|
Title
Intracellular glutathione level modulates the induction of apoptosis
by delta 12-prostaglandin J2.
Author
Kim HS; Lee JH; Kim IK
Address
Department of Biochemistry, Catholic University Medical College,
Socho-Ku, Seoul, Korea.
Source
Prostaglandins, 51(6):413-25 1996 Jun
Abstract
We studied the effect of intracellular glutathione (GSH), which
was known to conjugate readily with an alpha, beta-unsaturated
carbonyl of 9-deoxy-delta 9,12-13,14-dihydroPGD2 (delta 12-PGJ2),
on the cytotoxicity of delta 12-PGJ2. delta 12-PGJ2 caused DNA
fragmentation in human hepatocellular carcinoma Hep 3B cells,
which was blocked by cycloheximide (CHX). The delta 12-PGJ2-induced
apoptosis was augmented by GSH depletion resulted from pretreatment
with buthioninine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine
synthetase. On the contrary, N-acetyl-cysteine (NAC), a precursor
of cysteine, elevated the GSH level and protected cells from
initiating apoptosis by delta 12-PGJ2. Sodium arsenite, a thiol-reactive
agent, also induced apoptosis, which was potentiated or attenuated
by BSO or NAC treatment respectively. These results suggest that
the apoptosis-inducing activity of delta 12-PGJ2 is due to thiol-reactivity
and intracellular GSH modulates the delta 12-PGJ2-induced apoptosis
by regulating the accessibility of delta 12-PGJ2 to target proteins
containing thiol groups.
Title
Antioxidant administration to the mother prevents oxidative stress
associated with birth in the neonatal rat.
Author
Sastre J; Asensi M; Rodrigo F; PallardÍo FV; Vento M;
ViÍna J
Address
Departamento de Fisiologia, Facultad de Medicina, Universidad
de
Valencia, Spain.
Source
Life Sci, 54(26):2055-9 1994
Abstract
In the fetal-to-neonatal transition, important circulatory and
respiratory changes ensue which lead to oxidative stress evidenced
by changes in glutathione status. Administration of N-Acetyl-cysteine
(NAC), a glutathione precursor, to the mother might be a rational
approach to protect the fetus against oxidative stress. We have
found that NAC administration to pregnant rats partially prevents
the change in hepatic GSSG that occurs in the fetal-neonatal
transition: GSSG increased 11-fold (from 1 to 12 nmol/g) in controls
and less than two-fold (from 5 to 9 nmol/g) in animals exposed
to NAC in utero. The GSH/GSSG ratio in liver of NAC-treated newborns
was 411 +/- 216 and in liver of controls it was 283 +/- 176.
Thus, the oxidative stress that occurs in the fetal-to-neonatal
transition is partially prevented by oral NAC administration.
Title
N-acetyl cysteine enhances the response to interferon-alpha in
chronic hepatitis C: a pilot study.
Author
Beloqui O; Prieto J; Suárez M; Gil B; Qian CH; García
N; Civeira MP
Address
Department of Internal Medicine, Clínica Universitaria,
Universidad de Navarra, Pamplona, Spain.
Source
J Interferon Res, 13(4):279-82 1993 Aug
Abstract
Hepatitis C virus (HCV) is an RNA virus that replicates in both
the liver and lymphoid cells. Interferon-alpha (IFN-alpha) is
a useful treatment of chronic hepatitis C (CHC) although resistance
to this drug occurs frequently. The mechanisms underlying resistance
to IFN remain unknown. In this work, we have measured the levels
of glutathione in plasma and peripheral lymphoid cells from 15
healthy controls and 24 CHC patients, 10 of whom were without
treatment and 14 showed high serum alanine aminotransferase (ALT)
values despite therapy with lymphoblastoid IFN for more than
4 months. In all patients, glutathione levels in plasma and in
mononuclear cells were depressed in comparison to controls. In
IFN-unresponsive patients, the addition of 600 mg tid of oral
N-acetyl cysteine (NAC), a glutathione precursor, resulted in
a steady decrease of ALT values in all patients, with complete
normalization in 41% of cases after 5-6 months of combined therapy.
Administration of NAC alone for 1 month was without effect in
the 10 patients that were not receiving IFN. Supplementation
of IFN with NAC induced a near normalization of intralymphocytic
glutathione, but plasma levels were only moderately increased.
HCV replication was markedly inhibited in lymphocytes and viremia
was cleared in one of the 8 patients tested. In conclusion, NAC
enhances the response to IFN in CHC. Controlled studies are needed
to ascertain whether antioxidant therapy might act in synergy
with IFN in chronic viral hepatitis.
Title
Thiol suppression of human immunodeficiency virus type 1 replication
in primary cord blood monocyte-derived macrophages in vitro.
Author
Lioy J; Ho WZ; Cutilli JR; Polin RA; Douglas SD
Address
Division of Neonatology, Children's Hospital of Philadelphia,
Pennsylvania 19104.
Source
J Clin Invest, 91(2):495-8 1993 Feb
Abstract
We investigated the effects of glutathione (GSH), the major naturally
occurring thiol, and a pharmacologic thiol precursor of GSH,
N-acetyl cysteine (NAC), on the expression of human immunodeficiency
type 1 (HIV-1) in primary cord blood and adult donor monocyte-derived
macrophages (MDM). HIV-1 infection of cord blood and adult MDM
was accomplished after incubating 10-15-d-old cultures for 4
h with a monocyte-tropic strain of HIV-1 (Bal). After 1 wk in
culture cell supernatants were tested for reverse transcriptase
(RT) activity. MDM were exposed to 5, 10 and 20 mM concentrations
of both GSH and NAC before infection, during infection, and after
infection was established. GSH and NAC suppressed the replication
of HIV-1 in both primary cord blood and adult donor MDM in a
concentration dependent fashion. These suppressive effects were
more pronounced in cord-derived cells than in adult-derived cells.
In cells treated with GSH or NAC before infection, there was
no significant rise in RT activity as compared with controls.
Similarly, when cells were treated with GSH and NAC and simultaneously
infected, there was also no significant rise in RT activity after
1 wk in culture. In cells treated after infection was established,
RT values were suppressed 80-90% that of untreated controls.
This effect persisted for 1-2 wk after exposure to GSH and NAC.
Untreated controls demonstrated syncytium formation and lost
characteristics of spreading and elongation 2 wk after HIV-1
infection, whereas most of the treated cells remained free of
syncytium and retained cytoplasmic spreading, adherence, and
elongation. These data are consistent with other studies of thiol
suppression of HIV-1 replication and demonstrate a similar observation
for primary cultured cord MDM. These results may offer new approaches
toward cellular protection after infection with HIV-1.
Title
Inhibition with N-acetylcysteine of enhanced production of tumor
necrosis factor in streptozotocin-induced diabetic rats.
Author
Sagara M; Satoh J; Zhu XP; Takahashi K; Fukuzawa M; Muto G; Muto
Y; Toyota T
Address
Third Department of Internal Medicine, Tohoku University School
of Medicine, Sendai, Japan.
Source
Clin Immunol Immunopathol, 71(3):333-7 1994 Jun
Abstract
We previously reported that the in vivo production of the tumor
necrosis factor alpha (TNF) was significantly enhanced after
the onset of diabetes in spontaneous type 1 and 2 diabetic animals.
In this report we confirmed the enhanced production of TNF in
streptozotocin (STZ)-induced diabetes and then attempted to suppress
the enhanced TNF production with N-acetylcysteine (NAC), a precursor
of glutathione synthesis. The lipopolysaccharide-induced serum
TNF activities were significantly enhanced in STZ-induced diabetic
rats (6-18 weeks of age) compared with those of nondiabetic rats
throughout the 12-week experiment. A single, oral administration
of NAC (200 or 1000 mg/kg body wt) significantly suppressed the
enhanced TNF production in the diabetic rats compared with that
in untreated rats in a dose-dependent manner. On the other hand,
in the long-term (6 or 12 weeks) administrations, smaller doses
of NAC (50 or 200 mg/kg/day) also significantly inhibited the
enhanced production of TNF regardless of the dose of NAC. NAC
administration, however, did not suppress the TNF production
of nondiabetic rats. The long-term NAC administration affected
neither body weight nor levels of serum glucose, fructosamine,
albumin, and triglyceride. These results show that NAC administration
significantly suppressed the enhanced TNF production in diabetic
rats and indicate that NAC might be useful in preventing TNF-mediated
pathological conditions in diabetes.
Title
Inhibition of development of peripheral neuropathy in streptozotocin-induced
diabetic rats with N-acetylcysteine.
Author
Sagara M; Satoh J; Wada R; Yagihashi S; Takahashi K; Fukuzawa
M; Muto
G; Muto Y; Toyota T
Address
Third Department of Internal Medicine, Tohoku University School
of Medicine, Sendai, Japan.
Source
Diabetologia, 39(3):263-9 1996 Mar
Abstract
N-acetylcysteine (NAC) is a precursor of glutathione (GSH) synthesis,
a free radical scavenger and an inhibitor of tumour necrosis
factor alpha (TNF). Because these functions might be beneficial
in diabetic complications, in this study we examined whether
NAC inhibits peripheral neuropathy. Motor nerve conduction velocity
(MNCV) was significantly decreased in streptozotocin-induced-diabetic
Wistar rats compared to control rats. Oral administration of
NAC reduced the decline of MNCV in diabetic rats. Structural
analysis of the sural nerve disclosed significant reduction of
fibres undergoing myelin wrinkling and inhibition of myelinated
fibre atrophy in NAC-treated diabetic rats. NAC treatment had
no effect on blood glucose levels or on the nerve glucose, sorbitol
and cAMP contents, whereas it corrected the decreased GSH levels
in erythrocytes, the increased lipid peroxide levels in plasma
and the increased lipopolysaccharide-induced TNF activity in
sera of diabetic rats. Thus, NAC inhibited the development of
functional and structural abnormalities of the peripheral nerve
in streptozotocin-induced diabetic rats.
Title
A redox-based mechanism for cardioprotection induced by ischemic
preconditioning in perfused rat heart.
Author
Chen W; Gabel S; Steenbergen C; Murphy E
Address
Laboratory of Molecular Biophysics, National Institute of Environmental
Health Sciences, Research Triangle Park, NC 27709, USA.
Source
Circ Res, 77(2):424-9 1995 Aug
Abstract
Recent studies have suggested that mild redox alterations can
regulate cell function. Therefore, we tested the hypothesis that
alteration in the thiol redox state might be responsible for
the cardioprotective effects conferred by ischemic preconditioning
in the perfused rat heart. We find that preconditioning with
four 5-minute periods of ischemia, each separated by 5 minutes
of reflow, is associated with a significant loss of glutathione
(3.98 +/- 0.32 mumol/g dry wt, n = 8) compared with no preconditioning
(6.38 +/- 0.24 mumol/g dry wt, n = 14). We further find that
the addition of N-acetylcysteine (NAC, a glutathione precursor
and antioxidant) during the preconditioning protocol not only
blocks the loss of glutathione (5.60 +/- 0.31 mumol/g dry wt,
n = 9) but also blocks the protective effects of preconditioning.
It is observed that after 20 minutes of ischemia followed by
20 minutes of reflow, untreated hearts recover 38 +/- 7% (n =
5) of their initial preischemic contractile function, whereas
preconditioned hearts recover 91 +/- 11% (n = 7). Hearts preconditioned
in the presence of NAC recover 24 +/- 3% (n = 7) of their preischemic
function. Similarly, the addition of NAC reverses the protective
effect of preconditioning on creatine kinase release. On reflow
after 60 minutes of ischemia, creatine kinase release from control
hearts was 271 +/- 20 IU.20 min-1.g dry wt-1 (n = 5), whereas
preconditioned hearts release only 170 +/- 26 IU.20 min-1.g dry
wt-1 (n = 6), and hearts preconditioned in the presence of NAC
release 361 +/- 30 IU.20 min-1.g dry wt-1 (n = 5). We also find
that hearts preconditioned in the presence of NAC have less attenuation
of the decline in pHi than hearts preconditioned in the absence
of drug. Thus, a redox-sensitive mechanism may be involved in
the protection afforded by ischemic preconditioning.
Title
Posttranscriptional regulation of macrophage tissue factor expression
by antioxidants.
Author
Brisseau GF; Dackiw AP; Cheung PY; Christie N; Rotstein OD
Address
Department of Surgery, University of Toronto, Ontario, Canada.
Source
Blood, 85(4):1025-35 1995 Feb 15
Abstract
Tissue factor (TF) expression by cells of monocyte/macrophage
lineage represents an important mechanism underlying the initiation
of fibrin deposition at sites of extravascular inflammation.
Recent evidence suggests a role for oxidant stress in the signalling
pathway of various cell types by virtue of its ability to induce
DNA binding of various transcription factors, including nuclear
factor kappa B and AP-1. The effect of antioxidant treatment
on lipopolysaccharide (LPS)-induced TF expression was examined
in murine peritoneal macrophages and human monocytes. Both pyrrolidine
dithiocarbamate, an oxidant scavenger, and N-acetyl-cysteine,
a precursor of the endogenous antioxidant glutathione, inhibited
stimulation of macrophage procoagulant activity by LPS. Northern
blot analysis showed that neither of these agents reduced LPS-stimulated
TF mRNA accumulation, thereby suggesting a posttranscriptional
mechanism for the effect. Immunofluorescence studies of human
monocytes using polyclonal anti-TF antibody showed that N-acetyl-cysteine
treatment prevented the characteristic plasmalemmal localization
of TF antigen that occurs in response to LPS. Western blot analysis
showed that N-acetyl-cysteine reduced the accumulation of the
47-kD mature glycoprotein in LPS-treated cells, a finding consistent
with the results of the immunofluorescence studies. Furthermore,
these conditions did not result in an accumulation of the less
mature forms of TF. When considered together, these data suggest
that antioxidants exert their effects by impairing translation
and/or by causing degradation of newly translated protein. The
effect of antioxidants on tumor necrosis factor appeared to be
species specific, with no effect on LPS-induced tumor necrosis
factor in murine cells, but with inhibition in human monocytes.
The posttranscriptional effect of antioxidants on TF expression
data suggests a novel mechanism whereby these agents might modulate
monocyte/macrophage activation.
Title
N-acetylcysteine ameliorates reperfusion injury after warm hepatic
ischemia Ísee commentsÍ
Author
Fukuzawa K; Emre S; Senyuz O; Acarli K; Schwartz ME; Miller CM
Address
Department of Surgery, Mount Sinai Medical Center, New York,
New York
10029-6574.
Source
Transplantation, 59(1):6-9 1995 Jan 15
Abstract
glutathione is important in cellular defense against oxidative
stress. We postulated that administration of N-acetylcysteine
(NAC), a glutathione precursor, might help maintain or replenish
hepatic glutathione stores, thereby reducing reperfusion injury
in liver grafts after warm ischemia. Eighteen pigs were subjected
to 2 hr of warm hepatic ischemia and divided into a control group
(group A, n = 6), a preischemia treatment group (group B, n =
6: NAC, 150 mg/kg, continuous i.v. infusion 1 hr before ischemia),
and a postischemia treatment group (group C, n = 6: NAC, 150
mg/kg continuous i.v., begun 20 min before reperfusion and continued
for 1 hr). At initiation of laparotomy, we measured hepatic levels
of reduced glutathione (GSH), its oxidized form (GSSG), ATP,
aspartate aminotransferase (AST), and lactate dehydrogenase (LDH).
Before reperfusion, after 2 hr of warm ischemia, GSH, GSSG, and
ATP were measured. One hour after reperfusion, we measured GSH,
GSSG, ATP, AST, and LDH. Bile output was recorded every 10 min.
Postoperfusion AST and LDH were significantly lower in both treatment
groups than in controls. In group B, hepatic glutathione was
maintained at significantly higher levels than in controls, even
after ischemia (P < 0.05). In group C, although hepatic GSH
levels fell until reperfusion, after administration of NAC, hepatic
GSH reached the level of the preischemia treatment group. In
both treatment groups, GSH 1 hr after reperfusion was significantly
higher than in the controls (P < 0.01): regeneration of glutathione
was seen in all 6 animals in group C, compared with 2/6 in group
B and none in the control group. ATP recovery, bile output, and
survival were all better in the treatment groups than in the
control group. Pretreatment with NAC helps maintain hepatic glutathione
during warm ischemia; given after ischemia, NAC is effective
in replenishing depleted glutathione stores. Adjunctive use of
NAC was associated with improved glutathione homeostasis, improved
bile output and ATP regeneration, and increased survival.
Title
Differential effects of thiols on DNA modifications via alkylation
and Michael addition by alpha-acetoxy-N-nitrosopyrrolidine.
Author
Wang M; Nishikawa A; Chung FL
Address
Division of Chemical Carcinogenesis, American Health Foundation,
Valhalla, New York 10595.
Source
Chem Res Toxicol, 5(4):528-31 1992 Jul-Aug
Abstract
The hepatocarcinogen NPYR is metabolically activated by alpha-hydroxylation
mediated by cytochrome P-450 enzymes to yield a 4-oxobutylating
agent and 2-butenal (crotonaldehyde). Both are reactive intermediates
capable of modifying DNA with guanine either by simple alkylation
or by Michael type addition, respectively. In order to assess
the roles of these pathways in NPYR tumorigenesis, we are interested
in identifying agents which can selectively modify one of these
two pathways. In this study, we examined the effects of three
thiols--(mesna), glutathione (Glu), and N-acetylcysteine (NAC)--on
DNA adduct formation by alpha-acetoxyNPYR, a stable precursor
of alpha-hydroxyNPYR. Calf thymus DNA isolated from incubation
of alpha-acetoxyNPYR with or without thiol was hydrolyzed and
analyzed for the adducts formed by alkylation (adducts 1 and
2) and Michael addition (adducts 3-5). The results showed that
the addition of mesna completely blocked the formation of the
crotonaldehyde-derived adducts 3-5, whereas it exerted little
effect on the formation of the alkylated adducts 1 and 2. These
results indicate the preferential conjugation of mesna with crotonaldehyde.
In contrast, NAC had little selectivity on adduct formation;
levels of adducts 1 to 5 were were reduced by 36-75%. These results
suggest that NAC conjugated with both alkylating agent and crotonaldehyde.
Similar to mesna, Glu blocked the formation of the crotonaldehyde-derived
adducts (adducts 3-5) efficiently. However, unlike mesna, Glu
inhibited the formation of adduct 1, while it did not inhibit
the formation of adduct 2, although both adducts are presumably
derived from the 4-oxobutylating agent.(Abstract TRUNCATED
AT 250 WORDS)
Title
Intravenous N-acetylcysteine and lung glutathione of patients
with pulmonary fibrosis and normals.
Author
Meyer A; Buhl R; Kampf S; Magnussen H
Address
Krankenhaus Grosshansdorf, Zentrum für Pneumologie and Thoraxchirurgie,
Germany.
Source
Am J Respir Crit Care Med, 152(3):1055-60 1995 Sep
Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by a huge
alveolar oxidant burden and a deficiency of glutathione, a major
antioxidant, in the pulmonary epithelial lining fluid (ELF).
Therefore, a rational therapeutic strategy is to increase lung
glutathione to augment the pulmonary antioxidant protective screen.
To evaluate this concept, different doses of N-acetylcysteine
(NAC), a glutathione precursor, were administered intravenously
to eight patients with pulmonary fibrosis and six control subjects.
In patients, bronchoalveolar lavage fluid (BALF) total glutathione
increased significantly from 0.99 +/- 0.25 microM to 1.79 +/-
0.37 microM within 3 h following 1.8 g NAC, whereas 4.8 g NAC
had no additional effect (1.47 +/- 0.34 microM). In the control
subjects, NAC did not significantly alter BALF total glutathione
(baseline: 0.79 +/- 0.17 microM, 600 mg NAC: 0.92 +/- 0.33 microM,
1.8 g NAC: 1.39 +/- 0.41 microM, 4.8 g NAC: 1.33 +/- 0.46 microM).
The same was true in ELF, 1.8 g NAC significantly raised ELF
total glutathione in patients from 186 +/- 47 microM to near
normal levels (373 +/- 103 microM), with no further increase
following 4.8 g NAC (293 +/- 62 microM). In the control subjects,
ELF total glutathione remained unchanged independent of the NAC
dose (baseline: 342 +/- 91 microM, 600 mg NAC: 385 +/- 135 microM,
1.8 g NAC: 633 +/- 220 microM, 4.8 g NAC: 646 +/- 263 microM).
The increases in total glutathione were almost entirely due to
increased levels of reduced glutathione, the form functional
as an antioxidant. No adverse effects were noted.(Abstract
TRUNCATED AT 250 WORDS)
Title
N-acetylcysteine and glutathione as inhibitors of tumor necrosis
factor
production.
Author
Peristeris P; Clark BD; Gatti S; Faggioni R; Mantovani A; Mengozzi
M;
Orencole SF; Sironi M; Ghezzi P
Address
Mario Negri Institute for Pharmacological Research, Milan, Italy.
Source
Cell Immunol, 140(2):390-9 1992 Apr
Abstract
TNF is a major mediator in the pathogenesis of endotoxic shock,
and its inhibition has a protective effect in various animal
models of sepsis or endotoxin (lipopolysaccharide, LPS) toxicity.
LPS treatment also induces an oxidative damage mediated by increased
production of reactive oxygen intermediates. N-Acetylcysteine
(NAC) is an antioxidant and a precursor of the synthesis of glutathione
(GSH) and was reported to protect against LPS toxicity and LPS-induced
pulmonary edema. In this study we investigated the effect of
NAC on TNF production and LPS lethality in mice. The results
indicated that oral administration of NAC protects against LPS
toxicity and inhibits the increase in serum TNF levels in LPS-treated
mice. The inhibition was not confined to the released form of
TNF, since NAC also inhibited LPS-induced spleen-associated TNF.
On the other hand, the inhibitor of GSH synthesis, DL-buthionine-(SR)-sulfoximine
(BSO), had the opposite effect of potentiating LPS-induced TNF
production, and this was associated with a decrease in liver
GSH levels. Repletion of liver GSH with NAC reversed this effect.
NAC was also active in inhibiting TNF production and hepatotoxicity
in mice treated with LPS in association with a sensitizing dose
of Actinomycin D. These data indicate that GSH can be an endogenous
modulator of TNF production in vivo. On the other hand, NAC pretreatment
did not inhibit other effects of LPS, particularly induction
of serum IL-6, spleen IL-1 alpha, and corticosterone, in the
same experimental model, suggesting that the observed effect
could be specific for TNF.
Title
N-acetylcysteine administration alters the response to inspiratory
loading in oxygen-supplemented rats.
Author
Supinski GS; Stofan D; Ciufo R; DiMarco A
Address
Department of Medicine, Case Western Reserve University, Cleveland,
Ohio 44106, USA.
Source
J Appl Physiol, 82(4):1119-25 1997 Apr
Abstract
Based on recent studies, it has been suggested that free radicals
are elaborated in the respiratory muscles during strenuous contractions
and contribute to the development of muscle fatigue. If this
theory is correct, then it should be possible to attenuate the
development of diaphragm fatigue and/or delay the onset of respiratory
failure during loaded breathing by administering a free radical
scavenger. The purpose of the present experiment was, therefore,
to examine the effect of N-acetylcysteine (NAC), a free radical
scavenger and glutathione precursor, on the evolution of respiratory
failure in decerebrate unanesthetized rats breathing against
a large inspiratory resistive load. We compared the inspiratory
volume and pressure generation over time in animals pretreated
with either saline or NAC (150 mg/kg) and then loaded until respiratory
arrest. After arrest, the diaphragm was excised, and samples
were assayed for reduced (GSH) and oxidized glutathione. As a
control, we also assessed respiratory function and glutathione
concentrations in groups of nonloaded saline- and NAC-treated
animals. We found that NAC-treated animals were able to tolerate
loading better than the saline-treated group, maintaining higher
inspiratory pressures and sustaining higher inspired volumes.
Administration of NAC also increased the time that animals could
tolerate loading before the development of respiratory arrest.
In addition, although saline-treated loaded animals had significant
reductions in diaphragmatic GSH levels compared with unloaded
controls, the magnitude of this reduction was blunted by NAC
administration (i.e., GSH averaged 965 +/- 113, 568 +/- 83, 907
+/- 39, and 784 +/- 61 nmol/g for unloaded-saline, loaded-saline,
unloaded-NAC, and loaded-NAC groups, P < 0.05, with the value
for the loaded-saline group lower than the values for the two
unloaded groups; GSH for the loaded-NAC group was not different,
however, from unloaded controls). These data demonstrate that
administration of NAC, a free radical scavenger, slows the rate
of development of respiratory failure during inspiratory resistive
loading. |
|
Return to Main Page
