A Review on Various Uses of N-Acetyl Cysteine

Abstract

N-acetyl cysteine (NAC), as a nutritional supplement, is a greatly applied antioxidant in vivo and in vitro. NAC is a precursor of L-cysteine that results in glutathione elevation biosynthesis. It acts directly as a scavenger of free radicals, especially oxygen radicals. NAC is a powerful antioxidant. It is also recommended as a potential treatment option for different disorders resulted from generation of free oxygen radicals. Additionally, it is a protected and endured mucolytic drug that mellows tenacious mucous discharges. It has been used for treatment of various diseases in a direct action or in a combination with some other medications. This paper presents a review on various applications of NAC in treatment of several diseases.

Full text

CELL JOURNAL(Yakhteh), Vol 19, No 1, Apr-Jun (Spring) 2017 11
Review Article
A Review on Various Uses of N-Acetyl Cysteine
Vida Mokhtari, M.Sc.1, 2, 3, Parvaneh Afsharian, Ph.D.2, Maryam Shahhoseini, Ph.D.2,
Seyed Mehdi Kalantar, Ph.D.1, Ashraf Moini, M.D.3, 4*
1. Department of Molecular Cytogenetics, Research and Clinical Center for Infertility, University of Medical Sciences,
Yazd, Iran
2. Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine,
ACECR, Tehran, Iran
3. Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for
Reproductive Biomedicine, ACECR, Tehran, Iran
4. Department of Obstetrics and Gynecology, Roointan-Arash Hospital, Tehran, Iran
*Corresponding Address: P.O.Box: 16635-148, Department of Endocrinology and Female Infertility, Reproductive
Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
Email: a_moini@royaninstitute.org
Received: 19/Dec/2015, Accepted: 7/May/2016
Abstract
N-acetyl cysteine (NAC), as a nutritional supplement, is a greatly applied antioxidant in
vivo and in vitro. NAC is a precursor of L-cysteine that results in glutathione elevation
biosynthesis. It acts directly as a scavenger of free radicals, especially oxygen radicals.
NAC is a powerful antioxidant. It is also recommended as a potential treatment option for
different disorders resulted from generation of free oxygen radicals. Additionally, it is a
protected and endured mucolytic drug that mellows tenacious mucous discharges. It has
been used for treatment of various diseases in a direct action or in a combination with
some other medications. This paper presents a review on various applications of NAC in
treatment of several diseases.
Keywords: N-Acetyl Cysteine, Antioxidant, Oxidative Stress
Cell Journal(Yakhteh), Vol 19, No 1, Apr-Jun (Spring) 2017, Pages: 11-17
Citation: Mokhtari V, Afsharian P, Shahhoseini M, Kalantar SM, Moini A. A review on various uses of N-acetyl
cysteine. Cell J. 2017; 19(1): 11-17.
Introduction
N-acetyl cysteine (NAC), as a safe and
inexpensive medication, is commercially accessible
since long-time ago (1). This drug is not found in
natural sources, although cysteine is present in some
meals like chicken and turkey meats, garlic, yogurt,
and eggs (2). NAC is a well-tolerated mucolytic
drug that moderates clinging mucous secretions
and enhances glutathione S-transferase activity.
During oral administration, deacetylation reaction
of NAC happens while passing along the small
intestine as well as liver, thus its bioavailability is
decreased to 4-10%. NAC stimulates glutathione
biosynthesis, promotes detoxication, and acts
directly as a scavenger of free radicals. It is a
powerful antioxidant and a potential treatment
option for diseases characterized by the generation
of free oxygen radicals (3). Studies have shown no
maternal or fetal harmful effects of NAC treatment.
This nutritional supplement is an excellent source
of sulphydryl groups. NAC prevents apoptosis and
oxygen related genotoxicity in endothelial cells by
increasing intracellular levels of glutathione and
decreasing mitochondrial membrane depolarization
(4). The critical antioxidant power of NAC is due to
its role as a precursor of glutathione, which is one of
the most important naturally occurring antioxidants
(5). NAC combination with vitamin E, or vitamins
A+E, as well as essential fatty acids considerably
reduce reactive oxygen species (ROS), leading
to pregnancy rate improvement (6). Studies have
indicated that preserving impact of NAC against
the toxicity of chemicals is due to its dual role as a
nucleophile and as a -SH donor (7). In this study by
reviewing literatures, various applications of NAC
in treatment of some diseases are highlighted.
Polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is one of the

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Various Applications of NAC
most common endocrine glands-related diseases
affecting 5-10% of reproductive-age women (8). This
syndrome is considered as the most common cause
of anovulatory infertility. PCOS is also associated
with pregnancy complications such as recurrent
pregnancy loss (RPL). Different studies report the
prevalence of PCOS in women with a history of
RPL in a wide range of 10-82%. Findings show that
70.7% of PCOS women with a previous RPL had
thrombophilic disorders. In addition, prevalence of
protein C deciency is signicantly higher in PCOS
patients compared to the non-PCOS women (9).
The results of a study showed that women with
PCOS have a high prevalence of metabolic syndrome
and its individual components (obesity, hypertension,
glucose intolerance and triglycerides), particularly
decreased high density lipoprotein cholesterol (10). In
another study, women and their relatives with PCOS
had an increased prevalence of diabetes commonly in
mother’s side of the family (11).
As the rst medication option, clomiphene citrate
(CC) is applied for the induction of ovulation in PCOS
women. A collection of published results for treatment
with CC showed a pregnancy rate and a miscarriage
rate of 36 and 20.4%, respectively. One of the
frequently determined problems of this treatment is
resistance to CC in up to 40% of PCOS patients. NAC
is a mucolytic drug with insulin-sensitizing properties
that has been used successfully as a supporting
therapy in subjects with CC-resistant PCOS (8).
Recent studies have shown that a combination of CC
and NAC considerably increased both ovulation and
pregnancy rates in women with CC-resistant PCOS.
NAC has multiple biological effects, two of which
are potentially and directly related to pregnancy rate
improvement. NAC has mucolytic action, thus it can
revoke the negative effect of CC on cervical mucus.
Simultaneously, it has insulin sensitizing effect that
could assist in issues related to PCOS. The negative
inuence of CC on cervical mucus can create a
"hostile" environment for conception (1).
Researchers evaluated the effect of NAC, known
to resupply stores of the antioxidant glutathione, on
insulin secretion and peripheral insulin resistance
in subjects in association with PCOS. Moreover,
treatment of hyperinsulinemic patients by NAC
was found to tailor control parameters of glucose
in them and consequently, their insulin levels and
peripheral insulin sensitivity were reduced and
increased, respectively. Therefore, the antioxidant
effects of NAC may act as a therapeutic approach
to improve the level of circulating insulin as
well as insulin sensitivity in PCOS patients with
hyperinsulinemia (12).
Premature birth and recurrent pregnancy loss
Premature birth is the most common reason of
perinatal mortality and long-term unhealthiness
in low-income countries (13). Inammation,
fetal infection, and previous preterm delivery
are signicant risk factors for preterm birth and
neonatal brain injury (14). Rising infection with
bacterial vaginosis during pregnancy is related
to a risk factor for preterm delivery and low birth
weight. Antimicrobial medical care is, although,
not adequate for the prevention of preterm birth
and the inammatory as well as anti-inammatory
responses could make problem complex (3).
NAC by having an anti-inammatory outcome
can affect human term and preterm labors. NAC
restrains the inammatory response with no
respect whether infection is started before or after
treatment initiation with the drug. Shahin et al. (3)
concluded that in women with previous preterm
birth and bacterial vaginosis, 0.6 g of NAC daily
can be taken orally along with progesterone after
week 16 of pregnancy to protect against preterm
birth recurrence and improve neonatal outcome.
RPL is dened as the occurrence of three or
more consecutive pregnancy losses in the rst or
early second trimester of pregnancy (less than 20
weeks of gestation). It is one of the most common
clinical problems in reproduction that a certain
cause can be found in only 50% of cases (15).
Many etiologies have been suggested for RPL (16).
For example, molecular genetic background for
RPL is being increasingly understood, and some
polymorphisms associated with RPL have been
reported. According to the research directed up
to now, more than 40 gene products distinctively
have been distinguished to be expressed in women
with RPL compared to healthy women. These
genes may have regulatory roles in establishing
or maintaining normal pregnancy. In this manner,
any nucleotide modications in targeted genes
may result in distinct expression and activity
endangering general well-being during pregnancy.
A recent study showed a relationship between
c.179A>C mutation in the Bax promoter and RPL
and also, two polymorphisms, namely c.90G>C

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Mokhtari et al.
and c.95G>A in exon 1, found among patients
that can be considered as genetic factors making
people susceptible to miscarriages (17). Findings
of the other recent study revealed a new genetic
relationship between occurrences of RPL and
SULF1 gene mutation. SULFs are a protein family of
arylendosulfatase. They act as post synthetic editors
that can selectively release 6-O-sulfate groups from
heparin sulfates, consequently changing the sulfation
patterns of proteoglycans and binding site of many
growth factors. With such unique regulatory activity,
SULFs have an important role in many biological
processes, such as angiogenesis, cell signaling
and embryogenesis. In this gene family, SULF1
is expressed in the large number of embryonic
and adult tissues, while it has an important role
in viability and embryonic development (18). In
a study conducted by some researchers, high rate
of mutations in D-loop of mtDNA was observed
in maternal blood, a fact that may have a direct or
indirect role in inducing RPL. This outcome can
be utilized as part of the RPL evaluation, planning
conceivable medications for enhancing the results
of assisted reproduction (19). Some evidence has
shown that oxidative stress might be a contributory
factor in RPL (16). One phenomenon that is
known as a common patho-physiological pathway
for various etiologies of RPL, can be placental
oxidative stress. Amin concluded that NAC is a
well-tolerated drug that could potentially be an
effective treatment in patients with unexplained
RPL. Administration of a combination of NAC
and folic acid, in comparison with folic acid alone,
is resulted in prolongation of a living pregnancy up
to 20 weeks. In addition, combination of NAC and
folic acid were also associated with a signicant
increase in the take-home baby rate, as compared
to folic acid alone (4).
Acetaminophen toxicity
Acetaminophen administration is reported as
the most common drug overdose in pregnancy.
Acetaminophen readily crosses the placenta and
in toxic doses can result in fetal hepatic necrosis,
premature birth, spontaneous abortion, and fetal
death (2). NAC is an amino acid that contains
thiol group. It has been used for the treatment
of acetaminophen toxicity (20). N-Acetyl-p-
benzoquinonimine is a potent oxidative metabolite
of acetaminophen, resulting in hepatotoxicity, if
it is not reduced by glutathione. NAC is thought
to affect through multiple mechanisms including
replenishing glutathione, reducing N-acetyl-p-
benzoquinonimine directly, and performing non-
specic hepatoprotective actions related to its
antioxidant properties. This compound is used
to treat acetaminophen poisoning throughout
pregnancy (3). It is universally effective to prevent
hepatotoxicity, if it is administrated within 10
hours of acetaminophen overdose (21).
In addition, acetaminophen toxicity is a common
cause of drug-induced hepatotoxicity in children
and adults. NAC has been used for several decades
and it has been proven as a counterpoison choice
in treating acetaminophen-induced hepatotoxicity.
There is considerable clinical evidence to support
the fact that oral and intravenous NAC are equally
effective in the prevention of hepatotoxicity. An
important factor in evaluating the effectiveness of
NAC is the timing of therapy commencement in
relation to the administration. Patients that ingest
a severe overdose and have NAC therapy started
within 8 hours get well and have less than a 10% rate
of occurrence of hepatotoxicity. They generally do
not develop liver failure or death. Those patients
who have chronically taken immoderate doses
of acetaminophen over many hours and/or have
NAC therapy started more than 8 hours after an
acute overdose are at a risk of hepatotoxicity with
approximately 8-50% incidence (22).
Several recent studies have investigated the
antioxidant properties of NAC in feto-placental
metabolism (23, 24). NAC appears to attenuate
placental production of inammatory cytokine
interleukin 6 involved in placenta infection
and inammation in the pregnant rat model. A
murine model demonstrated benet of NAC in a
complicated pregnancy, manipulated by infection
and free radical production, suggesting the ability
of NAC to restore maternal and fetal oxidative
balance to reduce preterm birth caused by different
factors such as acetaminophen toxicity (21).
In vitro studies have shown that oxidative stress
might serve as a signal to initiate and propagate
the inammatory process, resulting in apoptosis of
placental tissues (6). Bloosesky et al. (25) showed
that preventative effect of NAC could reduce fetal
inammatory cytokines in response to maternal
lipopolysaccharide. Their results suggested that
prophylactic NAC administered in pregnancies
was associated with a risk of maternal infection/

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Various Applications of NAC
inammation, likely protecting fetus from adverse
inammatory sequelae.
Administration of N-acetyl cysteine for infertile
patients undergoing assisted reproductive
techniques
Elgindy et al. (5) found that 1200 mg NAC (daily)
supplementation, started with administration
of human menopausal gonadotrophin till the
day of human chorionic gonadotrophin, did
not signicantly increase pregnancy rate in
intracytoplasmic sperm injection (ICSI) cycles
using the long agonist protocol. NAC treatment was
associated with insignicant decrease in granulosa
cell apoptosis, as well as insignicant increase in
fertilization rate and grade-one embryo formation.
Larger-scale studies, possibly with higher doses
and/or longer duration of NAC administration,
should be performed to identify any signicant
effects. In addition, Cheraghi et al. (26) conducted
a study to determine the effect of co-administration
of NAC and metformin on ovulation induction in
PCOS patients with ICSI cycle. They detected that
co-administration of these two components has no
benet for ovulation induction in PCOS patients
with ICSI cycle. In another study, Rizk et al. (27)
investigated the effect of NAC on performance of
CC in ovulation induction. They concluded that
the combination of NAC with CC is an effective
way for ovulation induction in young women
undergoing ICSI cycles.
Chronic bronchitis
Chronic bronchitis is dened as the presence
of chronic productive cough for more than
three months in each of two sequential years.
Therefore, an important goal in the treatment of
chronic bronchitis is to decrease the frequency
and duration of intensication, and to decrease
symptoms in patients with aggravations. In some
European countries, mucolytic drugs, particularly
NAC may be used as an anti-inammatory
drug as well as an antioxidant (28, 29). In these
countries, it is believed that NAC can decrease the
frequency of aggravations and improve symptoms
in patients with chronic bronchitis. Recently, a
comprehensive review in literature survey has
concluded in the eld of the effectiveness of any
oral mucolytic drugs that a decline of aggravations,
days of disability and days of antibiotic treatment
was averagely determined in patients with chronic
clogging pulmonary disease (30).
Ulcerative colitis
Ulcerative colitis is a chronic inammatory
disorder which multiple casual factors can affect it.
Human colitis has many similar characteristics to
acetic acid (AA)-induced colitis, as a reproducible
and simple model. Studies have indicated that
some signaling pathways contributing in cell
apoptosis and growth, angiogenesis, redox-
regulated gene expression, and inammatory
response can be affected by NAC (6, 31-33).
Therefore, NAC may not only protect against
the direct detrimental impacts of oxidants, but
also advantageously modify inammatory events
in colitis (34). The benecial inuences of NAC
were related to the changes including: i. Softened
colonic injury, ii. Decreased oxidative stress, iii.
Lowered cell apoptosis, iv. Increased recovery of
the injured colon, and v. Increased formation of the
tight junction (6).
Liver cancer
Liver cancer is one of the most common life-
threatening malignancies, all over the world
and up to now, there is no effective drug for
the treatment of liver tumors (35). Although,
interferon (IFN) is the most applied medication
in chronic hepatitis and hepatocarcinoma, due to
its immune response activation property and also
regulation of differentiation and cell growth (36).
NAC, as an enhancer of glutathione biosynthesis
(37), is one of the frequently used antioxidant
drugs for treatment of liver disorders (38, 39).
Cell culture and animal models have shown that
NAC can preserve normal cells against toxicity of
radiotherapy and chemotherapy, but not cancerous
cells (37). Administration of NAC may play a
role in treatment of some forms of cancer, while
induced damages in DNA can be completely
blocked by NAC (38).
Muscle performance
Investigations showed no effect of NAC on non-
fatigued muscle, although after three minutes of
repetitive contractions, it caused a considerably
enhanced force output, up to approximately
15%. This means that NAC can improve muscle
performance. This result is originated from the

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Mokhtari et al.
fact that oxidative stress plays a causal role in the
fatigue process, since NAC is a scavenger of free
radicals causing oxidative stress. It has been well-
reported that infusion of NAC can be effective
on enhancing the overall redox status in vivo. It
has also been shown that NAC infusion could
minimize the muscle fatigue (40).
Hemodialysis
Homocysteine (Hcy) is a sulphur-containing
amino acid that is produced in body, by the
metabolism of the methionine amino acid
(41). Hcy level in patients with hemodialysis
is associated with kidney-related disorders.
However, in the treated hemodialysis patients,
some studies have shown that NAC administration
could affect plasma Hcy levels. There are some
reports indicating that NAC, with an antioxidant
property, has declined plasma Hcy level in the end
stage renal disease (ESRD) patients undergoing
hemodialysis. Although, lower dosage of NAC (for
example, 600 mg/day for a period of one month)
could not help to decrease Hcy plasma levels in
these patients (42).
Asthma
Asthma is a chronic disorder associated with
inammation and immune cell inltration of
airways (43). Airway hyper-responsiveness
(AHR) can be originated from consistent presence
of inammatory mediators and immune cells
in airways. AHR is clinically determined with
breathlessness, coughing and wheezing symptoms
(44). Studies showed the preventive effect of
NAC antioxidant on the AHR and steroid resistant
accumulation of inammatory cells in the airways
of the animal model with acute exacerbation of
asthma (45-47).
Alzheimer
Alzheimer disease (AD) is known as a
multifactorial disease with many abnormalities
in physiological, biochemical, and neurochemical
point of view. Aging is the major risk factor for
AD that coexists with other causes of cognitive
decline, particularly vascular dementia (48).
Some factors, such as mitochondrial dysfunction,
abnormal protein aggregation, metal accumulation,
inammation and excitotoxicity play important
roles in AD pathology. Although the relationship
between these factors and development of AD is
multidirectional, oxidative damage is considered
as a common thread linking some of these factors
(49). Results of different studies showed that
lipoic acid (LA) and NAC decreased levels of
oxidative and apoptotic markers via protection of
mitochondrial function (50-53). Combination of
both LA and NAC maximizes this protective effect
suggesting that this may prevent mitochondrial
decay associated with aging and age-related
disorders such as AD. Antioxidant therapies based
on LA and NAC seem promising since they can
act on mitochondria, one key source of oxidative
stress in aging and neurodegeneration (50).
Parkinson
Parkinson disease (PD) is a very prevalent
neurodegenerative disorder caused by unknown
deterioration of cells which generate dopamine
in the pars compacta, a part of the substantial
nigra located in the midbrain (54). In terms of
pathogenesis, PD appears to be multi-factorial
disorder, including environmental factors, acting
on genetically vulnerable individuals when they
are older (55, 56). A wide range of both genetic
and environmental factors have been proposed as
contributing to the initiation and progression of
PD, but aging is the single most important risk
factor for this disorder and undoubtedly interferes
in PD progression through its accumulative
oxidative damage, decrease in antioxidant ability
and impairment of mitochondrial bio-energetic
capacity in the brain (57, 58). Taking into account
that most of PD patients experience accumulative
oxidative damage, some clinical studies have
demonstrated the controversial effect of some
antioxidant administrations -such as NAC- on
treatment of PD (59-61). Some improvements have
been reported for systemic administration of NAC
in animal models, such as: i. Enhancement of brain
level of glutathione, ii. Reduction of oxidative
damage-markers, iii. Enhancement of brain
synaptic and non-synaptic brain mitochondrial
complex I activities, and iv. Protection against
dopamine-induced cell death (59).
Conclusion
A review on NAC literature shows that this
agent is a safe and well-tolerated supplementary
drug without any considerable side effects. It

CELL JOURNAL(Yakhteh), Vol 19, No 1, Apr-Jun (Spring) 2017 16
Various Applications of NAC
is as an antioxidant with a free radical scavenger
property, as important characteristic of this medical
supplement. It has been used as a benecial drug
treatment for some disorders such as poly cystic
ovary syndrome patients with CC resistance,
preterm birth, acetaminophen toxicity, RPL, chronic
bronchitis, ulcerative colitis, liver cancer, muscle
performance, hemodialysis, asthma, Alzheimer
and Parkinson. Although in some cases, such as
improving pregnancy rate in ICSI cycles, NAC
action is still unclear and further investigations are
necessary.
Acknowledgments
The authors would like to thank Royan Institute
experts for their helpful comments and sugges-
tions. There is no conict of interest in this study.
References
1. Youssef G, Meguid Ali A, Alaa N, Makin B, Waly M, Abou-
Setta A. N-acetyl-cysteine in anovulatory women: the im-
pact of postcoital test. Middle East Fertil Soc J. 2006; 11:
109-112.
2. Larsson SC, Håkansson N, Wolk A. Dietary cysteine and
other amino acids and stroke incidence in women. Stroke.
2015; 46(4): 922-926.
3. Shahin AY, Hassanin IM, Ismail AM, Kruessel JS, Hirch-
enhain J. Effect of oral N-acetyl cysteine on recurrent pre-
term labor following treatment for bacterial vaginosis. Int J
Gynaecol Obstet. 2009; 104(1): 44-48.
4. Amin AF, Shaaban OM, Bediawy MA. N-acetyl cysteine
for treatment of recurrent unexplained pregnancy loss.
Reprod Biomed Online. 2008; 17(5): 722-726.
5. Elgindy EA, El-Huseiny AM, Mostafa MI, Gaballah AM,
Ahmed TA. N-acetyl cysteine: could it be an effective ad-
juvant therapy in ICSI cycles? A preliminary study. Reprod
Biomed Online. 2010; 20(6): 789-796.
6. Agarwal A, Allamaneni SSR. Oxidants and antioxidants in
human fertility. Middle East Fertil Soc J. 2004; 9(3): 187-
197.
7. Wang Q, Hou Y, Yi D, Wang L, Ding B, Chen X, et al. Pro-
tective effects of N-acetyl cysteine on acetic acid-induced
colitis in a porcine model. BMC Gastroenterol. 2013; 13:
133.
8. Nasr A. Effect of N-acetyl cysteine after ovarian drilling in
clomiphene citrate-resistant PCOS women: a pilot study.
Reprod Biomed Online. 2010; 20(3): 403-409.
9. Moini A, Tadayon SH, Tehranian A, Mohammadi Yeganeh
L, Akhoond MR, Salman Yazdi R. Association of throm-
bophilia and polycystic ovarian syndrome in women with
history of recurrent pregnancy loss. Gynecol Eendocrinol.
2012; 28(8): 590-593.
10. Moini A, Javanmard F, Eslami B, Aletaha N. Prevalence
of metabolic syndrome in polycystic ovarian syndrome
women in a hospital of Tehran. Iran J Reprod Med. 2012;
10(2): 127-130.
11. Moini A, Eslami B. Familial associations between poly-
cystic ovarian syndrome and common diseases. J Assist
Reproduction Genet. 2009; 26(2-3): 123-127.
12. Sekhon LH, Gupta S, Kim Y, Agarwal A. Female infertil-
ity and antioxidants. Curr Womens Health Rev. 2010; 6:
84-95.
13. Woods JR. Reactive oxygen species and preterm prema-
ture rupture of membranes a review. Placenta. 2001; 22
Suppl A: S38-44.
14. Mercer BM, Goldenberg RL, Das A, Moawad AH, Iams
JD, Meis PJ. The preterm prediction study: a clinical risk
assessment system. Am J Obstet Gynecol. 1996; 174(6):
1885-1893.
15. American College of Obstetricians and Gynecologists.
ACOG practice bulletin. Management of recurrent preg-
nancy loss. Number 24, February 2001. (Replaces Tech-
nical Bulletin Number 212, September 1995). American
College of Obstetricians and Gynecologists. Int J Gynae-
col Obstet. 2002; 78(2): 179-190.
16. Poston L, Raijmakers MT. Trophoblast oxidative stress,
antioxidants and pregnancy outcome--a review. Placenta.
2004; 25 Suppl A: S72-78.
17. Mohammad Seyedhassani S, Houshmand M, Mehdi
Kalantar S, Aatoonian A, Modabber G, Hashemi Gorgi
F, et al. BAX pro-apoptotic gene alterations in repeated
pregnancy loss. Arch Med Sci. 2011; 7(1): 117-122.
18. Zahraei M, Sheikhha MH, Kalantar SM, Ghasemi N, Jaha-
ninejad T, Rajabi S, et al. The association of arylendosul-
fatase 1 (SULF1) gene polymorphism with recurrent mis-
carriage. J Assist Reprod Genet. 2014; 31(2): 157-161.
19. Seyedhassani SM, Houshmand M, Kalantar SM, Modab-
ber G, Aatoonian A. No mitochondrial DNA deletions but
more D-loop point mutations in repeated pregnancy loss.
J Assist Reprod Genet. 2010; 27(11): 641-648.
20. Harada M, Kishimoto K, Furuhashi T, Naito K, Nakashima
Y, Kawaguchi Y, et al. Infertility observed in reproductive
toxicity study of N-acetyl L-cysteine in rats. Biol Reprod.
2003; 69(1): 242-247.
21. Crowell C, Lyew RV, Givens M. Caring for the mother, con-
centrating on the fetus: intravenous N-acetyl cysteine in
pregnancy. Am J Emerg Med. 2008; 26(6): 735. e1-735.e2.
22. Green JL, Heard KJ, Reynolds KM, Albert D. Oral and in-
travenous acetylcysteine for treatment of acetaminophen
toxicity: A systematic review and meta-analysis. West J
Emerg Med. 2013; 14(3): 218-226.
23. Beloosesky R, Gayle DA, Amidi F, Nunez SE, Babu J, De-
sai M, et al. N-acetyl-cysteine suppresses amniotic uid
and placenta inammatory cytokine responses to lipopoly-
saccharide in rats. Am J Obstet Gynecol. 2006; 194(1):
268-273.
24. Paintlia MK, Paintlia AS, Singh AK, Singh I. Attenuation
of lipopolysaccharide-induced inammatory response and
phospholipids metabolism at the feto-maternal interface
by N-acetyl cysteine. Pediatr Res. 2008; 64(4): 334-339.
25. Beloosesky R, Weiner Z, Khativ N, Maravi N, Mandel
R, Boles J, et al. Prophylactic maternal n-acetylcysteine
before lipopolysaccharide suppresses fetal inammatory
cytokine responses. Am J Obstet Gynecol. 2009; 200(6):
665.e1-665.e1-5.
26. Cheraghi E, Mehranjani MS, Shariatzadeh MA, Nasr Es-
fahani MH, Ebrahimi Z. Co-administration of metformin
and n-acetyl cysteine fails to improve clinical manifesta-
tions in pcos individual undergoing icsi. Int J Fertil Steril.
2014; 8(2): 119-128.
27. Rizk AY, Bedaiwy MA, Al-Inany HG. Clomiphene-acetyl
cysteine combination as a new protocol to a friendly IVF
cycle. Middle East Fertil Soc J. 2005; 10(2): 130-134.
28. Larson M. Clinical recognition of N-acetyl cysteine in
chronic bronchitis. Eur Respir Rev. 1992; 2(7): 5-8.
29. Tunek A. Possible mechanisms behind the anti-inamma-
tory effects of N-acetyl cysteine; is metabolism essential?
Eur Respir Rev. 1992; 2(7): 35-38.
30. Stey C, Steurer J, Bachmann S, Medici TC, Tramèr MR.

CELL JOURNAL(Yakhteh), Vol 19, No 1, Apr-Jun (Spring) 2017 17
Mokhtari et al.
The effect of oral N-acetylcysteine in chronic bronchitis: a
quantitative systematic review. Eur Respir J. 2000; 16(2):
253-262.
31. Sadowska AM, Manuel-Y-Keenoy B, De Backer WA.
Antioxidant and anti-inammatory efcacy of NAC in the
treatment of COPD: discordant in vitro and in vivo dose-
effects: a review. Pulm Pharmacol Ther. 2007; 20(1): 9-22.
32. Jones DP, Maellaro E, Jiang S, Slater AF, Orrenius S. Ef-
fects of N-acetyl-L-cysteine on T-cell apoptosis are not
mediated by increased cellular glutathione. Immunol Lett.
1995; 45(3): 205-209.
33. Cai T, Fassina G, Morini M, Aluigi MG, Masiello L, Fon-
tanini G, et al. N-acetylcysteine inhibits endothelial cell
invasion and angiogenesis. Lab Invest. 1999; 79(9): 1151-
1159.
34. Cuzzocrea S, Mazzon E, Dugo L, Serraino I, Ciccolo A,
Centorrino T, et al. Protective effects of N-acetyl cysteine
on lung injury and red blood cell modication induced by
carrageenan in the rat. FASEB J. 2001; 15(7): 1187-1200.
35. Kretzman NA, Chiela E, Matte U, Marroni N, Marroni CA.
N-acetylcysteine improves antitumoural response of inter-
feron alpha by NF-kB downregulation in liver cancer cells.
Comp Hepatol. 2012; 11(1): 4.
36. Goldstein D, Laszlo J. The role of interferon in cancer
therapy: a current perspective. CA Cancer J Clin. 1988;
38(5): 258-277.
37. Wanamarta AH, van Rijn J, Blank LE, Haveman J, van
Zandwijk N, Joenje H. Effect of N-acetyl cysteine on the
antiproliferative action of X-rays or bleomycin in cultured
human lung tumor cells. J Cancer Res Clin Oncol. 1989;
115(4): 340-344.
38. Millea PJ. N-acetyl cysteine: multiple clinical applications.
Am Fam Physician. 2009; 80(3): 265-269.
39. Moreno-Otero R, Trapero-Marugn M. Hepatoprotective
effects of antioxidants in chronic hepatitis C. World J Gas-
troenterol. 2010; 16(15): 1937-1938.
40. Kerksick C, Willoughby D. The antioxidant role of glu-
tathione and N-acetyl cysteine supplements and exercise-
induced oxidative stress. J Int Soc Sports Nutr. 2005; 2(2):
38-44.
41. Wierzbicki AS. Homocysteine and cardiovascular dis-
ease: a review of the evidence. Diab Vasc Dis Res. 2007;
4(2): 143-150.
42. Khosravi M, Shohrati M, Falaknazi K. Does N-acetyl
cysteine have a dose-dependent effect on plasma homo-
cysteine concentration in patients undergoing hemodialy-
sis? Int J Nephrol Urol. 2009; 1(1): 27-32.
43. Song DJ, Min MG, Miller M, Cho JY, Broide DH. Environ-
mental tobacco smoke exposure does not prevent corti-
costeroids reducing inammation, remodeling, and airway
hyperreactivity in mice exposed to allergen. Am J Physiol
Lung Cell Mol Physiol. 2009; 297(2): L380-387.
44. Li JJ, Wang W, Baines KJ, Bowden NA, Hansbro PM,
Gibson PG, et al. IL-27/IFN-γ induce MyD88-dependent
steroid-resistant airway hyperresponsiveness by inhibit-
ing glucocorticoid signaling in macrophages. J Immunol.
2010; 185(7): 4401-4409.
45. Eftekhari P, Hajizadeh S, Raofy MR, Masjedi MR, Yang M,
Hansbro N, et al. Preventive effect of N-acetylcysteine in
a mouse model of steroid resistant acute exacerbation of
asthma. Excli J. 2013; 12: 184-192.
46. Blesa S, Cortijo J, Mata M, Serrano A, Closa D, Santan-
gelo F, et al. Oral N-acetyl cysteine attenuates the rat pul-
monary inammatory response to antigen. Eur Respir J.
2003; 21(3): 394-400.
47. Blesa S, Cortijo J, Martinez-Losa M, Mata M, Seda E,
Santangelo F, et al. Effectiveness of oral N-acetyl cysteine
in a rat experimental model of asthma. Pharmacol Res.
2002; 45(2): 135-140.
48. Markesbery WR. The role of oxidative stress in Alzheimer
disease. Arch Neurol. 1999; 56(12): 1449-1452.
49. Perry G, Castellani RJ, Hirai K, Smith MA. Reactive oxy-
gen species mediate cellular damage in Alzheimer dis-
ease. J Alzheimers Dis. 1998; 1(1): 45-55.
50. Moreira PI, Harris PL, Zhu X, Santos MS, Oliveira CR,
Smith MA, et al. Lipoic acid and N-acetyl cysteine de-
crease mitochondrial-related oxidative stress in Alzheimer
disease patient broblasts. J Alzheimers Dis. 2007; 12(2):
195-206.
51. Moreiraa PI, Carvalhob C, Zhuc X, Smithc MA, Perryd
G. Mitochondrial dysfunction is a trigger of Alzheimer’s
disease pathophysiology. Biochim Biophys Acta. 2010;
1802(1): 2-10.
52. Hardas SS, Sultana R, Clark AM, Beckett TL, Szweda LI,
Murphy MP, et al. Oxidative modication of lipoic acid by
HNE in Alzheimer disease brain. Redox Biol. 2013; 1: 80-85.
53. Kerksick C, Willoughby D. The Antioxidant role of glu-
tathione and N-acetyl cysteine supplements and exercise-
induced oxidative stress. J Int Soc Sports Nutr. 2005; 2:
38-44.
54. Agid Y, Ruberg M, Javoy-Agid F, Hirsch E, Raisman-Vo-
zari R, Vyas S, et al. Are dopaminergic neurons selectively
vulnerable to Parkinson’s disease? Adv Neurol. 1993; 60:
148-164.
55. Veldman BA, Wijn AM, Knoers N, Praamstra P, Horstink
MW. Genetic and environmental risk factors in Parkinson’s
disease. Clin Neurol Neurosurg. 1998; 100(1): 15-26.
56. Williams AC, Smith ML, Waring RH, Ramsden DB. Idi-
opathic Parkinson’s disease: a genetic and environmental
model. Adv Neurol. 1999; 80: 215-218.
57. Bowling AC, Mutisya EM, Walker LC, Price DL, Cork
LC, Beal MF. Age-dependent impairment of mitochon-
drial function in primate brain. J Neurochem. 1993; 60(5):
1964-1967.
58. Curti D, Giangare MC, Redol ME, Fugaccia I, Benzi G.
Age-related modication of cytochrome c oxidase activity
in discrete brain regions. Mech Ageing Dev. 1990; 55(2):
171-180.
59. Martinez-Banclocha MA. N-acetyl cysteine in the treat-
ment of Parkinson’s disease. What are we waiting for?
Med Hypotheses. 2012; 79(1): 8-12.
60. Shahripour RB, Harrigan MR, Alexandrov AV. N-acetyl
cysteine (NAC) in neurological disorders: mechanisms of
action and therapeutic opportunities. Brain Behav. 2014;
4(2): 108-122.
61. Dehay B, Bourdenx M, Gorry P, Przedborski S, Vila M,
Hunot S, et al. Targeting α-synuclein for treatment of Par-
kinson’s disease: mechanistic and therapeutic considera-
tions. Lancet Neurol. 2015; 14(8): 855-866.