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Title
The role of oxidative stress in HIV disease.
Author
Pace GW; Leaf CD
Address
Research Triangle Pharmaceuticals, Durham, NC, USA.
Source
Free Radic Biol Med, 19(4):523-8 1995 Oct
Abstract
Evidence has accumulated suggesting that HIV-infected patients
are under chronic oxidative stress. Perturbations to the antioxidant
defense system, including changes in levels of ascorbic acid,
tocopherols, carotenoids, selenium, superoxide dismutase, and
glutathione, have been observed in various tissues of these patients.
Elevated serum levels of hydroperoxides and malondialdehyde also
have been noted and are indicative of oxidative stress during
HIV infection. Indications of oxidative stress are observed in
asymptomatic HIV-infected patients early in the course of the
disease. Oxidative stress may contribute to several aspects of
HIV disease pathogenesis, including viral replication, inflammatory
response, decreased immune cell proliferation, loss of immune
function, apoptosis, chronic weight loss, and increased sensitivity
to drug toxicities. glutathione may play a role in these processes,
and thus, agents that replete glutathione may offer a promising
treatment for HIV-infected patients. Clinical studies are underway
to evaluate the efficacy of the glutathione-repleting agents,
L-2-oxothiazolidine-4-carboxylic acid (OTC) and N-acetylcysteine
(GSH), in HIV-infected patients.
Title
Macrophages regulate intracellular glutathione levels of lymphocytes.
Evidence for an immunoregulatory role of cysteine.
Author
Gmünder H; Eck HP; Benninghoff B; Roth S; Dröge W
Address
Institute of Immunology and Genetics, German Cancer Research
Center.
Source
Cell Immunol, 129(1):32-46 1990 Aug
Abstract
Macrophages consume cystine and generate approximately equivalent
amounts of acid-soluble thiol. Stimulation of macrophages with
bacterial lipopolysaccharide (LPS) or tumor necrosis factor (TNF)
strongly augments the amount of thiol released into the culture
supernatant. cysteine constitutes most of the acid-soluble thiol.
The intracellular glutathione level and the DNA synthesis activity
in mitogenically stimulated lymphocytes are strongly increased
by either exogenously added cysteine, or (syngeneic) macrophages.
This cysteine dependency is observed even in the presence of
relatively high extracellular cystine concentration as they occur
in the blood plasma. The extracellular cysteine concentration
also has a strong influence on the intracellular glutathione
concentration, viability, and DNA synthesis of cycling T cell
clones. Moreover, the cysteine concentration in the culture medium
on Day 3 and Day 4 of a 5-day allogeneic mixed lymphocyte culture
(i.e., in the late phase of incubation) has a strong influence
on the generation of cytotoxic T cell activity, indicating that
regulatory effects of cysteine are not restricted to the early
phase of the blastogenic response. The inhibitory effect of cysteine
starvation on the DNA synthesis of the T cell clones and on the
activation of cytotoxic T lymphocytes can be explained essentially
by the depletion of intracellular glutathione, since similar
effects are observed after treatment with buthionine sulfoximine
(BSO), a specific inhibitor of the glutathione biosynthesis.
BSO has practically no influence, however, on the N alpha-benzyloxycarbonyl
Ne-t-butyloxycarbonyl-L-lysine-thiobenzyl-ester (BLT)-esterase
activity and hemolytic activity of the cell lysates from cytotoxic
T cells against sheep red blood cells (perforin activity). Taken
together, our experiments indicate that cysteine has a regulatory
role in the immune system analogous to the hormone-like lymphokines
and cytokines. It is released by macrophages at a variable and
regulated rate and regulates immunologically relevant functions
of lymphocytes in the vicinity.
Title
Requirement for prooxidant and antioxidant states in T cell mediated
immune responses.--Relevance for the pathogenetic mechanisms
of AIDS?
Author
Dröge W; Eck HP; Gmünder H; Mihm S
Address
Abteilung Immunchemie, Deutsches Krebsforschungszentrum, Heidelberg.
Source
Klin Wochenschr, 69(21-23):1118-22 1991 Dec 15
Abstract
The discovery of decreased plasma cysteine and cystine levels
and elevated plasma glutamate levels in HIV-infected patients
has led to intense investigations into the role of cysteine in
T cell-mediated immune responses. A large body of evidence indicates
that certain aspects of the T cell response require the action
of active oxygen derivatives while other aspects of the response
require the action of antioxidants such as cysteine and glutathione
(GSH). The prooxidant and antioxidant states may be required
sequentially at different times during T cell activation. The
extremely weak cystine transport activity of T cells together
with oxidizing metabolites from inflammatory microenvironments
appear to be important factors that support the prooxidant state.
The relatively high cystine transport activity of the antigen-presenting
macrophages, in contrast, provides these cells with a "cysteine
pumping" function that allows the antigen binding T cells
in their vicinity to shift to the antioxidant state. The difference
between the membrane transport activities for cysteine of T cells
and macrophages thus appears to be the key element of a mechanism
that facilitates both, the prooxidant state of T cells and their
regulated shift to the antioxidant state. When T cells do not
receive sufficient amounts of cysteine, the intracellular GSH
levels and rates of DNA synthesis activity decrease, and the
cells may suffer from various manifestations of oxidative damage.(Abstract
TRUNCATED AT 250 WORDS)
Title
Characterization of an oxidation-resistant tumor cell line and
its sensitivity to immune response and chemotherapy.
Author
Sauri H; Kim AT; Shau H
Address
Division of Surgical Oncology, UCLA School of Medicine 90024-1782,
USA.
Source
J Surg Res, 58(5):526-35 1995 May
Abstract
Aerobic cells have several scavenger systems for protection from
reactive oxygen species (ROS). We developed an ROS-resistant
variant of the human erythroleukemic cell line K562 by culturing
cells in glucose oxidase to produce hydrogen peroxide. Testing
the activity of the scavenger systems for ROS showed these cells
had a 25- to 28-fold increase in catalase activity. We therefore
termed this variant cell line K562-CAT. There was no similar
increase in glutathione content or activity of superoxide dismutase
and glutathione peroxidase. To determine what effect the increased
catalase activity would have on the immune response to these
tumor cells, we compared K562 and K562-CAT sensitivity to tumor
necrosis factor-alpha (TNF alpha) activated polymorphonuclear
neutrophil (PMN), natural killer (NK), and lymphokine-activated
killer (LAK) cells. K562-CAT showed a significant increase in
resistance to TNF alpha-activated PMN but not to NK or LAK, confirming
the role of ROS in the former but not the latter. We also tested
K562-CAT sensitivity to cisplatin and mitomycin C, agents known
to involve ROS in their cytotoxic mechanism. There was no increased
resistance in K562-CAT compared to parental K562, indicating
that catalase is not involved in tumor cell resistance to those
drugs. Given the characteristics of its resistance to the immune
response, K562-CAT or a similar catalase-hyperexpressing cell
line could be useful in determining the significance of TNF alpha-activated
PMN in antitumor defenses.
Title
Selenium and the selenium-dependent glutathione peroxidase in
rheumatoid arthritis.
Author
Tarp U
Address
Department of Rheumatology, Aarhus University Hospital.
Source
Dan Med Bull, 41(3):264-74 1994 Jun
Abstract
Selenium is an essential component in the two antioxidant enzymes
glutathione peroxidase (GSH-Px) and phospholipid hydroperoxide
glutathione peroxidase (PLGSH-Px). Free oxygen radicals are involved
in the inflammatory process seen in rheumatoid arthritis (RA)
and are generated mainly through the phagocytic activity of the
polymorphonuclear leucocytes. Several experimental studies indicate
that selenium is important to the functioning of the immune system
and to the inflammatory process. A low selenium status among
patients with RA has been reported from areas with both high
and low natural selenium intake. The reduction in the serum level
is approx. 10%. This reduction is related to the clinical disease
activity in arthritis patients in both cross-sectional and longitudinal
studies, and selenium concentrations have been found to fluctuate
during the disease. Reduced selenium concentrations have been
reported in red blood cells, too, and concentrations have been
found to be slightly reduced in the polymorphonuclear leucocytes.
Studies do not agree on the activity of GSH-Px among RA patients.
Thus activity levels have been reported to range from low to
high. Those studies that have focused on the subgroup of patients
with high persistent disease activity have reported reduced GSH-Px
activities in both serum, red blood cells and polymorphonuclear
leucocytes. Selenium supplementation using organic selenium compounds
in doses of around 250 microgram/day increases the selenium concentration
in serum and red blood cells considerably. However, supplementation
is not reflected in the selenium level in polymorphonuclear leucocytes
from RA patients as opposed to healthy subjects, in whom the
level of selenium in polymorphonuclear leucocytes increases.
Selenium supplementation increased GSH-Px activity in serum,
red blood cells and platelets from RA patients, but in the polymorphonuclear
leucocytes the increase was not sufficient to reach the levels
of the controls. This apparent lack of de novo synthesis of GSH-Px
in polymorphonuclear leucocytes from RA patients may be explained
by their inability to increase their selenium content in spite
of high levels of available extracellular selenium. this may
be in accordance with the lack of anti-arthritic effect of selenium
supplementation in controlled clinical studies among RA patients.
Several experimental studies have reported inhibition of GSH-Px
by antirheumatic drugs, in particular gold. In addition, gold
has been found to reduce selenium in rat plasma. These interactions
can, however, be modified by increasing the amount of selenium
in the feed. Among RA patients there is no clear evidence of
an interaction between gold, selenium and
Title
glutathione and inflammatory disorders of the lung.
Author
Cantin AM; Bégin R
Address
Unité de Recherche Pulmonaire, Centre Hospitalier Universitaire
de Sherbrooke, QC, Canada.
Source
Lung, 169(3):123-38 1991
Abstract
glutathione (GSH) is an essential tripeptide present in most
eukaryotic cells. Because of its sulfhydryl group, GSH is a versatile
molecule capable of protecting cells against oxidants and toxic
xenobiotics. However, it also plays key roles in multiple metabolic
pathways, such as the synthesis of certain leukotrienes, proteins,
and DNA precursors as well as the activation of enzymes, the
regulation of immune responses and others. Not only is GSH synthesized
by cells for local use but it also participates in an elaborate
intercellular exchange process regulated by the gamma-glutamyl
cycle. Extracellular GSH in plasma and in alveolar epithelial
lining fluid is thus subject to variations according to the degree
of expression of gamma-glutamyl cycle enzymes and the rate of
consumption of GSH by electrophilic molecules. Bronchoalveolar
lavage has allowed us to observe many of these variations of
GSH within the extracellular environment of the normal and diseased
human lung. Studies of lung GSH have lead to a better understanding
of pathogenic processes and have stimulated investigations of
novel therapeutic approaches in lung inflammatory disorders.
Title
Inhibition of murine AIDS by reduced glutathione.
Author
Palamara AT; Garaci E; Rotilio G; Ciriolo MR; Casabianca A; Fraternale
A; Rossi L; Schiavano GF; Chiarantini L; Magnani M
Address
Department of Experimental Medicine, University of Rome Tor Vergata,
Italy.
Source
AIDS Res Hum Retroviruses, 12(14):1373-81 1996 Sep 20
Abstract
The imbalance of the redox state in cells and body fluids in
HIV-1-infected patients may result in progression of the disease
as well as in immunologic disfuctions. In this report, we have
evaluated whether the direct administration of high doses of
reduced glutathione (GSH) exerts any antiviral activity and/or
improves immune functions in a murine immunodeficiency animal
model. Intramuscular administration of 50 or 100 mg GSH/mouse
for five consecutive days weekly to LP-BM5-infected mice did
not show local or systemic signs of acute toxicity. During the
first 3 weeks from infection, a period in which clinical signs
of disease were not yet detectable, GSH significantly reduced
the viral load in lymph nodes and spleen as evaluated by a PCR
semiquantitative assay of the proviral DNA content. At 10 weeks
a GSH concentration-dependent reduction of splenomegaly, lymphadenopathy
and hypergammaglobulinemia was evident in all treated mice. Evaluation
of proviral DNA content showed that GSH was effective in inhibiting
LP-BM5 infectivity in lymph nodes, spleen, and bone marrow at
100 mg/day, while it was less effective when administered at
50 mg/day. At 10 weeks some animals receiving the highest GSH
dose died, thus only the mice receiving 50 mg GSH were followed
up to 15 weeks without signs of toxicity. In this case, almost
not significant differences among infected untreated or treated
animals were observed. Thus, GSH is effective in reducing the
proviral DNA load in the first period of infection. These data
and the failure of sulfhydril supplementation to further counteract
the progression of disease after 10 weeks of infection suggest
that combinations of GSH and other antiviral agents may be useful
for improving current antiviral therapies.
Title
Decreased release of glutathione into the systemic circulation
of patients with HIV infection.
Author
Helbling B; von Overbeck J; Lauterburg BH
Address
Department of Clinical Pharmacology, University of Bern, Switzerland.
Source
Eur J Clin Invest, 26(1):38-44 1996 Jan
Abstract
Low glutathione (GSH) in patients with HIV infection could contribute
to their immune deficiency since GSH plays an important role
in the function of lymphocytes and sulphydryls decrease the expression
of HIV in vitro. In order to gain more insight into the mechanisms
responsible for the deranged sulphydryl homeostasis in HIV infection,
the release of GSH into the circulation, an estimate of the systemic
production of GSH, was determined using a pharmacokinetic approach.
The basal plasma concentrations of free GSH (3.3 +/- 1.3 vs.
5.3 +/- 1.9 mumol L(-1)) and cysteine (7.7 +/- 2.6 vs. 13.4 +/-
4.9 mumol L(-1)) were significantly lower in eight HIV-infected
patients than in eight controls. Upon infusion of GSH at a constant
rate of 1 mumol min-1 kg-1, GSH in plasma reached a new plateau.
The increment in plasma GSH was significantly larger in the HIV-infected
patients than in the controls. The input of GSH into the circulation
(12.9 +/- 5.7 vs. 30.1 +/- 11.7 mumol min-1; P < 0.01) and
the clearance of GSH (25 +/- 7 vs. 35 +/- 7 mL min-1 kg-1) were
significantly lower in patients with HIV-infection. During infusion
of GSH the concentration of cysteine in peripheral blood mononuclear
cells of the HIV-infected patients increased significantly. Nevertheless,
intracellular GSH did not increase. Thus, the consumption of
GSH is not increased in HIV infection. Rather, the present data
suggest that GSH in patients with HIV infection is low because
of a decreased systemic synthesis of GSH.
Title
Relationship between selenium, immunity and resistance against
infection.
Author
Dhur A; Galan P; Hercberg S
Address
Institut Scientifique et Technique de l'Alimentation, Centre
de Recherche sur les Anémies Nutritionnelles, Paris, France.
Source
Comp Biochem Physiol C, 96(2):271-80 1990
Abstract
1. Food selenium content, selenium supply and selenium needs
are presented, along with methods of evaluation of selenium status.
glutathione peroxidase, a selenium-containing enzyme, is ubiquitous
in the organism. 2. Some experimental studies on animal models
reported a positive relationship between selenium status and
resistance against infections. 3. Only one study in humans concerned
the mechanisms of immune functions in selenium deficiency. Several
experimental works suggest that severe selenium deficiency compromises
T-cell dependent immune functions such as the blastogenic response
to mitogens, but selenium deficiency was concomitant with vitamin
E deficiency in most of them. Delayed hypersensitivity response
is controversial in selenium-supplemented rats and guinea-pigs.
4. Selenium deficiency in animals decreases the antibody response,
especially if associated with vitamin E deficiency. Low dietary
selenium supplementation of healthy animals has a positive effect
upon humoral responses. 5. Despite some controversies, most experimental
studies on selenium-deficient animals report normal phagocytosis
and an altered bactericidal capacity of neutrophils. The decrease
in glutathione peroxidase activity of polymorphonuclear cells
following selenium deficiency could explain some of these alterations.
6. Splenic Natural Killer cells activity is enhanced in selenium-supplemented,
healthy animals.
Title
Asthma and oxidant stress: nutritional, environmental, and genetic
risk factors.
Author
Greene LS
Address
Department of Anthropology, University of Massachusetts/Boston
02125-3393, USA.
Source
J Am Coll Nutr, 14(4):317-24 1995 Aug
Abstract
A considerable body of evidence suggests that oxidant stress
results in inflammation and tissue damage in the respiratory
system, and later in immune damage, and that individuals with
lowered cellular reducing capacity are at increased risk to develop
asthma. Reducing capacity in the erythrocyte is generated through
the pentose phosphate pathway and this pathway also generates
a major portion of the reducing capacity in all cells of the
body. Therefore, dietary, environmental, and genetic factors
which diminish cellular reducing capacity will increase tissue
vulnerability to oxidant stress and are likely to increase asthma
risk. Dietary selenium deficiency lowers red cell glutathione
peroxidase activity and is associated with an increased risk
for asthma, and low dietary intakes of vitamins C and E also
appear to increase asthma risk. High body iron stores increase
free radical production and may also elevate asthma risk. Environmental
lead exposure depresses the activities of a several enzyme systems
that influence cellular reducing capacity (glucose-6-phosphate
dehydrogenase, NAD synthetase, glutathione peroxidase, superoxide
dismutase, catalase) and consequently may increase asthma risk.
Genetically-determined low activity of glucose-6-phosphate dehydrogenase
lowers cellular reducing capacity and may also heighten asthma
risk. Simple dietary and environmental interventions may significantly
reduce oxidant stress and prevent or minimize the development
of asthmatic symptoms and should prove to be a cost effective
approach to asthma management in addition to current pharmacological
strategies.
Title
Dichotomy of glutathione regulation of the activation of resting
and preactivated lymphocytes.
Author
Ting CC; Hargrove ME; Liang SM; Liang CM; Sharrow SO
Address
Division of Cancer Biology, National Cancer Institute, National
Institutes of Health, Bethesda, Maryland 20892.
Source
Cell Immunol, 142(1):40-53 1992 Jun
Abstract
The present study has examined the effect of GSH on two lines
of IL-2-dependent activated killer cells, LAK cells and alpha
CD3-activated killer (CD3-AK) cells. We found that GSH added
during first 24 hr decreased the generation of LAK and CD3-AK
cells from resting lymphocytes, whereas after 48 hr of activation,
the addition of GSH increased the killer cell activity. In addition,
BSO, an inhibitor of GSH biosynthesis, decreased the proliferation
and cytotoxic activities of activated killer cells, and the inhibitory
effect was reversed by GSH. These results indicate that GSH downregulates
the generation of LAK or CD3-AK cells from resting lymphocytes,
but it upregulates the further differentiation of preactivated
killer cells. The effect of GSH thus varied with the state of
activation of the killer cells. Culturing CD3-AK cells in GSH
did not change the distribution of T cell subsets, did not affect
the cells' ability to produce lymphokine (IL-2), and did not
induce suppressor cells. One striking change as revealed by flow
cytometry analysis was that the levels of IL-2 receptor and TCR
(alpha/beta)-CD3 were reduced by 80 and 30%, respectively, after
48 hr culturing in GSH. Determination of the mRNA of IL-2 receptor
suggests that a post-transcriptional block existed. It appears
that the negative effect of GSH on the function of surface IL-2
receptors or T cell receptors on resting lymphocytes severely
affected the signal transduction through these receptors and
thus abrogated or reduced LAK or CD3-AK cell response. In contrast,
for preactivated killer cells, upregulation by intracellular
GSH of IL-2 utilization is a dominant effect, thus allowing further
differentiation of these killer cells. Our results indicate that
the balance between the activation signal (IL-2 or alpha CD3)
and the immunoregulatory signal (induced by GSH) may determine
the outcome of the immune response.
Title
The role of glutathione in aging and cancer.
Author
Richie JP Jr
Address
American Health Foundation, Valhalla, New York 10595.
Source
Exp Gerontol, 27(5-6):615-26 1992 Sep-Dec
Abstract
The incidence and mortality rates from most cancers increase
exponentially with age. It is likely that this aging phenomenon
is partially due to specific changes that occur in the host resulting
in an increased susceptibility to neoplasia. Our hypothesis is
that one such host factor is a deficiency in GSH, based on the
importance of this compound in the detoxification of a wide variety
of exogenous and endogenous carcinogens and free radicals, as
well as in the maintenance of immune function.
Title
N-acetylcysteine: a new approach to anti-HIV therapy.
Author
Roederer M; Ela SW; Staal FJ; Herzenberg LA; Herzenberg LA
Address
Department of Genetics, Stanford University, CA 94305.
Source
AIDS Res Hum Retroviruses, 8(2):209-17 1992 Feb
Abstract
Several investigators have implicated depletion of glutathione
(GSH) and production of reactive oxygen intermediates (ROIs)
in the regulation of the human immunodeficiency virus (HIV).
We have shown directly that N-acetylcysteine (GSH) blocks HIV
expression in chronic and acute infection models, and HIV replication
in normal peripheral blood mononuclear cells. GSH is a cysteine
prodrug which maintains intracellular thiol levels during oxidative
stress and replenishes depleted GSH. The observed antiviral effect
of GSH is due to inhibition of viral stimulation by ROIs, which
are produced in response to inflammatory cytokines. We have also
shown that HIV-infected individuals have decreased intracellular
GSH levels in their circulating T cells. Since GSH is the major
protection against the production of ROIs, we hypothesize that
the observed decrease is due to a chronic oxidative stress induced
by continual exposure to elevated levels of inflammatory cytokines.
Together, these results provide a rationale for clinical trials
testing the efficacy of GSH-replenishing drugs such as GSH in
the treatment of AIDS. GSH is different than many other antiviral
drugs in that it inhibits host-mediated stimulation of viral
replication arising in normal immune responses, and may thereby
extend latency. In addition, it inhibits the action of inflammatory
cytokines which may mediate cachexia, thereby raising the possibility
that it may alleviate the deleterious wasting that accompanies
late stage AIDS.
Title
The role of glutathione in aging and cancer.
Author
Richie JP Jr
Address
American Health Foundation, Valhalla, New York 10595.
Source
Exp Gerontol, 27(5-6):615-26 1992 Sep-Dec
Abstract
The incidence and mortality rates from most cancers increase
exponentially with age. It is likely that this aging phenomenon
is partially due to specific changes that occur in the host resulting
in an increased susceptibility to neoplasia. Our hypothesis is
that one such host factor is a deficiency in GSH, based on the
importance of this compound in the detoxification of a wide variety
of exogenous and endogenous carcinogens and free radicals, as
well as in the maintenance of immune function. |
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