Prod. 1987 Jul-Aug;50(4):612-7

The hepatoprotective activity against CCl4 toxicity in isolated rat hepatocytes of some polyphenolic compounds, such as cynarin, isochlorogenic acid, chlorogenic acid, luteolin-7-glucoside, and two organic acids, caffeic and quinic, from Cynara scolymus, is tested. Only cynarine and, to a lesser extent, caffeic acid showed cytoprotective action. The possible relationship between the molecular structure and the protective effect found is discussed.

Preventive effect of malotilate on carbon tetrachloride-induced liver damage and collagen accumulation in the rat.

Ala-Kokko L, Stenback F, Ryhanen L. Collagen Research Unit, Biocenter, Oulu, Finland.

Biochem J. 1987 Sep 1;246(2):503-9

Malotilate is a new drug suggested for use in chronic liver diseases. It is shown here to prevent liver damage caused by CCl4. The concomitant administration of malotilate with CCl4 significantly decreased hydroxyproline accumulation in the liver, liver prolyl 4-hydroxylase and liver and serum galactosylhydroxylysyl glucosyltransferase activities. However, it had no effect on the daily urinary hydroxyproline excretion or the hydroxyproline content of the skin, liver or lungs in normal young growing rats. It also had no specific inhibitory effect on hydroxyproline synthesis or secretion in fibroblast cultures, and did not affect the amount of procollagen-alpha 1(I)-specific mRNAs in these cultures. Thus it seems to have no direct inhibitory effect on collagen metabolism. In addition to inhibition of liver collagen accumulation, malotilate was also able to prevent the development of morphological changes in the liver such as focal necrosis, fatty infiltration and inflammatory changes. It also normalized almost completely the standard liver-function tests. It is possible that malotilate may prevent excessive collagen deposition by inhibiting the inflammation caused by CCl4-induced liver damage.

Preventive effect of malotilate on dimethylnitrosamine-induced liver fibrosis in the rat.

Ala-Kokko L, Stenback F, Ryhanen L. Department of Medical Biochemistry, University of Oulu, Finland.

J Lab Clin Med. 1989 Feb;113(2):177-83

Dimethylnitrosamine-induced liver damage, which leads to hepatic failure and death of the animal, was prevented by treatment with malotilate. The accumulation of collagen and the morphologic changes caused by dimethylnitrosamine, such as inflammatory cell accumulation and fibrosis, were also prevented by this drug. Malotilate drastically reduced the increases in the amount of type I procollagen alpha 2-chain mRNA and activities of the enzymes prolyl 4-hydroxylase and galactosylhydroxylysyl glucosyltransferase, which are early events in liver fibrosis preceding the deposition of collagen. Even when started 14 days after dimethylnitrosamine induction, malotilate treatment was able to reduce liver damage. We suggest that the effect of malotilate is a result of the inhibition of inflammation.

Polyenylphospha-tidylcholine prevents carbon tetrachloride-induced lipid peroxidation while it attenuates liver fibrosis.

Aleynik SI, Leo MA, Ma X, Aleynik MK, Lieber CS. Alcohol Research Center, Veternas Affairs Medical Center, Bronx, New York 10468, USA.

J Hepatol. 1997 Sep;27(3):554-61

BACKGROUND/AIMS: Polyenylphosphatidylcholine protects against alcoholic cirrhosis in the baboon and carbon tetrachloride-induced cirrhosis in rats. This study addresses the possible mechanism of the protective effect of polyenylphosphatidylcholine.

METHODS: For 8 weeks, rats were injected with either carbon tetrachloride in peanut oil or peanut oil alone (control), and pair-fed nutritionally adequate liquid diets with equivalent amounts of linoleic acid either as polyenylphosphatidylcholine or as safflower oil. Other rats were injected for 9 weeks with heterologous albumin and fed the same liquid diets. Lipid peroxidation was measured by F2-isoprostanes and 4-hydroxynonenal.

RESULTS: Carbon tetrachloride-induced lipid peroxidation was strikingly attenuated with polyenylphosphatidylcholine supplementation. Levels of hepatic F2-isoprostanes and 4-hydroxynonenal paralleled liver fibrotic scores and collagen accumulation. Polyenylphosphatidylcholine also attenuated the fibrosis induced in rats with human albumin, but in this case, levels of hepatic 4-hydroxynonenal did not change, nor were they significantly affected by polyenylphos-phatidylcholine. Neither carbon tetrachloride injection nor polyenylphosphatidylcholine treatment changed the arachidonic acid content (a major precursor of F2-isoprostanes and 4-hydroxynonenal) in liver phospholipids, and hepatic vitamin E was not significantly altered.

CONCLUSIONS: The hepatic protection of polyenylphosphatidylcholine against carbon tetrachloride appears to be due, at least in part, to an antioxidant effect, whereas the protection against heterologous albumin-induced fibrosis suggests that an additional mechanism, such as stimulation of collagenase activity, may also be responsible.

Gallstones: A National Health Problem

ALF.

2002. New York: American Liver Foundation.

Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease.

Alter, M.J., Margolis, H.S., Bell, B.P. et al.

MMWR 1998 Sep 16; 47(RR-19): 1-39.

No Abstract Available

Nutritional support of the pediatric surgical patient.

Amii LA, Moss RL. Division of Pediatric Surgery, Stanford University School of Medicine, Packard Children's Hospital, Palo Alto, CA 94304, USA.

Curr Opin Pediatr. 1999 Jun;11(3):237-40

This review discusses the important developments in pediatric surgical nutrition over the past year. Sepsis and total parenteral nutrition-associated cholestasis remain complex problems for patients on total parenteral nutrition. Investigations suggest that total parenteral nutrition may compromise bactericidal activity, increasing the risk of sepsis. Sepsis possibly sensitizes the liver to cholestatic injury. Small volume enteral feeds may restore immune system function. Current research does not support an association between phytosterols in parenteral lipid solutions and total parenteral nutrition-associated cholestasis. Methionine has been identified as a potential hepatotoxin. Ursodeoxycholic acid and S-adenosyl-L-methionine are the most promising treatments of total parenteral nutrition-associated cholestasis. Small bowel transplant is now a reasonable option for patients with irreversible intestinal failure. Patient and graft survival rates have improved with FK-506 (Tacrolimus) immunosuppression. Isolated intestinal grafts have the best survival rate (92% at 1 year). Most surviving graft recipients are weaned off of total parenteral nutrition. The Cox Proportional Hazard model may help to identify candidates for small bowel transplant. This equation predicts the duration of dependence on total parenteral nutrition. Patients with irreversible intestinal failure can then be referred for early small bowel transplantation.

Holistic Health Encyclopedia

Anon.

2002. Oakford, PA: Telstar Innovations.

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

Arend A, Zilmer M, Vihalemm T, Selstam G, Sepp E. Department of Anatomy, University of Tartu, Estonia. arend@ut.ee

Ann Nutr Metab. 2000;44(5-6):217-22

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

Taurine has a protective effect against thioacetamide-induced liver cirrhosis by decreasing oxidative stress.

Balkan J, Dogru-Abbasoglu S, Kanbagli O, Cevikbas U, Aykac-Toker G, Uysal M. Department of Biochemistry, Istanbul Medical Faculty, University of Istanbul, Capa, Turkey.

Hum Exp Toxicol. 2001 May;20(5):251-4

Thioacetamide (TAA) administration (0.3 g/l of tap water for a period of 3 months) to rats resulted in hepatic cirrhosis as assessed by biochemical and histopathological findings. This treatment caused an increase in the levels of malondialdehyde (MDA) and diene conjugates (DCs) and a decrease in the levels of glutathione (GSH), vitamin E, vitamin C and the activities of glutathione peroxidase (GSH-Px) in the liver of rats. Superoxide dismutase (SOD) activities were unchanged. Taurine (2% w/w, added to the chow diet) was administered together with TAA (0.3 g/l of drinking water) for 3 months. Taurine was found to decrease TAA-induced hepatic lipid peroxidation and to increase TAA-depleted vitamin E levels and GSH-Px activities. Histopathological findings also suggested that taurine has an inhibitive effect on TAA-induced hepatic cirrhosis. These results indicate that taurine treatment has a protective effect against TAA-induced liver cirrhosis by decreasing oxidative stress.

Double-blind trial of silymarin vs. placebo in the treatment of chronic hepatitis.

Berenguer, J. et al.

Munch. Med. Wochenschr. 1977; 119: 240 60.

No Abstract Available

The pharmacology of the antioxidant lipoic acid.

Biewenga GP, Haenen GR, Bast A. Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, Department of Pharmacochemistry, The Netherlands.

Gen Pharmacol. 1997 Sep;29(3):315-31

Lipoic acid is an example of an existing drug whose therapeutic effect has been related to its antioxidant activity. 2. Antioxidant activity is a relative concept: it depends on the kind of oxidative stress and the kind of oxidizable substrate (e.g., DNA, lipid, protein). 3. In vitro, the final antioxidant activity of lipoic acid is determined by its concentration and by its antioxidant properties. Four antioxidant properties of lipoic acid have been studied: its metal chelating capacity, its ability to scavenge reactive oxygen species (ROS), its ability to regenerate endogenous antioxidants and its ability to repair oxidative damage. 4. Dihydrolipoic acid (DHLA), formed by reduction of lipoic acid, has more antioxidant properties than does lipoic acid. Both DHLA and lipoic acid have metal-chelating capacity and scavenge ROS, whereas only DHLA is able to regenerate endogenous antioxidants and to repair oxidative damage. 5. As a metal chelator, lipoic acid was shown to provide antioxidant activity by chelating Fe2+ and Cu2+; DHLA can do so by chelating Cd2+. 6. As scavengers of ROS, lipoic acid and DHLA display antioxidant activity in most experiments, whereas, in particular cases, pro-oxidant activity has been observed. However, lipoic acid can act as an antioxidant against the pro-oxidant activity produced by DHLA. 7. DHLA has the capacity to regenerate the endogenous antioxidants vitamin E, vitamin C and glutathione. 8. DHLA can provide peptide methionine sulfoxide reductase with reducing equivalents. This enhances the repair of oxidatively damaged proteins such as alpha-1 antiprotease. 9. Through the lipoamide dehydrogenase-dependent reduction of lipoic acid, the cell can draw on its NADH pool for antioxidant activity additionally to its NADPH pool, which is usually consumed during oxidative stress. 10. Within drug-related antioxidant pharmacology, lipoic acid is a model compound that enhances understanding of the mode of action of antioxidants in drug therapy.

The Miracle Nutrient: Coenzyme Q10

Bliznakov, E.G.

1987. New York: Bantam.

Effect of the flavanolignans of Silybum marianum L. on lipid peroxidation in rat liver microsomes and freshly isolated hepatocytes.

Bosisio E, Benelli C, Pirola O. Institute of Pharmacological Sciences, Faculty of Pharmacy, University of Milan, Italy.

Pharmacol Res. 1992 Feb-Mar;25(2):147-54

The effect of several flavanolignans (silicristin, silidianin, silybin and isosilybin) present in silymarin, the extract of Silybum marianum fruits, was tested on lipid peroxidation in rat liver microsomes and freshly isolated hepatocytes. In microsomes lipid peroxidation was generated by ADP/Fe2+ and NADPH. All flavanolignans inhibited peroxidation in a concentration dependent manner. In hepatocytes lipid peroxidation was induced by ADP/Fe3+ complex and cell damage was evaluated as LDH activity released in the medium. The inhibition of the peroxidative process by flavanolignans was also evident in this model, even if with a potency order different from that found in microsomes. In contrast, the effect on LDH release was significant only for silybin and isosilybin, the other compounds being inactive on this parameter.

Hepatitis C.

Buggs, A.M.

eMed. J. 2002 April 26 (http://www.emedicine.com/aaem/topic247.htm).

Lecithin and choline in human health and disease.

Canty DJ, Zeisel SH. Department of Nutrition, Food, and Hotel Management at New York University, NY.

Nutr Rev. 1994 Oct;52(10):327-39

Choline is involved in methyl group metabolism and lipid transport and is a component of a number of important biological compounds including the membrane phospholipids lecithin, sphingomyelin, and plasmalogen; the neurotransmitter acetylcholine; and platelet activating factor. Although a required nutrient for several animal species, choline is not currently designated as essential for humans. However, recent clinical studies show it to be essential for normal liver function. Additionally, a large body of evidence from the fields of molecular and cell biology shows that certain phospholipids play a critical role in generating second messengers for cell membrane signal transduction. This process involves a cascade of reactions that translate an external cell stimulus such as a hormone or growth factor into a change in cell transport, metabolism, growth, function, or gene expression. Disruptions in phospholipid metabolism can interfere with this process and may underlie certain disease states such as cancer and Alzheimer's disease. These recent findings may be appropriate in the consideration of choline as an essential nutrient for humans.

Severe recurrent hepatic encephalopathy that responded to oral branched chain amino acids.

Chalasani N, Gitlin N. Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Am J Gastroenterol. 1996 Jun;91(6):1266-8

Hepatic encephalopathy is a neuropsychiatric syndrome occurring in patients with acute or chronic liver disease. Its pathogenesis remains unclear; however, it appears to be multifactorial. There are several conventional treatments for this condition, such as lactulose, neomycin, and protein restriction. There is significant controversy regarding the role of branched chain amino acids in the treatment of chronic hepatic encephalopathy. We describe a patient who had hepatic encephalopathy secondary to Budd-Chairi syndrome and a mesoatrial shunt that failed vigorous conventional therapy. She required multiple hospitalizations for severe recurrent encephalopathy. The patient was considered for a colonic exclusion procedure for the management of intractable encephalopathy. However, branched amino acid therapy was instituted as a last measure before the contemplated surgery, and the patient's encephalopathy responded in dramatic fashion, and she remained free from encephalopathy during a prolonged follow-up.

The American Medical Association Encyclopedia of Medicine

Clayman, C.B.

1989. New York: Random House.

Early diagnosis and treatment of hepatocellular carcinoma.

Columbo, M.

Leadership Medica 2001 Jan (http://info@leadershipmedica.com).

Alpha-Lipoic acid protects against hemolysis of human erythrocytes induced by peroxyl radicals.

Constantinescu A, Tritschler H, Packer L. Department of Molecular and Cell Biology, University of California Berkeley 94720.

Biochem Mol Biol Int. 1994 Jul;33(4):669-79

The azo initiator of peroxyl radicals 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) induces oxidative hemolysis in human erythrocytes and subsequent hemoglobin oxidation. Using the degree of hemolysis versus time as an indication of the oxidative damage it was found that i) both reduced and oxidized alpha-lipoic acid protected against oxidative damage; ii) simultaneous treatment of erythrocytes with ascorbate and dihydrolipoate or alpha-lipoate has a synergistic tendency to protect cells against hemolysis; iii) glutathione in combination with dihydrolipoic acid or alpha-lipoic acid has an additive effect on hemolysis protection. The spin trapping reagent 5,5-dimethyl-1-pyrroline N-oxide (DMPO) formed an adduct with the peroxyl/alkoxyl radicals produced by thermal decomposition of AAPH in the presence of oxygen. The formation of this adduct was prevented by reduced or oxidized lipoic acid, reduced glutathione or ascorbate. It is concluded that AAPH-peroxyl radicals progressively damage the cells and the released hemoglobin is subsequently oxidized to methemoglobin which might further enhance the oxidative damage. The protective effect of antioxidants is exerted outside the cells by directly scavenging AAPH-alkoxyl radicals.

Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey.

Conte D, Fraquelli M, Fornari F, Lodi L, Bodini P, Buscarini L. IRCCS Maggiore Hospital, Milan, Italy. Gastrbia@imiucca.csi.unimi.it

Arch Intern Med. 1999 Jan 11;159(1):49-52

BACKGROUND: Increased gallstone prevalence and incidence in cirrhosis have already been reported in different series, including a limited number of patients with cirrhosis.

OBJECTIVE: To evaluate the frequency of gallstones and related risk factors in a large series of patients with cirrhosis.

PATIENTS AND METHODS: The cross-sectional study involved 1010 patients with cirrhosis related to alcohol abuse, chronic viral infection, or miscellaneous causes (42%, 48%, and 10%, respectively) in Child class A, B, or C (48%, 36%, and 16%, respectively). In the longitudinal study gallstone development was monitored ultrasonographically in 618 patients free of gallstones at enrollment.

RESULTS: The overall prevalence of gallstone(s) was 29.5% and increased significantly with age without differences according to sex or cause of cirrhosis. Multiple logistic regression analysis showed that only Child classes B and C were significantly related to a higher risk of gallstone (odds ratio, 1.63 for class C vs class A and 1.91 for class B vs class A; P = .001). During a mean+/-SD follow-up of 50 months+/-9 months, 141 (22.8%) of 618 patients developed gallstone(s), with an estimated cumulative probability of 6.5%, 18.6%, 28.2%, and 40.9% at 2, 4, 6, and 8 years, respectively. Multivariate analysis showed that Child class (hazard ratio, 2.8 for class C vs class A and 1.8 for class B vs class A; P = .002 and P = .001, respectively) and high-body mass index (hazard ratio, 1.31; P = .04) carried a significantly greater risk of gallstone formation.

CONCLUSION: Cirrhosis per se represents a major risk factor for gallstones whose prevalence and incidence were far higher than those reported in a general population from the same area.

Who gets alcoholic liver disease: nature or nurture?

Day CP. Newcastle upon Tyne and Freeman Hospital. c.p.day@ncl.ac.uk

J R Coll Physicians Lond. 2000 Nov-Dec;34(6):557-62

The factors determining why fewer than 10% of drinkers develop advanced alcoholic liver disease remain largely unknown. There is a weak relationship between disease risk and the dose and pattern of alcohol consumed. Obesity increases the risk of all stages of alcoholic liver disease, probably reflecting the role of steatosis in the pathogenesis of more advanced disease. Women develop disease at a lower intake than men due, in part, to their lower volume of distribution for alcohol, but also potentially to increased gut permeability to endotoxin. Recent studies suggest a non-gender-linked genetic component to disease susceptibility and recent case-control studies have suggested that polymorphisms of genes encoding cytokines and other immunoregulatory molecules may exert a significant effect. The pattern of polymorphisms associated with risk suggests that antibody-mediated mechanisms play a role in disease pathogenesis. This has implications for treatment and for identifying high risk individuals at an early stage.

The effects of silymarin on experimental phalloidine poisoning.

Desplaces A, Choppin J, Vogel G, Trost W.

Arzneimittelforschung. 1975 Jan;25(1):89

The hepatoprotective action of silymarin, the active principle extracted from the fruit of Silybum marianum (L.) Gaertn., in animals (dogs, rabbits, rats, mice) intoxicated with phalloidine is evident, both after protective and curative treatment. A dose of 15 mg/kg of silymarin protects every animal when given 60 min before the toxin. When injected 10 mim after phalloidine, a dose of 100 mg/kg of silymarin again provides total protection. However, as the time span between administration of the toxic substance and start of treatment increases, so the efficacy of silymarin decreases; after 30 min its curative effect is negligible. The histochemical and histoenzymological studies show that during intoxication of the mice by phalloidine, silymarin inhibits the effect of the toxic substance and regulates the functions of the hepatocyte, when given either 60 min before or 10 min after phalloidine.

Protective effect of N-acetylcysteine on rat liver cell membrane during methanol intoxication.

Dobrzynska I, Skrzydlewska E, Kasacka I, Figaszewski Z. Institute of Chemistry, University in Bialystok, Poland.

J Pharm Pharmacol. 2000 May;52(5):547-52

Methanol is oxidized in-vivo to formaldehyde and then to formate, and these processes are accompanied by the generation of free radicals. We have studied the effect of N-acetylcysteine on liver cell membrane from rats intoxicated with methanol (3.0 g kg(-1)). Evaluation of the effect was achieved by several methods. Lipid peroxidation and surface charge density were measured. An ultrastructural study of the liver cells was undertaken. The concentration of marker enzymes of liver damage (alanine aminotransferase and aspartate aminotransferase) in blood serum was measured. Methanol administration caused an increase in lipid peroxidation products (approximately 30%) as well as in surface charge density (approximately 60%). This might have resulted in the membrane liver cell damage visible under electron microscopy and a leak of alanine aminotransferase and aspartate aminotransferase into the blood (increase of approximately 70 and 50%, respectively). Ingestion of N-acetylcysteine with methanol partially prevented these methanol-induced changes. Compared with the control group, lipid peroxidation was increased by approximately 3% and surface charge density by approximately 30%. Alanine aminotransferase and aspartate aminotransferase activity increased by 9 and 8%, respectively, compared with the control group. The results suggested that N-acetylcysteine was an effective antioxidant in methanol intoxication. It may have efficacy in protecting free radical damage to liver cells following methanol intoxication.

Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver.

Ferenci P, Dragosics B, Dittrich H, Frank H, Benda L, Lochs H, Meryn S, Base W, Schneider B. 1st Department of Gastroenterology and Hepatology, University of Vienna, Austria.

J Hepatol. 1989 Jul;9(1):105-13

Silymarin, the active principle of the milk thistle Silybum marianum, protects experimental animals against various hepatotoxic substances. To determine the effect of silymarin on the outcome of patients with cirrhosis, a double blind, prospective, randomized study was performed in 170 patients with cirrhosis. 87 patients (alcoholic 46, non-alcoholic 41; 61 male, 26 female; Child A, 47; B, 37; C, 3; mean age 57) received 140 mg silymarin three times daily. 83 patients (alcoholic 45, non-alcoholic 38; 62 male, 21 female; Child A, 42; B, 32; C, 9: mean age 58) received a placebo. Non-compliant patients and patients who failed to come to a control were considered as 'drop outs' and were withdrawn from the study. All patients received the same treatment until the last patient entered had finished 2-years of treatment. The mean observation period was 41 months. There were 10 drop outs in the placebo group and 14 in the treatment group. In the placebo group, 37 (+2 drop outs) patients had died, and in 31 of these, death was related to liver disease. In the treatment group, 24 (+4 drop outs) had died, and in 18 of these, death was related to liver disease. The 4-year survival rate was 58 +/- 9% (S.E.) in silymarin-treated patients and 39 +/- 9% in the placebo group (P = 0.036). Analysis of subgroups indicated that treatment was effective in patients with alcoholic cirrhosis (P = 0.01) and in patients initially rated 'Child A' (P = 0.03). No side effects of drug treatment were bserved.(ABSTRACT TRUNCATED AT 250 WORDS)

Motonuclear changes after cranial nerve injury and regeneration.

Fernandez E, Pallini R, Lauretti L, La Marca F, Scogna A, Rossi GF. Center for Research in Regeneration of the Nervous System, Catholic University Medical School, Rome, Italy.

Arch Ital Biol. 1997 Sep;135(4):343-51

Little is known about the mechanisms at play in nerve regeneration after nerve injury. Personal studies are reported regarding motonuclear changes after regeneration of injured cranial nerves, in particular of the facial and oculomotor nerves, as well as the influence that the natural molecule acetyl-L-carnitine (ALC) has on post-axotomy cranial nerve motoneuron degeneration after facial and vagus nerve lesions. Adult and newborn animal models were used. Massive motoneuron response after nerve section and reconstruction was observed in the motonuclei of all nerves studied. ALC showed to have significant neuroprotective effects on the degeneration of axotomized motoneurons. Complex quantitative, morphological and somatotopic nuclear changes occurred that sustain new hypotheses regarding the capacities of motoneurons to regenerate and the possibilities of new neuron proliferation. The particularities of such observations are described and discussed.

Protective antioxidant effect of vitamins C and E in streptozotocin induced diabetic rats.

Garg MC, Bansal DD. Department of Biochemistry, Panjab University, Chandigarh 160 014, India.

Indian J Exp Biol. 2000 Feb;38(2):101-4

We have investigated the protective effect of vitamin C and E together supplementation on oxidative stress and antioxidant enzyme activities in the liver of streptozotocin-induced diabetic rats, unsupplemented diabetic and control rats. We also determined the levels of both the vitamins and oxidative stress in plasma. Vitamin supplementation in diabetic rats lowered plasma and liver lipid peroxidation, normalised plasma vitamin C levels and raised vitamin E above normal levels. In liver, the activity of glutathione peroxidase was raised significantly and that of glutathione-S-transferase was normalised by vitamin supplementation in diabetic rats. The levels of lipid peroxidation products in plasma and liver of vitamin-supplemented diabetic rats and activities of antioxidant enzymes in liver suggest that these vitamins reduce lipid peroxidation by quenching free radicals.

Artischockenblatterextrakt: in vitro Nachweis einer Hemmwirkung auf die cholesterin-Biosynthese.

Gebhardt, R.

Med. Welt. 1995; 46: 393 5.

No Abstract Available

Protective effect of exogenous coenzyme Q in rats subjected to partial hepatic ischemia and reperfusion.

Genova ML, Bonacorsi E, D'Aurelio M, Formiggini G, Nardo B, Cuccomarino S, Turi P, Pich MM, Lenaz G, Bovina C. Department of Biochemistry G. Moruzzi, University of Bologna, Italy.

Biofactors. 1999;9(2-4):345-9

In a surgical model of liver ischemia lipid peroxidation occurs, as shown by increase of lipid peroxidation end products, endogenous CoQ9 is oxidized and mitochondrial respiration is lowered; however, pre-treatment of the rats by i.p. injection of CoQ10 for 14 days normalizes the above parameters, presumably by way of the observed high extent of reduction of the incorporated quinone; moreover, liver homogenates of the CoQ10-treated rats are more resistant than those of non-treated rats to oxidative stress induced by an azido free radical initiator. This preliminary study suggests that CoQ10 pre-treatment can be of beneficial effect against oxidative damage during liver surgery transplantation.

Mosby Medical Encyclopedia, Revised Edition 1996.

Glanze, W.D.

St. Louis, MO: C.V. Mosby.

The genetics of alcoholism.

Gordis, E.

Alcohol Alert (No. 18 PH 357) 1992 Jul (updated 2000 Oct). Bethesda, MD: National Institute on Alcohol Abuse and Alcoholism/Public Health Service/National Institutes of Health.

Hydrazine sulfate: is it an anticancer agent?

Green, S.

The Scientific Review of Alternative Medicine 1997 Fall/Winter. Amherst, NY: Prometheus Books.

Acetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity.

Hagen TM, Ingersoll RT, Wehr CM, Lykkesfeldt J, Vinarsky V, Bartholomew JC, Song MH, Ames BN. Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.

Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9562-6

Mitochondrial function and ambulatory activity were monitored after feeding old rats acetyl-L-carnitine (ALCAR). Young (3-5 mo) and old (22-28 mo) rats were given a 1.5% (wt/vol) solution of ALCAR in their drinking water for 1 mo, were sacrificed, and their liver parenchymal cells were isolated. ALCAR supplementation significantly reverses the age-associated decline of mitochondrial membrane potential, as assessed by rhodamine 123 staining. Cardiolipin, which declines significantly with age, is also restored. ALCAR increases cellular oxygen consumption, which declines with age, to the level of young rats. However, the oxidant production per oxygen consumed, as measured by 2',7'-dichlorofluorescin fluorescence levels, is approximately 30% higher than in untreated old rats. Cellular glutathione and ascorbate levels were nearly 30% and 50% lower, respectively, in cells from ALCAR-supplemented old rats than in untreated old rats, further indicating that ALCAR supplementation might increase oxidative stress. Ambulatory activity in young and old rats was quantified as a general measure of metabolic activity. Ambulatory activity, defined as mean total distance traveled, in old rats is almost 3-fold lower than in young animals. ALCAR supplementation increases ambulatory activity significantly in both young and old rats, with the increase being larger in old rats. Thus, ALCAR supplementation to old rats markedly reverses the age-associated decline in many indices of mitochondrial function and general metabolic activity, but may increase oxidative stress.

Mitochondrial decay in aging. Reversal through supplementation of acetyl-L-carnitine and N-tert-butyl-alpha-phenyl-nitrone.

Hagen TM, Wehr CM, Ames BN. Department of Molecular and Cell Biology, University of California at Berkeley 94720, USA. tory.hagen@orst.edu

Ann N Y Acad Sci. 1998 Nov 20;854:214-23

We show that mitochondrial function in the majority of hepatocytes isolated from old rats (24 mo) is significantly impaired. Mitochondrial membrane potential, cardiolipin levels, respiratory control ratio, and overall cellular O2 consumption decline, and the level of oxidants increases. To examine whether dietary supplementation of micronutrients that may have become essential with age could reverse the decline in mitochondrial function, we supplemented the diet of old rats with 1% (w/v) acetyl-L-carnitine (ALCAR) in drinking water. ALCAR supplementation (1 month) resulted in significant increases in cellular respiration, mitochondrial membrane potential, and cardiolipin values. However, supplementation also increased the rate of oxidant production, indicating that the efficiency of mitochondrial electron transport had not improved. To counteract the potential increase in oxidative stress, animals were administered N-tert-butyl-alpha-phenyl-nitrone (30 mg/kg) (PBN) with or without ALCAR. Results showed that PBN significantly lowered oxidant production as measured by 2,7'-dichlorofluorescin diacetate (DCFH), even when ALCAR was coadministered to the animals. Thus, dietary supplementation with ALCAR, particularly in combination with PBN, improves mitochondrial function without a significant increase in oxidative stress.

Antihepatotoxic actions of flavonolignans from Silybum marianum fruits.

Hikino H, Kiso Y, Wagner H, Fiebig M.

Planta Med. 1984 Jun;50(3):248-50

No Abstract Available

The effect of polyene phosphatidylcholine (Essentiale forte) in the treatment of liver steatosis and ultrasound findings?preliminary study. [Article in Czech]

Horejsova M, Urban J. II. interni klinika, Institutu postgradualniho vzdelavani ve zdravotnictvi, Praha.

Cas Lek Cesk. 1994 Jun 13;133(12):366-9

BACKGROUND. Steatosis of the liver is the most frequent diffuse liver disease and its detection increased markedly due to ultrasonography. The presence of lipid particles in hepatocytes alters the ultrastructure of cellular membranes. The damaged cell is unable to meet adequately the energy requirements of phospholipid synthesis, the latter being the basic component of cellular and subcellular membranes. Substitution of "essential" phospholipids plays an important role in their regeneration.

OBJECTIVE. The objective of the open trial without controls was to obtain preliminary information on the effectiveness of Essentiale forte cps. in the treatment of steatosis of the liver of varying etiology in a group of 30 women, focused on changes in the ultrasonic pictures and a parallel follow-up of laboratory findings and subjective feelings, to be followed subsequently by a placebo controlled double blind trial.

METHODS AND RESULTS. Ultrasonic examinations were made using a Hewlett-Packard apparatus (77065AR). The sonographic criterium of steatosis was the finding of a diffusely enhanced echogenicity of the liver parenchyma associated as a rule with varying degrees of hepatomegaly with a smooth rounded margin and readily apparent hepatic veins with a normal lumen. The preparation Essentiale forte, cps. Rhone-Poulenc Rorer Co., contains natural "essential" phospholipids, diglyceride esters of cholinephosphoric acid (enriched with unsaturated fatty acids (linolic, linoleic, oleic) 300 mg, vitamin B1 6 mg, vitamin B2 6 mg, vitamin B6 6 mg, vitamin B12 6 micrograms, nicotinamide 30 mg, vitamin E 6 mg. Six tablets per day (2 x 3 tablets) were administered for six months. The clinical, ultrasonic and laboratory examination were made at the onset of the trial and then after the second and sixth month. From the total number of 28 women who completed treatment in 29 % (8 woman) were free from sonographic signs of steatosis and only in 25 % (7 women) the finding remained unaltered. In the remainder the ultrasonic picture improved only partly, in 10 of 11 women (91 %) the non-homogeneity of the parenchyma disappeared, in 3 of 12 women (25 %) the conduction of acoustic signals improved. The authors recorded also regression of hepatomegaly from 12.9 +/- 1.5 cm to 11.4 +/- 1.0 cm (p < 0.0001). There was also a significant decline of laboratory values: ALT from 1.650 +/- 1.612 mu kat/l to 0.812 +/- 0.392 mu kat/l (p < 0.0014), AST from 1.308 +/- 1.341 mu kat/l to 0.613 +/- 0.206 mu kat/l (p < 0.0038), GMT from 2.525 +/- 3.374 mu kat/l to 0.976 +/- 0.727 mu kat/l (p < 0.0078). A statistically significant decline was also found in mean values of total bilirubin (p < 0.0316), cholesterol (p < 0.0129) and triglycerides (p < 0.001). In all patients subjective sensations improved (p < 0.05).

CONCLUSIONS. The authors provided evidence than in 53.6 % of patients the effect of six-month treatment with Essentiale forte was very good (improvement of all investigated parameters), partial in 42.9 % (improvement of laboratory findings and subjective complaints) ad not quite satisfactory in 3.6 % (only improvement of subjective feelings).

Folate depletion and elevated plasma homocysteine promote oxidative stress in rat livers.

Huang RF, Hsu YC, Lin HL, Yang FL. Department of Nutrition and Food Sciences, Fu-Jen University, Hsin-Chuang, Taiwan, Republic of China. rweifen@mails.fju.edu.tw

J Nutr. 2001 Jan;131(1):33-8

This study was designed to determine whether nutritional folate depletion exerts hepatic oxidative stress in relation to elevated plasma homocysteine. To mimic various extents of folate depletion status in vivo, male Wistar rats were fed an amino acid-defined diet containing either 8 (control), 2, 0.5, or 0 mg folic acid/kg diet. After a 4-wk feeding period, the plasma and hepatic folate concentrations of the rats decreased significantly with each decrement of dietary folate. Folate depletion did not significantly affect two major liver antioxidants: reduced glutathione and alpha-tocopherol. Conversely, folate depletion decreased Cu-Zn superoxide dismutase and glutathione peroxidase activities, but had no effect on catalase activity in liver homogenates. Lipid peroxidation products, as measured by thiobarbituric acid-reactive substances, were significantly higher in livers of folate-depleted rats than in those of the controls. This occurrence of hepatic oxidative stress in folate-depleted rats was confirmed by demonstrating an increased susceptibility of livers of folate-depleted rats to lipid peroxidation induced by additional H2O2 or Fe(2+) treatments compared with the controls. Decreasing dietary folate intake resulted in graded increases in plasma homocysteine concentrations of folate-depleted rats. Elevated plasma homocysteine and decreased plasma and hepatic folate concentrations in folate-depleted rats were all strongly and significantly correlated with increased liver lipid peroxidation (/r/ > or = 0.58, P < 0.0003). These data demonstrate that folate depletion and elevated plasma homocysteine promote oxidative stress in rat livers.

Regulation of methionine adenosyltransferase activity by the glutathione level in rat liver during ischemia-reperfusion.

Ito K, Miwa N, Hagiwara K, Yano T, Shimizu-Saito K, Goseki N, Iwai T, Horikawa S. Department of Surgery, Tsuchiura Kyodo Hospital, Tsuchiura 300-0053, Japan.

Surg Today. 1999;29(10):1053-8

Hepatic ischemia was induced by clamping the hepatic artery, portal vein, and bile duct. After 15 min of ischemia, the hepatic glutathione (GSH) content rapidly decreased. On the other hand, after the start of reperfusion, the hepatic GSH levels promptly increased and reached a peak at about 1 h, and thereafter decreased to a minimum level by 2 h. Under such conditions, we examined the changes in the methionine adenosyltransferase (MAT) activity in the liver. Though the time course of MAT activity was somewhat delayed compared with that of the hepatic GSH levels, both patterns were substantially similar during ischemia-reperfusion. In contrast to the changes in the MAT activity during ischemia-reperfusion, the levels of MAT protein were unchanged during these periods. When endogenous antioxidant coenzyme Q(10) (CoQ(10)) was administered to rats prior to ischemia, both the reduction in the MAT activity and hepatic GSH levels induced by ischemia-reperfusion were protected. Our findings suggest that CoQ(10) may posttranslationally regulate the MAT activity via the changes in the GSH level in the liver.

Preferential use of branched-chain amino acids as an energy substrate in patients with liver cirrhosis.

Kato M, Miwa Y, Tajika M, Hiraoka T, Muto Y, Moriwaki H. First Department of Internal Medicine, Gifu University School of Medicine.

Intern Med. 1998 May;37(5):429-34

We analyzed basal energy metabolism in 20 healthy volunteers and 41 cirrhotic patients by indirect calorimetry. Subjects were then given either glucose, branched-chain amino acids (BCAA) or fatty acids as an energy substrate. Resting energy expenditure (REE), nonprotein respiratory quotient (npRQ), and oxidation rates of glucose (% CHO), protein (% PRO) and fat (% FAT) were analyzed. REE and %FAT were significantly higher and % CHO and %PRO were significantly lower in cirrhosis than in controls. These changes correlated with disease severity. Glucose and BCAA were utilized efficiently as energy substrates and reduced %FAT in cirrhosis. Energy efficacy (increased energy expenditure/energy equivalent of the supplemented nutrient) was significantly higher in BCAA (96 +/- 16%) than in glucose (41 +/- 8%) (p<0.01) and fatty acids (27 +/- 13%) (p<0.05). Patients with cirrhosis have an increased energy requirement. BCAA seems to be the preferred substrate to meet this demand, because its energy efficacy is higher than glucose or fatty acids in cirrhosis.

Antiviral effect of flavonoids on human viruses.

Kaul TN, Middleton E Jr, Ogra PL.

J Med Virol. 1985 Jan;15(1):71-9

The effect of several naturally occurring dietary flavonoids including quercetin, naringin, hesperetin, and catechin on the infectivity and replication of herpes simplex virus type 1 (HSV-1), polio-virus type 1, parainfluenza virus type 3 (Pf-3), and respiratory syncytial virus (RSV) was studied in vitro in cell culture monolayers employing the technique of viral plaque reduction. Quercetin caused a concentration-dependent reduction in the infectivity of each virus. In addition, it reduced intracellular replication of each virus when monolayers were infected and subsequently cultured in medium containing quercetin. Preincubation of tissue culture cell monolayers with quercetin did not affect the ability of the viruses to infect or replicate in the tissue culture monolayers. Hesperetin had no effect on infectivity but it reduced intracellular replication of each of the viruses. Catechin inhibited the infectivity but not the replication of RSV and HSV-1 and had negligible effects on the other viruses. Naringin had no effect on either the infectivity or the replication of any of the viruses studied. Thus, naturally occurring flavonoids possess a variable spectrum of antiviral activity against certain RNA (RSV, Pf-3, polio) and DNA (HSV-1) viruses acting to inhibit infectivity and/or replication.

Alpha-lipoic acid supplementation: tissue glutathione homeostasis at rest and after exercise.

Khanna S, Atalay M, Laaksonen DE, Gul M, Roy S, Sen CK. Department of Physiology, Faculty of Medicine, University of Kuopio, 70211 Kuopio, Finland.

J Appl Physiol. 1999 Apr;86(4):1191-6

Antioxidant nutrients have demonstrated potential in protecting against exercise-induced oxidative stress. alpha-Lipoic acid (LA) is a proglutathione dietary supplement that is known to strengthen the antioxidant network. We studied the effect of intragastric LA supplementation (150 mg/kg, 8 wk) on tissue LA levels, glutathione metabolism, and lipid peroxidation in rats at rest and after exhaustive treadmill exercise. LA supplementation increased the level of free LA in the red gastrocnemius muscle and increased total glutathione levels in the liver and blood. The exercise-induced decrease in heart glutathione S-transferase activity was prevented by LA supplementation. Exhaustive exercise significantly increased thiobarbituric acid-reactive substance levels in the liver and red gastrocnemius muscle. LA supplementation protected against oxidative lipid damage in the heart, liver, and red gastrocnemius muscle. This study reports that orally supplemented LA is able to favorably influence tissue antioxidant defenses and counteract lipid peroxidation at rest and in response to exercise.

Silymarin inhibits the development of diet-induced hypercholesterolemia in rats.

Krecman V, Skottova N, Walterova D, Ulrichova J, Simanek V. Institute of Medical Chemistry, Medical Faculty, Palacky University, Olomouc, Czech Republic.

Planta Med. 1998 Mar;64(2):138-42

To study the ability of silymarin, a standardized mixture of antioxidant flavonolignans from the medicinal plant Silybum marianum, and of silybin, the main flavonolignan of silymarin, to inhibit the development of diet-induced hypercholesterolemia the rats were fed high cholesterol diet (HCD). Silymarin or silybin were given as dietary supplements, and their influences on serum cholesterol levels were compared to those of probucol, an antioxidant hypocholesterolemic drug. Anticholesterolemic effect of silymarin was parallel to that of probucol, and dose-dependent at dietary drug concentrations of 0.1-0.5-1.0% (w/w). However, in contradistinction to probucol, silymarin caused an increase in high density lipoprotein (HDL)-cholesterol and a decrease in liver cholesterol content, changes considered to be of benefit. In addition to its anticholesterolemic effect silymarin partially prevented the HCD-induced decrease in liver reduced glutathione, an endogenous antioxidant. Silybin was not so effective as silymarin suggesting that either other constituent(s) of silymarin may be responsible for its anticholesterolemic effect or the bioavailability of silybin alone might be lower than that of silybin as a compound of silymarin.

Subchronic inhalation toxicity of nitromethane and 2-nitropropane.

Lewis TR, Ulrich CE, Busey WM.

J Environ Pathol Toxicol. 1979 May-Jun;2(5):233-49

Nitromethane (NM) and 2-nitropropane (2-NP) and versatile compounds employed in a wide variety of industrial applications, thus providing ample opportunity for occupational exposure. The purpose of this study was to determine the subchronic inhalation toxicity of NM and 2-NP in order to recommend acceptable exposure levels in the workplace. Fifty male rats and 15 male rabbits were exposed to either 98 ppm or 745 ppm of NM or 27 or 207 ppm of 2-NP 7 hours/day, 5 days/week, for periods up to 24 weeks. Fifty rats and 15 rabbits were exposed to filtered air for similar lengths of time and served as controls. Ten rats from each exposure and control group were sacrificed following 2 days, 10 days, 1 month, 3 months, and 6 months of exposure. Five rabbits from each exposure or control group were sacrificed at 1, 3, and 6 months of exposure. Effects relatable to exposure to NM were decreased body weight gain in rats following 8 weeks of exposure to 745 ppm, and a thyroid effect evidenced by an increased thyroid weight and decreased serum thyroxin levels, most notable in rabbits. Liver weights were significantly elevated in rats exposed to 207 ppm of 2-NP for 1, 3, and 6 months. No exposure-related gross or microscopic alterations were seen in any of the tissues examined for rats and rabbits exposed to 745 and 98 ppm of NM and 27 ppm of 2-NP or in tissues of rabbits exposed to 207 ppm of 2-NP. Liver neoplasms were seen in all 10 rats killed following 6 months of exposure to 207 ppm of 2-NP, indicating that 2-NP is a potent carcinogen in the rat.

Inhibition of nitric oxide synthesis in primary cultured mouse hepatocytes by alpha-lipoic acid.

Liang JF, Akaike T. Department of Biomolecular Engineering, Tokyo Institute of Technology, Yokohama, Japan. junfeng@umich.edu

Chem Biol Interact. 2000 Jan 3;124(1):53-60

Recent work shows that septic or endotoxic shock is associated with lipopolysaccharide and cytokine mixture-induced nitric oxide (NO) synthesis in liver. Here we found that DL-alpha-lipoic acid inhibited but other thiol-containing antioxidants such as glutathione and N-acetylcysteine enhanced lipopolysaccharide and cytokine mixture (referred as LPS/CM)-induced NO synthesis in hepatocytes. The inhibitory action of alpha-lipoic acid on hepatocyte NO synthesis was as potent as that of NG-monomethyl-L-arginine without obvious cytotoxicity. Deletion by diethylmaleate or inhibition by buthionine sulfoximine of intracellular glutathione caused a significant decrease in hepatocyte NO synthesis, implying that increased intracellular reduced glutathione levels could not be the reason for alpha-lipoic acid inhibited NO synthesis. alpha-Lipoic acid inhibition of NO synthesis seems to be from alpha-lipoic acid improved carbohydrate metabolism in hepatocytes. Since alpha-lipoic acid is an essential compound existing naturally in physiological systems, it may serve as both a research and therapeutic agent for sepsis.

Prevention and treatment of liver fibrosis based on pathogenesis.

Lieber CS. Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center and Mount Sinai School of Medicine, New York 10468, USA. liebercs@aol.com

Alcohol Clin Exp Res. 1999 May;23(5):944-9

Multiple agents have been proposed for the prevention and treatment of fibrosis. S-adenosylmethionine was reported to oppose CCl4-induced fibrosis in the rat, to attenuate the consequences of the ethanol-induced oxidative stress, and to decrease mortality in cirrhotics. Anti-inflammatory medications and agents that interfere with collagen synthesis, such as inhibitors of prolyl-4-hydroxylase and antioxidants, are also being tested. In nonhuman primates, polyenylphosphatidylcholine (PPC), extracted from soybeans, protected against alcohol-induced fibrosis and cirrhosis and prevented the associated hepatic phosphatidylcholine (PC) depletion by increasing 18:2 containing PC species; it also attenuated the transformation of stellate cells into collagen-producing transitional cells. Furthermore, it increased collagen breakdown, as shown in cultured stellate cells enriched with PPC or pure dilinoleoyl PC, the main PC species present in the extract. Because PPC and dilinoleoyl PC promote the breakdown of collagen, there is reasonable hope that this treatment may be useful for the management of fibrosis of alcoholic, as well as nonalcoholic, etiologies and that it may affect not only the progression of the disease, but may also reverse pre-existing fibrosis, as demonstrated for CCl4-induced cirrhosis in the rat and as presently tested in an ongoing clinical trial.

Protective effect of melatonin against oxidative stress induced by ligature of extra-hepatic biliary duct in rats: comparison with the effect of S-adenosyl-L-methionine.

Lopez PM, Finana IT, De Agueda MC, Sanchez EC, Munoz MC, Alvarez JP, De La Torre Lozano EJ. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Cordoba, Spain. bb1molop@lucano.uco.es

J Pineal Res. 2000 Apr;28(3):143-9

In the present research, we studied the effect of the administration of melatonin or S-adenosyl-L-methionine (S-AMe) on oxidative stress and hepatic cholestasis produced by double ligature of the extra-hepatic biliary duct (LBD) in adult male Wistar rats. Hepatic oxidative stress was evaluated by the changes in the amount of lipid peroxides and by the reduced glutathione content (GSH) in lysates of erythrocytes and homogenates of hepatic tissue. The severity of the cholestasis and hepatic injury were determined by the changes in the plasma enzyme activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), g-glutamyl-transpeptidase (GGT), and levels of albumin, total bilirubin (TB) and direct bilirubin (DB). Either melatonin or S-AMe were administered daily 3 days before LBD, and for 10 days after biliary obstruction. LDB caused highly significant increases in plasma enzyme activities and in bilirubin and lipid peroxides levels in erythrocytes and hepatic tissue. At the same time, this procedure produced a notable decrease in the GSH pools in these biological media. Both melatonin and S-AMe administration were effective as antioxidants and hepatoprotective substances, although the protective effects of melatonin were superior; it prevented the GSH decrease and reduced significantly the increases in enzyme activities and lipid peroxidation products produced by biliary ligature. S-AMe did not modify the increased GGT activity nor did it decrease greatly the TB levels (43% melatonin vs. 14% S-AMe). However, S-AMe was effective in preventing the loss of GSH in erythrocytes and hepatic tissue, as was melatonin. The obtained data permit the following conclusions. First, the LDB models cause marked hepatic oxidative stress. Second, the participation of free radicals of oxygen in the pathogenecity and severity of cholestasis produced by the acute obstruction of the extra-hepatic biliary duct is likely. Third, the results confirm the function of S-AMe as an antioxidant and hepatoprotector. Finally, melatonin is far more potent and provides superior protection as compared to S-AMe. Considering the decrease in oxidative stress and the intensity of cholestasis, these findings have interesting clinical implications for melatonin as a possible therapeutic agent in biliary cholestasis and parenchymatous liver injury.

Age-associated decline in ascorbic acid concentration, recycling, and biosynthesis in rat hepatocytes-reversal with R alpha lipoic acid supplementation.

Lykkesfeldt J, Hagen TM, Vinarsky V, Ames BN. Department of Molecular and Cell Biology, University of California at Berkeley, 94720, USA. jopl@kvl.dk

FASEB J. 1998 Sep;12(12):1183-9

Ascorbic acid recycling from dehydroascorbic acid and biosynthesis from gulono-1,4-lactone were used as measures of cellular response capacity to increased oxidative stress induced by tert-butylhydroperoxide. The hepatic ascorbic acid concentration was 54% lower in cells from old rats when compared to cells isolated from young rats (P<0.0005). Freshly isolated hepatocytes from old rats exhibited a significantly decreased ascorbic acid recycling capacity in response to oxidative stress (P<0.005) compared to cells from young rats. Ascorbic acid synthesis in these cells from old animals was unaffected by various concentrations of tert-butylhydroperoxide, but amounted to only approximately half of the biosynthetic rate when compared to cells from young animals (P<0.001). Cells from young animals were not significantly affected by the tert-butylhydroperoxide treatments. The results demonstrate a declining ability with age to respond to increased oxidative stress. (R)-alpha-Lipoic acid, a mitochondrial coenzyme, is a powerful antioxidant. A two-week dietary supplementation of old animals with 0.5% (R)-alpha-lipoic acid prior to cell isolation almost completely reversed the age-associated effects on ascorbic acid concentration (P<0.0001), recycling (P<0.05) and biosynthesis after oxidative stress. These results provide further evidence for the potential of alpha-lipoic acid in treatment of diseases related to oxidative stress. Furthermore, the study extends the value of ascorbic acid as a biomarker of oxidative stress.

Polyenylphosphatidylcholine attenuates non-alcoholic hepatic fibrosis and accelerates its regression.

Ma X, Zhao J, Lieber CS. Alcohol Research and Treatment Center, Bronx V.A. Medical Center, NY 10468, USA.

J Hepatol. 1996 May;24(5):604-13

BACKGROUND/AIMS: Polyenylphosphatidylcholine protects against alcoholic cirrhosis in the baboon. This study assesses whether the antifibrotic effect also pertains to a species other than the baboon and to agents other than alcohol.

METHODS: Rats were injected with either CC14 in peanut oil or peanut oil alone, and pair-fed nutritionally adequate liquid diets, with or without polyenylphosphatidylcholine. Other rats were injected with heterologous albumin instead of CC14. To assess whether polyenylphosphatidylcholine is active on established fibrosis, rats were also given CC14 for 8 weeks, and then divided into two groups and pair-fed a diet with or without polyenylphosphatidylcholine.

RESULTS: After 8 weeks of CC14, the animals were sacrificed; chromotrope aniline blue and Sirius red stains of liver revealed fibrosis or cirrhosis in animals given CC14 alone, whereas the effect was attenuated in the polyenylphosphatidylcholine-supplemented animals. Hepatic collagen content was decreased by 25 to 32% (p < 0.05) and serum ALT and AST were significantly less increased. The expression of liver collagen type I mRNA was significantly increased in CC14 treated rats and was not significantly affected by polyenylphosphatidylcholine although there was a trend towards a lesser increase polyenylphosphatidylcholine also attenuated liver fibrosis produced by the injection of heterologous albumin. CC14-induced liver fibrosis regressed more rapidly in polyenylphosphatidylcholine-treated animals than controls, both histologically and by measurement of collagen (p < 0.05).

CONCLUSIONS: Polyenylphosphatidylcholine (a) attenuates hepatic fibrosis induced by CC14 or human albumin in rats; and (b) accelerates the regression of pre-existing fibrosis.

Effects of Cynara scolymus extracts on the regeneration of rat liver.

Maros T, Racz G, Katonai B, Kovacs VV.

Arzneimittelforschung. 1966 Feb;16(2):127-9

No Abstract Available

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