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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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