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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 (NAC) blocks HIV
expression in chronic and acute infection models, and HIV replication
in normal peripheral blood mononuclear cells. NAC is a cysteine
prodrug which maintains intracellular thiol levels during oxidative
stress and replenishes depleted GSH. The observed antiviral effect
of NAC 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 NAC in
the treatment of AIDS. NAC 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
Modulation of lymphocyte functions and immune responses by cysteine
and cysteine derivatives.
Author
Dröge W; Eck HP; Gmünder H; Mihm S
Address
Division of Immunochemistry, Deutsches Krebsforschungszentrum,
Heidelberg, F.R.G.
Source
Am J Med, 91(3C):140S-144S 1991 Sep 30
Abstract
Mitogenically stimulated human peripheral blood lymphocytes and
T cell clones were found to have weak membrane transport activity
for the disulfide cystine but strong membrane transport activity
for the thiol amino acid cysteine. cysteine, however, is represented
at the lowest concentration among all protein-forming amino acids
in the blood plasma. Complementary laboratory experiments have
shown that the cysteine supply is indeed limiting for important
lymphocyte functions. Proliferative responses of mitogenically
stimulated lymphocytes and T-cell clones and the activation of
cytotoxic T cells in allogeneic mixed lymphocyte cultures are
strongly influenced by small variations in the extracellular
cysteine concentration even in the presence of relatively high
and approximately physiologic concentrations of cystine. cysteine
can be substituted by N-acetylcysteine but not by cystine. The
more detailed analysis revealed that the extracellular supply
of cysteine influences strongly the intracellular level of glutathione
(GSH) and also the activity of the transcription factor NF kappa
B that regulates the expression of several immunologically relevant
genes. In vitro experiments including double-chamber experiments
with macrophages and lymphocytes revealed, moreover, that cysteine
plays an important role as a regulatory mediator between these
cell types. The cysteine supply is impaired directly or indirectly
in several pathologic conditions that are associated with immunodeficiencies,
including the acquired immune deficiency syndrome (AIDS). cysteine
or cysteine derivatives may therefore be considered for the treatment
of patients with HIV-1 infection.
Title
Physiological and nutritional importance of selenium.
Author
Nève J
Address
Université Libre de Bruxelles, Institut de Pharmacie,
Belgique.
Source
Experientia, 47(2):187-93 1991 Feb 15
Abstract
The essential trace element selenium has recently attracted attention
because of its potentialities in the maintenance of human health.
Selenium forms part of the active site of the peroxide-destroying
enzyme glutathione peroxidase, and it also has other functions,
for example in biotransformation, detoxification and the immune
response. Functional and clinical consequences of selenium deficiency
states have been described, and the selenium requirement, which
is influenced by the usual selenium exposure, has been discussed.
Wide variations have been found in selenium status in different
parts of the world, and populations or groups of patients exposed
to marginal deficiency are more numerous than was previously
thought. Current research activities in the field of human medicine
and nutrition are devoted to the possibilities of using selenium
for the prevention or treatment of degenerative or free radical
diseases such as neurological disorders, inflammatory diseases
or cancer. Pharmacological selenium doses are also recommended
as an adjuvant in some treatments.
Title
Nutritional antioxidants and the modulation of inflammation:
theory and practice.
Author
Grimble RF
Address
Institute of Human Nutrition, University of Southampton, UK.
Source
New Horiz, 2(2):175-85 1994 May
Abstract
Highly potent substances are produced by the immune system. These
substances include cytokines and oxidant molecules, such as hydrogen
peroxide, free radicals, and hypochlorous acid. The purpose of
immune cell products is to destroy invading organisms and damaged
tissue, bringing about recovery. However, oxidants and cytokines
can damage healthy tissue. Excessive or inappropriate production
of these substances is associated with mortality and morbidity
after infection and trauma, and in inflammatory diseases. Oxidants
enhance interleukin-1, interleukin-8, and tumor necrosis factor
production in response to inflammatory stimuli by activating
the nuclear transcription factor, NF kappa B. Sophisticated antioxidant
defenses directly and indirectly protect the host against the
damaging influence of cytokines and oxidants. Indirect protection
is afforded by antioxidants, which reduce activation of NF kappa
B, thereby preventing up-regulation of cytokine production by
oxidants. Cytokines increase both oxidant production and antioxidant
defenses, thus minimizing damage to the host. While antioxidant
defenses interact when a component is compromised, the nature
and extent of the defenses are influenced by dietary intake of
sulfur amino acids, for glutathione synthesis, and vitamins E
and C. In animal studies, in vivo and in vitro responses to inflammatory
stimuli are influenced by dietary intake of copper, zinc, selenium,
N-acetylcysteine, cysteine, methionine, taurine, and vitamin
E. Information from animal studies has yet to be fully translated
into a clinical context. However, N-acetylcysteine, vitamin E,
and a cocktail of antioxidant nutrients have reduced inflammatory
symptoms in inflammatory joint disease, acute and chronic pancreatitis,
and adult respiratory distress syndrome. Impaired antioxidant
defenses may contribute to disease progression after infection
with human immunodeficiency virus. Powerful arguments have been
advanced for treatment with antioxidants to slow progression
of acquired immunodeficiency syndrome.
Title
Nutritional implications in vascular endothelial cell metabolism.
Author
Hennig B; Toborek M; McClain CJ; Diana JN
Address
Department of Nutrition, University of Kentucky 40506-0054, USA.
Source
J Am Coll Nutr, 15(4):345-58 1996 Aug
Abstract
Endothelial cells interact with blood components and the abluminal
tissues, thus playing an active role in many aspects of vascular
function. Numerous physiologic and pathophysiologic stimuli are
often mediated by nutrients that can contribute to the overall
functions of endothelial cells in the regulation of vascular
tone, coagulation, cellular growth, immune and inflammatory responses.
Therefore, nutrient-mediated functional changes of the endothelium
and the underlying tissues may be significantly involved in disease
processes such as atherosclerosis. There is evidence that individual
nutrients or nutrient derivatives may either provoke or prevent
metabolic and physiologic perturbations of the vascular endothelium.
Diets high in fat and/or calories are considered a risk factor
for the development of atherosclerosis. Our research has shown
that certain diet-derived lipids and their derivatives can disrupt
normal endothelial integrity, thus reducing the ability of the
endothelium to act as a selectively permeable barrier to blood
components. Mechanisms underlying fatty acid-mediated endothelial
cell dysfunction may be related to changes in fatty acid composition
as well as to an increase in cellular oxidative stress. Selective
lipid accumulation and fatty acid changes in endothelial cells
can modulate membrane fluidity, proteoglycan metabolism and signal
transduction mechanisms. Most importantly, dietary fats rich
in certain unsaturated fatty acids, may be atherogenic by enhancing
the formation of reactive oxygen intermediates. A subsequent
imbalance in cellular oxidative stress/antioxidant status can
activate oxidative stress-responsive transcription factors, which
in turn may promote cytokine production, expression of adhesion
molecules on the surface of endothelial cells, and thus intensify
an inflammatory response in atherosclerosis. Our data also suggest
that certain nutrients, which have antioxidant and/or membrane
stabilizing properties, can protect endothelial cells by interfering
with lipid/cytokine-mediated endothelial cell dysfunction. These
findings contribute to the understanding of the interactive role
of dietary fats with inflammatory components, as well as with
nutrients that exhibit antiatherogenic properties, in the development
of atherosclerosis.
Title
HIV-induced cysteine deficiency and T-cell dysfunction--a rationale
for treatment with N-acetylcysteine.
Author
Dröge W; Eck HP; Mihm S
Address
Division of Immunochemistry, Deutsches Krebsforschungszentrum,
Heidelberg, FRG.
Source
Immunol Today, 13(6):211-4 1992 Jun
Abstract
Markedly decreased plasma cystine and cysteine concentrations
have been found in HIV-infected patients at all stages of the
disease and in SIV-infected rhesus macaques. The elevated glutamate
levels found in the same patients aggravate the cysteine deficiency
by inhibiting the membrane transport activity for cystine. The
intact immune system appears to require a delicate balance between
pro-oxidant and antioxidant conditions, maintained by a limited
and well-regulated supply of cysteine. This balance is obviously
disturbed in HIV infection and may contribute to the pathogenesis
of AIDS.
Title
Latent antioxidant deficiency in the East German population--causes
and clinical significance. II
Author
Kuklinski B; Zimmermann R; Rühlmann C; Herzfeld A
Address
Klinik für Innere Medizin, Karl-Marx-Universität Leipzig.
Source
Z Gesamte Inn Med, 45(2):38-42 1990 Jan 15
Abstract
The hitherto yielded results of the research groups for arteriosclerosis
and trace elements of the Medical Clinic of Leipzig University
were summarized and valuated. The most important results were
than in 800 healthy persons of three counties of the GDR who
were examined depending on sex and age a serum selenium deficiency
with regional differences was stated and this deficiency could
be increased by an antiatherogenic mode of nutrition (n = 94,
p less than 0.001). A consecutive depletion of vitamin E out
of normal values was to be explained as a reference of an insufficient
status of antioxidants. Analyses on nearly 1,000 foodstuffs and
sorts of coffee, tea, tobacco, alcohol, etc. showed as cause
a high-degree depletion of vegetable foodstuffs in selenium.
The established daily minimum uptake of selenium of 12 to 15
micrograms by cooked foods was covered by above all cholesterol-rich
animal foodstuffs and was further lowered by their withdrawal.
In a double blind study first results of a supplementation of
sodium selenite referred to a favourable influence on the immune
status. After explanation of the reasons which may lead to an
additional insufficiency of antioxidants was postulated that
the protection from activated oxygen species is indicated both
for the primary prevention of autoimmunigenic, atherogenic and
cancerogenic diseases and for the curative medicine by a supplementation
of selenium.
Title
Serum selenium concentrations in rheumatoid arthritis.
Author
O'Dell JR; Lemley-Gillespie S; Palmer WR; Weaver AL; Moore GF;
Klassen
LW
Address
University of Nebraska Medical Center, Omaha 68198-2265.
Source
Ann Rheum Dis, 50(6):376-8 1991 Jun
Abstract
Selenium is a trace element and an essential part of the enzyme
glutathione peroxidase, which protects cells from oxidative damage.
Selenium has been shown to have antiproliferative, anti-inflammatory,
antiviral, and immune altering effects. Serum selenium concentrations
in 101 patients with seropositive rheumatoid arthritis were found
to be significantly lower than those in 29 normal, healthy controls
(mean (SD) 148 (42) v 160 (25) micrograms/l) and also lower than
those in eight patients with fibrositis (148 (42) v 166 (25)
micrograms/l). It is speculated that serum selenium concentrations
may modulate the effect of viral or other infections in subjects
with the appropriate genetic background and in this way enhance
the development or progression of rheumatoid arthritis.
Title
Antioxidant vitamins and disease--risk of a suboptimal supply
Author
Ballmer PE; Reinhart WH; Gey KF
Address
Departement Medizin, Inselspital, UniversitÍat Bern.
Source
Ther Umsch, 51(7):467-74 1994 Jul
Abstract
Reactive oxygen species (ROS) such as the superoxide (O2.-) and
the hydroxyl radical (OH.) are aggressive chemical compounds
that can induce tissue injury, e.g. by peroxidation of polyunsaturated
fatty acids in cell membranes or directly by DNA damage. Many
pathological conditions are in part caused by ROS. There are
various biological defense systems directed towards radicals:
specific enzymes, e.g. superoxide dismutase or glutathione peroxidase;
nonessential antioxidants, e.g. the plasma proteins and uric
acid; and the essential antioxidants, e.g. vitamin C, vitamin
E and carotenoids. This review focuses on various clinical conditions
where ROS are of major pathogenetic significance: ageing, cancer,
stroke, hematologic disorders, adult respiratory distress syndrome
(ARDS) and organ preservation in transplantation medicine. Moreover,
the complementary system of the vitamins C and E in defense against
ROS is shortly discussed and the need for further studies about
the effects of antioxidant treatment, such as interventional
studies, proposed. The chronic exposure of the organism to ROS
is an important factor for tissue injury in the process of ageing.
Lipofuscin is a typical product of lipid peroxidation and inversely
correlates with longevity of an organism. The ingestion of higher
doses of antioxidative vitamins was recently shown to be protective
for the development of cataracts, a degenerative disorder of
the eye. The impairment of the immune system in elderly people
might be prevented by a higher intake of multivitamin supplements.
Whether supplementation with antioxidative vitamins can extend
the life span in humans, as was shown in experimental animals,
remains unanswered.(Abstract TRUNCATED AT 250 WORDS)
Title
Immunocompetence and oxidant defense during ascorbate depletion
of healthy men.
Author
Jacob RA; Kelley DS; Pianalto FS; Swendseid ME; Henning SM; Zhang
JZ;
Ames BN; Fraga CG; Peters JH
Address
Western Human Nutrition Research Center, USDA Agricultural Research
Service, Presidio of San Francisco, CA 94129.
Source
Am J Clin Nutr, 54(6 Suppl):1302S-1309S 1991 Dec
Abstract
To determine nonscorbutic effects of moderate vitamin C deficiency
we measured immune function and oxidative damage in eight healthy
men (25-43 y) who consumed 5-250 mg/d of ascorbic acid over 92
d on a metabolic unit. During ascorbic acid intakes of 5, 10,
or 20 mg/d, subjects attained a state of moderate ascorbic acid
deficiency as ascorbic acid concentrations in plasma, leucocytes,
semen, and buccal cells dropped to less than 50% of baseline
with no scorbutic symptoms observed. No changes in cell proliferation,
erythrocyte antioxidant enzymes, and DNA strand breaks were observed;
however, blood levels of glutathione and NAD(P) decreased during
ascorbic acid deficiency, as did delayed hypersensitivity responsiveness.
Concentrations of the oxidatively modified DNA base, 8-hydroxydeoxyguanosine
in sperm DNA and fecapentaenes, ubiquitous fecal mutagens, were
increased during ascorbic acid depletion. Moderate vitamin C
deficiency, in the absence of scurvy, results in alteration of
antioxidant chemistries and may permit increased oxidative damage.
Title
N-acetylcysteine (NAC) and glutathione (GSH): antioxidant and
chemopreventive properties, with special reference to lung cancer.
Author
van Zandwijk N
Address
Department of Chest Oncology, HET Nederlands Kanker Institute,
Amsterdam, The Netherlands.
Source
J Cell Biochem Suppl, 22():24-32 1995
Abstract
Lung cancer arises as a focal transformation of chronically injured
epithelium with cigarette smoke as one of its well-recognized
causes. Apart from oxidants (free radicals), cigarette smoke
contains such a multitude of (pre)carcinogens that it is astonishing
that not every heavy smoker becomes a victim of malignancy. This
points to the interindividual variability in susceptibility to
carcinogens; several lines of evidence suggest that metabolic
factors are involved in such variability. Metabolism of carcinogens
as well as the subsequent (multi)steps of carcinogenesis are
affected by host factors and governed by the balance between
opposing forces, such as metabolic activation and detoxification,
formation and scavenging of radicals, and DNA damage and repair,
which seem to imply that carcinogenic compounds can initiate
tumor growth only in amounts saturating detoxification mechanisms.
In this context it is well known that glutathione (GSH) plays
a crucial role in the detoxification of xenobiotics. N-Acetylcysteine
(NAC), an aminothiol and synthetic precursor of intracellular
cysteine and GSH, has been used for many years in Europe as a
mucolytic drug. Clinically, it is a safe agent without major
side effects and has been considered to have a place in cancer
prevention, too. The antimutagenic and anticarcinogenic properties
of NAC could be ascribed to multiple protective mechanisms, such
as NAC nucleophilicity, antioxidant activity, its ability to
act as a precursor of intracellular reduced GSH, modulation of
detoxification, and DNA repair processes. On these grounds, NAC
has emerged as a most promising cancer chemopreventive agent.(Abstract
TRUNCATED AT 250 WORDS)
Title
N-acetylcysteine for lung cancer prevention.
Author
van Zandwijk N
Address
Department of Chest Oncology, The Netherlands, Cancer Institute/Antoni
van Leeuwenhoek Huis, Amsterdam.
Source
Chest, 107(5):1437-41 1995 May
Abstract
Lung cancer arises as a focal transformation of chronically injured
epithelium with cigarette smoke as one of its well recognized
causes. Apart from oxidants, cigarette smoke contains several
precarcinogens, and it is surprising that not every heavy smoker
becomes a victim of malignant disease. This points to the interindividual
variability in susceptibility to carcinogens and there are several
lines of evidence that metabolic factors are involved in such
variability. Metabolism of carcinogens and also the subsequent
multisteps of carcinogenesis are affected by host factors and
governed by the balance between opposite forces, such as metabolic
activation and detoxification, formation, and scavenging of radicals
and DNA damage and repair. This implies that carcinogenic compounds
can initiate tumor growth only in amounts saturating detoxification
mechanisms. In this context it is well known that glutathione
plays a crucial role in the detoxification of xenobiotics. N-acetylcysteine
(NAC), an aminothiol and precursor of intracellular cysteine
and glutathione, has been shown not only to be an efficient antidote
in acetaminophen poisoning but also to possess important chemopreventive
properties. In this article, sites and mechanisms of the therapeutic
action of NAC are reviewed with special reference to its chemopreventive
characteristics.
Title
Attenuation of influenza-like symptomatology and improvement
of cell-mediated immunity with long-term N-acetylcysteine treatment.
Author
De Flora S; Grassi C; Carati L
Address
Institute of Hygiene and Preventive Medicine, University of Genoa,
Italy.
Source
Eur Respir J, 10(7):1535-41 1997 Jul
Abstract
N-acetylcysteine (NAC), an analogue and precursor of reduced
glutathione, has been in clinical use for more than 30 yrs as
a mucolytic drug. It has also been proposed for and/or used in
the therapy and/or prevention of several respiratory diseases
and of diseases involving an oxidative stress, in general. The
objective of the present study was to evaluate the effect of
long-term treatment with NAC on influenza and influenza-like
episodes. A total of 262 subjects of both sexes (78% > or
= 65 yrs, and 62% suffering from nonrespiratory chronic degenerative
diseases) were enrolled in a randomized, double-blind trial involving
20 Italian Centres. They were randomized to receive either placebo
or NAC tablets (600 mg) twice daily for 6 months. Patients suffering
from chronic respiratory diseases were not eligible, to avoid
possible confounding by an effect of NAC on respiratory symptoms.
NAC treatment was well tolerated and resulted in a significant
decrease in the frequency of influenza-like episodes, severity,
and length of time confined to bed. Both local and systemic symptoms
were sharply and significantly reduced in the NAC group. Frequency
of seroconversion towards A/H1N1 Singapore 6/86 influenza virus
was similar in the two groups, but only 25% of virus-infected
subjects under NAC treatment developed a symptomatic form, versus
79% in the placebo group. Evaluation of cell-mediated immunity
showed a progressive, significant shift from anergy to normoergy
following NAC treatment. Administration of N-acetylcysteine during
the winter, thus, appears to provide a significant attenuation
of influenza and influenza-like episodes, especially in elderly
high-risk individuals. N-acetylcysteine did not prevent A/H1N1
virus influenza infection but significantly reduced the incidence
of clinically apparent disease. |
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