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Role of ROS and Nutritional Antioxidants in Human Diseases


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The overproduction of reactive oxygen species (ROS) has been implicated in the development of various chronic and degenerative diseases such as cancer, respiratory, neurodegenerative, and digestive diseases. Under physiological conditions, the concentrations of ROS are subtlety regulated by antioxidants, which can be either generated endogenously or externally supplemented. A combination of antioxidant-deficiency and malnutrition may render individuals more vulnerable to oxidative stress, thereby increasing the risk of cancer occurrence. In addition, antioxidant defense can be overwhelmed during sustained inflammation such as in chronic obstructive pulmonary diseases, inflammatory bowel disease, and neurodegenerative disorders, cardiovascular diseases, and aging. Certain antioxidant vitamins, such as vitamin D, are essential in regulating biochemical pathways that lead to the proper functioning of the organs. Antioxidant supplementation has been shown to attenuate endogenous antioxidant depletion thus alleviating associated oxidative damage in some clinical research. However, some results indicate that antioxidants exert no favorable effects on disease control. Thus, more studies are warranted to investigate the complicated interactions between ROS and different types of antioxidants for restoration of the redox balance under pathologic conditions. This review highlights the potential roles of ROS and nutritional antioxidants in the pathogenesis of several redox imbalance-related diseases and the attenuation of oxidative stress-induced damages.
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fphys-09-00477 May 16, 2018 Time: 17:2 # 1
published: 17 May 2018
doi: 10.3389/fphys.2018.00477
Edited by:
Murugesan Velayutham,
University of Pittsburgh, United States
Reviewed by:
Michalis G. Nikolaidis,
Aristotle University of Thessaloniki,
Mutay Aslan,
Akdeniz University, Turkey
Li Zuo
These authors have contributed
equally to this work.
Specialty section:
This article was submitted to
Oxidant Physiology,
a section of the journal
Frontiers in Physiology
Received: 02 February 2018
Accepted: 16 April 2018
Published: 17 May 2018
Liu Z, Ren Z, Zhang J, Chuang C-C,
Kandaswamy E, Zhou T and Zuo L
(2018) Role of ROS and Nutritional
Antioxidants in Human Diseases.
Front. Physiol. 9:477.
doi: 10.3389/fphys.2018.00477
Role of ROS and Nutritional
Antioxidants in Human Diseases
Zewen Liu1,2, Zhangpin Ren3, Jun Zhang4, Chia-Chen Chuang1,5 ,
Eswar Kandaswamy1, Tingyang Zhou1,5 and Li Zuo1,5*
1Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, The Ohio State
University College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States,
2Department of Anesthesiology, Affiliated Ezhou Central Hospital, Wuhan University, Ezhou, China, 3Department of
Pediatrics, Affiliated Ezhou Central Hospital, Wuhan University, Ezhou, China, 4Department of Rehabilitation, Affiliated Ezhou
Central Hospital, Wuhan University, Ezhou, China, 5Interdisciplinary Biophysics Graduate Program, The Ohio State
University, Columbus, OH, United States
The overproduction of reactive oxygen species (ROS) has been implicated in
the development of various chronic and degenerative diseases such as cancer,
respiratory, neurodegenerative, and digestive diseases. Under physiological conditions,
the concentrations of ROS are subtlety regulated by antioxidants, which can be either
generated endogenously or externally supplemented. A combination of antioxidant-
deficiency and malnutrition may render individuals more vulnerable to oxidative stress,
thereby increasing the risk of cancer occurrence. In addition, antioxidant defense
can be overwhelmed during sustained inflammation such as in chronic obstructive
pulmonary diseases, inflammatory bowel disease, and neurodegenerative disorders,
cardiovascular diseases, and aging. Certain antioxidant vitamins, such as vitamin D,
are essential in regulating biochemical pathways that lead to the proper functioning of
the organs. Antioxidant supplementation has been shown to attenuate endogenous
antioxidant depletion thus alleviating associated oxidative damage in some clinical
research. However, some results indicate that antioxidants exert no favorable effects
on disease control. Thus, more studies are warranted to investigate the complicated
interactions between ROS and different types of antioxidants for restoration of the
redox balance under pathologic conditions. This review highlights the potential roles of
ROS and nutritional antioxidants in the pathogenesis of several redox imbalance-related
diseases and the attenuation of oxidative stress-induced damages.
Keywords: antioxidants, cancer, GI diseases, neurodegenerative diseases, oxidative stress, respiratory diseases,
Malnutrition is a poor prognostic sign in various diseases, and it is considered a
major health concern in developing countries (Muller and Krawinkel, 2005). Reactive
oxygen species (ROS) are involved in many important cellular activities including gene
transcription, signaling transduction, and immune response. Common ROS include hydroxyl
radical (OH), superoxide (O2•−) and hydrogen peroxide (H2O2) (Rogers et al., 2014;
Zuo et al., 2015b). An overproduction of ROS can result in oxidative damage to
biomolecules such as lipids, proteins, and DNA, which has been implicated in the
development of aging as well as various ailments including cancer, respiratory, cardiovascular,
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Liu et al. Nutritional Antioxidants in Oxidative Diseases
neurodegenerative, and digestive diseases. It is reported that
the deleterious effects of excess ROS, or oxidative stress
(OS), eventually lead to cell death [71]. The body has
equipped several mechanisms to counteract the detrimental
effects of OS. Antioxidants, either endogenously generated
or externally supplied, are capable of scavenging ROS and
reducing the oxidation of cellular molecules, thus alleviating
OS (Gilgun-Sherki et al., 2001). Antioxidants obtained from
the diet are essential in supplying endogenous antioxidants
for the neutralization of OS. Indeed, malnutrition and certain
antioxidant deficiencies have been correlated with diseases
such as chronic obstructive pulmonary disease (COPD) and
Crohn’s disease (CD) (King et al., 2008;Alzoghaibi, 2013).
A disturbed nutritional and redox balance is frequently observed
in these patients. Malnutrition-induced antioxidant deficiency
may contribute to increased risks of disease occurrence and
poor treatment outcomes (Ames and Wakimoto, 2002;Evatt
et al., 2008;Schols et al., 2014). Currently, the clinical awareness
of nutritional balance in disease occurrence, progression, and
outcomes is limited. An update on the literature review that
focuses on the relationship between patients’ nutritional status
and disease development is needed. In this review, we will outline
the roles of ROS in common OS-associated diseases and aging as
well as discuss the effects of nutritional antioxidants as treatments
or adjuvants.
Respiratory diseases such as COPD and asthma have been
identified as major health problems due to increased prevalence
and mortality worldwide (Masoli et al., 2004;Pauwels and
Rabe, 2004). Environmental exposures to air pollutants and
cigarette smoke contribute greatly to an increase in OS in COPD
(Figure 1). The toxicity of oxidants directly damages alveoli and
connective tissues of the lungs, exacerbating the development
of COPD (van Eeden and Sin, 2013). Excessive ROS formation
can also activate inflammatory cells, which in turn generate
more ROS in the lungs. This process initiates a vicious cycle
of chronic inflammation and OS, as seen in COPD (van Eeden
and Sin, 2013). OS is also implicated in the pathophysiology
of asthma (Comhair and Erzurum, 2010). Although it remains
inconclusive regarding whether increased OS in asthma is a
causative factor of the disease or a consequence of inflammation,
OS is suggested to play a pivotal role in asthma progression
(Cho and Moon, 2010). In bronchial asthma, OS aggravates
airway inflammation by activating transcription factors such
as nuclear factor-kappa B (NF-κB), mitogen-activated protein
kinase (MAPK), activator protein-1 (AP-1), as well as pro-
inflammatory mediators (Figure 1). Moreover, it enhances airway
hyper-responsiveness and stimulates mucin secretion, both of
which are associated with severe asthma (Fitzpatrick et al., 2009;
Cho and Moon, 2010;Zuo et al., 2016). OS-induced damages
in the respiratory system and the reduced antioxidant defenses
further lead to an increase in endogenous ROS formation (Jiang
et al., 2014).
In addition to OS, low body mass index (BMI) and
malnutrition are suggested to correlate with the severity of
COPD (King et al., 2008). Underweight COPD patients tend
to experience more pulmonary damage, exercise intolerance,
and increased mortality rates, in comparison to individuals
with normal weights (King et al., 2008;Ferreira et al., 2012).
Malnutrition can lead to respiratory muscle mass reduction,
which lowers the strength and endurance of these muscles
(Ferreira et al., 2012). In addition, decreased intake or availability
of dietary antioxidants such as vitamins C and E, carotenoids, and
polyphenols, can weaken the antioxidant system and exacerbate
disease progression (Figure 1 and Table 1) (Sies et al., 2005;
King et al., 2008). A dietary pattern that is rich in vegetables,
fruits, fish, and whole grains has been associated with improved
pulmonary function and a lower risk of COPD (Varraso et al.,
2015). It is suggested that nutritional supplementation enhances
respiratory muscle function in malnourished COPD patients,
thereby improving their quality of life (Ferreira et al., 1998).
For example, Hornikx et al. (2012) reported that high doses
of vitamin D supplementation strengthen respiratory muscle
function and exercise capacity in individuals with COPD. As the
most well-known nutritional antioxidant, vitamin C is capable of
reducing oxidative damages and inflammation in the pulmonary
system by scavenging excess ROS and activating NF-κB pathway,
respectively (Tecklenburg et al., 2007). Furthermore, melatonin,
a powerful antioxidant and a regulator of the sleep-wake cycle,
can also attenuate OS-related lung deterioration (Figure 1 and
Table 1) (Gumral et al., 2009). These findings support the
potential use of nutritional antioxidants as an adjuvant to COPD
treatment. Similarly, several observational studies suggest that
nutritional antioxidants from diets or supplements can improve
asthma control and lung function in asthmatic patients (Moreno-
Macias and Romieu, 2014). A systematic review has proposed
that there is an inverse association between dietary intake of
vitamins A and C and incidence of asthma (Table 1) (Allen
et al., 2009). Vitamin C functions in conjunction with vitamin E
to stimulate the regeneration of membrane-bound α-tocopherol
from its oxidized states (Moreno-Macias and Romieu, 2014).
In addition, dietary carotenoids have been shown to correlate
with improved asthma outcomes and lung function (Wood et al.,
The linkage between OS and the development of respiratory
diseases suggests a pivotal role of nutritional antioxidants
(Romieu, 2005). Vulnerable populations include those with
deficiency in dietary antioxidants, increased exposure to
environmental sources of oxidants, and poor access to nutritional
antioxidants (Moreno-Macias and Romieu, 2014). It is important
to note that although antioxidants may help to mitigate the
progression of respiratory diseases, antioxidant supplements
can act as pro-oxidants or OS inducers if consumed at
levels that significantly surpass the recommended dietary
intake (Pham-Huy et al., 2008). The potential benefits and
risks of nutritional antioxidant supplementation trials in
respiratory diseases should be considered on a case-by-case
basis. Furthermore, it remains unknown whether OS is a
consequence or the causative factor for some pulmonary
diseases. Therefore, antioxidant treatment may not be an
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FIGURE 1 | Schematic illustrating the roles of OS and nutrient antioxidants in COPD. AP-1, activator protein-1; COPD, chronic obstructive pulmonary diseases;
MAPK, mitogen-activated protein kinase; OS, oxidative stress.
effective approach to modify disease progression although it
may be able to alleviate OS-related symptoms (Margaritelis,
Cardiovascular diseases (CVD) are the leading cause of mortality
in the United States, resulting in nearly one million deaths each
year (Madamanchi et al., 2005;Heidenreich et al., 2011). The
majority of CVD is correlated with atherosclerosis development,
in which OS play a causal role (Madamanchi et al., 2005).
Excessive ROS can be generated in vascular cells from NAD(P)H
oxidase (Nox), nitric oxide synthases (NOS) uncoupling, and
mitochondria, which cause oxidative modifications of low density
lipoprotein (LDL) (Azumi et al., 2002;Ambrose and Barua,
2004;Madamanchi et al., 2005). The oxidized LDL (ox-LDL)
transported through the arterial lumens induces apoptosis of
endothelial cells and smooth muscle cells (SMCs). By taking
up ox-LDL, macrophages may transform into foam cells, which
secrete growth mediators to attract SMCs into the intima.
SMCs can secret extracellular matrix that forms a thin fibrous
cap surrounding the fatty streak (Madamanchi et al., 2005;
Cachofeiro et al., 2008). With the continuous propagation of
SMCs, monocytes, and macrophages, fatty streaks are ultimately
converted into more advanced fibrous plaque (Madamanchi
et al., 2005), potentially leading to vessel occlusion (Cachofeiro
et al., 2008). Further, OS has also been implicated in the
development cardiac hypertrophy, ischemic-reperfusion injury,
and myocyte apoptosis, all of which may contribute to heart
failure (Madamanchi et al., 2005;Zhou et al., 2018).
Considering the implications of ROS in CVD development,
numerous studies have been performed to evaluate the effects
of nutritional antioxidants in CVD patients. Consumption of
fruit and vegetable is found to increase the levels of antioxidants
such as carotene and vitamin C in the blood as well as decrease
the cholesterol oxidation (Zino et al., 1997;Asplund, 2002).
Therefore, the potential benefits of fruits and vegetables in CVD
have been broadly investigated. In a meta-analysis consisting of
16 prospective cohort studies and 833,234 participants, CVD-
related mortality was found to be inversely correlated with
fruit and vegetable consumption (Wang et al., 2014a). Another
study involving 2002 patients with coronary atherosclerosis
showed that supplementation of natural α-tocopherol (RRR-
AT) can significantly reduce the incidence of CVD-related death
and non-fatal myocardial infarction (Table 1) (Stephens et al.,
1996). However, different results are present suggesting no
beneficial effect of vitamin supplementation on CVD mortality
or morbidity (Kris-Etherton et al., 2004). For example, a meta-
analysis study, which involved 81,788 participants, reported that
daily supplementation of either vitamin E at a dose of 50–800
IU or βcarotene at a dose of 15–80 mg did not decrease the
mortality associated with CVD (Vivekananthan et al., 2003).
Therefore, vitamin E and βcarotene may not be the only active
constituent of fruits and vegetables that exert cardiovascular
protective effects. Instead, other antioxidant compounds such as
lycopene and polyphenols could play a more important role in the
protection against CVD as will be discussed below (Ignarro et al.,
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TABLE 1 | Roles of nutritional antioxidants in human diseases and aging.
Nutritional antioxidant Common dietary sources Supplemental effects on human diseases or aging
Anthocyanin Strawberries, black rice (Peng et al., 2014;
Winter et al., 2017).
Alleviated astrogliosis and preserved neuromuscular
junctions and muscle function in ALS (Winter et al., 2017).
Extended lifespan in animal models (Peng et al., 2014).
Lipoic acid Muscle meats, kidney, liver, and heart; low content in fruits
and vegetables (Shay et al., 2009).
Protected neurons against OS-induced mitochondrial
dysfunction (Moreira et al., 2010;
Zuo and Motherwell, 2013).
Lycopene Tomatoes, watermelon, papaya, apricot, and pink grapefruit
(Sesso et al., 2005;Wood et al., 2012).
Improved clinical asthma outcomes by suppressing
airway inflammation (Wood et al., 2012).
Reduced LDL oxidation in blood (Ignarro et al., 2007).
Intake of lycopene was inversely correlated with CVD
incidence (Kohlmeier and Hastings, 1995;
Arab and Steck, 2000;Rao and Agarwal, 2000).
Melatonin White mustard (seed), black mustard (seed), almond (seed),
celery, walnuts, sweet corn, rice
(Bonnefont-Rousselot and Collin, 2010).
Attenuated OS-related lung deterioration in lung diseases
(Gumral et al., 2009).
Phytochemicals Fruits (Mazo et al., 2017)Potentially prevent or delay the development of PD
(Mazo et al., 2017).
Polyphenols Fruit, vegetables, coffee, tea, and cereals
(Ignarro et al., 2007).
Higher polyphenol intake was linked with reduced risk of
CVD (Vita, 2005).
Anti-cancer activity against lung, breast, tongue, gastric,
larynx, colon, and prostate cancers
(Manikandan et al., 2012;Sak, 2014).
Extended lifespan in animal models (Peng et al., 2014).
Resveratrol Purple wine and peanuts (Anekonda, 2006). Protected neurons from Aβand OS-induced toxicity
(Anekonda, 2006;Bellaver et al., 2014).
Selenium Tuna, oyster, salmon, eggs, green peas, pepper, onion,
pork, beef (Navarro-Alarcon and Cabrera-Vique, 2008).
A combination of selenium and vitamin E protected
against oxidative damage in the colon of rats with
ulcerative colitis (Bitiren et al., 2010).
Theaflavins Black tea (Peng et al., 2014). Extended lifespan in animal models (Peng et al., 2014).
Vitamin A Eggs, dairy products, orange-colored fruits, green leafy and
yellow-colored vegetables (Tang, 2010).
Intake of vitamins A and C was inversely associated with
the incidence of asthma (Allen et al., 2009).
Vitamin C Strawberry, Grapefruit, broccoli, and orange
(Proteggente et al., 2002).
Reduced airway inflammation and exercise-induced
bronchoconstriction in asthma (Tecklenburg et al., 2007).
Intake of vitamins A and C was inversely associated with
the incidence of asthma (Allen et al., 2009).
Vitamin D Fatty ocean fish, sunlight (Holick et al., 2011). Improved respiratory muscle function and exercise
capability in COPD (Hornikx et al., 2012).
Increased the bone mineral density and reduced the risk
of hip and other fractures in the elderly (Lips, 2001).
Vitamin E Wheat germ oil, sunflower oil, hazelnut, and almonds
(Reboul et al., 2006)
Reduced the incidence of CVD death and non-fatal
myocardial infarction (Stephens et al., 1996).
Attenuated functional decline associated with AD
(Sano et al., 1997).
A combination of vitamin E and coenzyme Q10 improved
energy generation in some cases of Friedreich ataxia
(Lodi et al., 2001).
A combination of selenium and vitamin E protected
against oxidative damage in the colon of rats with
ulcerative colitis (Bitiren et al., 2010).
Aβ, amyloid-β; AD, Alzheimer disease; ALS, amyotrophic lateral sclerosis; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular diseases; LDL, low-density
lipoprotein; OS, oxidative stress; PD, Parkinson’s disease.
2007). Furthermore, the inconsistency in treatment outcomes
are likely associated with antioxidant formulation. Most of the
trials reporting inefficacy of vitamin E have used all-racemic α
tocopherol, which is a major constituent of synthetic vitamin
E (Hoppe and Krennrich, 2000;Madamanchi et al., 2005). By
contrast, RRR-AT, the natural form of vitamin E has been
associated with better treatment effects (Hoppe and Krennrich,
2000;Madamanchi et al., 2005). Thus, further research is needed
to address the difference between RRR-AT and all-racemic α
tocopherol in terms of their therapeutic efficacy. Additionally,
the complicated redox mechanisms of antioxidant are far from
clear now. Some of the antioxidant such as vitamin C may
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exhibit prooxidant properties when administrated at high doses
(Madamanchi et al., 2005). This could partially explain why some
of the trials using antioxidant supplementation failed to show any
protective effect.
Lycopene is a natural dietary antioxidant most abundant
in tomatoes. An inverse association was found between CVD
incidence and consumption of either tomatoes or lycopene
(Kohlmeier and Hastings, 1995;Arab and Steck, 2000;Rao and
Agarwal, 2000). This could be attributed to the protective effects
of lycopene against LDL oxidation by inhibiting cholesterol
synthesis and improving LDL degradation (Table 1) (Ignarro
et al., 2007). An early population-based study was conducted
to evaluate the relationship between the risk of myocardial
infarction and the status of three types of carotenoids including
lycopene, αcarotene, and βcarotene, respectively. It was found
that only lycopene had significant protective effects (Kohlmeier
et al., 1997). Therefore, lycopene may be one of the primary
contributors that underlie the protective mechanisms of vegetable
consumption against CVD (Kohlmeier et al., 1997). Additionally,
polyphenols are the most abundant antioxidants in human diet
(1 g/d), widespread in fruit, vegetables, coffee, tea, and cereals
(Ignarro et al., 2007). Epidemiologic studies found a significantly
reduced risk for CVD with higher polyphenol intake (Table 1)
(Vita, 2005). Beverages rich in flavonoid such as tea can markedly
improve endothelial function. However, tea consumption did
not reduce the oxidative markers in the blood. So it remains
elusive whether this beneficial effect of tea is elicited by its
antioxidant effects (Vita, 2005). Indeed, increasing evidence has
suggested that the protective effects of polyphenols are not solely
contributed by their antioxidant ability but more likely correlated
with their anti-inflammatory effects as well as the regulation of
vasodilation and apoptosis of endothelial cells (Quinones et al.,
Neurons are particularly vulnerable to OS-induced damage due
to their weakened antioxidant defense system, high demand
for oxygen consumption, and abundant polyunsaturated fatty
acid content in their cell membranes (Rego and Oliveira,
2003). A growing number of studies indicate that ROS may be
generated via different mechanisms and play complex roles in the
development of neurodegenerative diseases such as Alzheimer’s
disease (AD), Huntington’s disease (HD), amyotrophic lateral
sclerosis (ALS), Parkinson’s disease (PD), and spinocerebellar
ataxia (SCA) (Davila and Torres-Aleman, 2008;Hakonen et al.,
2008;Patten et al., 2010;Blesa et al., 2015;Covarrubias-Pinto
et al., 2015;Zuo et al., 2015b). AD is a major cause of dementia
in elderly (Harman, 2006). Although the exact pathogenesis of
AD remains elusive, aging-related progressive increase in OS
has been considered a chief contributor to the formation of AD
lesions (Harman, 2006;Pimplikar et al., 2010). Evidence has
suggested that oxidative events occur prior to the onset of plaque
pathology and amyloid-β(Aβ) accumulation, which further
supports the critical roles of OS in the initiating stage of AD
(Lin and Beal, 2006;Wang et al., 2014b). In AD, OS modulates
JNK/p38 MAPK pathways, leading to the accumulation of Aβ
and the hyper-phosphorylation of tau proteins (Patten et al.,
2010). HD is an autosomal dominant inherited disease, which
is caused by a mutated expansion of CAG repeat in exon 1 of
HD gene and its resulted mutant protein product “huntingtin”
(mHtt) (Browne and Beal, 2006). OS is not the initiation
factor of HD. However, severe OS is a typical feature of HD
and may contribute to the increased DNA oxidation in the
HD brain (Browne and Beal, 2006). OS-induced mitochondrial
dysfunction is commonly observed in HD and the impairment
of respiratory chain can exacerbate ROS formation (Browne and
Beal, 2006). Furthermore, mitochondrial aconitase, an important
tricarboxylic acid (TCA)-cycle enzyme, is significantly impaired
in HD. The decline in aconitase activity is thought to be caused by
ROS-induced oxidation of Fe-S cluster within aconitase (Browne
and Beal, 2006). As a result, OS is responsible for the metabolic
defects seen in HD (Browne and Beal, 2006). In HD, OS is also
related to decreased expression of glucose transporter (GLUT)-
3, which results in the inhibition of glucose uptake and the
over-accumulation of lactate (Covarrubias-Pinto et al., 2015). It
remains inconclusive whether OS is an initiator or consequence
of neurodegeneration in PD. However, excessive ROS production
is a critical component of the mechanisms underlying PD
progression (Jenner, 2003). Loss of antioxidant defense, especially
glutathione (GSH) content is found early in PD although the
cause remains unknown (Jenner, 2003). High levels of oxidation
of protein, DNA, and lipids are observed in PD. The toxic
products from the oxidative damage may lead to neural cell death
(Jenner, 2003). In the substantia nigra pars compacta (SNc) of
PD patients, reduced activity of Complex I in the mitochondrial
respiratory chain contributes to excessive ROS generation and
consequently induces the apoptosis of dopaminergic neurons
(Blesa et al., 2015). In ALS, superoxide dismutase (SOD) 1
mutation and mitochondrial degeneration represent one of the
major mechanisms underlying ALS pathology (Rotunno and
Bosco, 2013). Specifically, significant vacuolar degeneration of
mitochondria was observed just before the death of neuron in
SOD1 mutant mice, indicating that mitochondrial dysfunction
initiates the onset of ALS (Lin and Beal, 2006). Mutant SOD1
has been shown to abnormally interact with mitochondria,
leading to cytochrome crelease and activation of apoptosis
(Lin and Beal, 2006). A decline in antioxidant capability due
to SOD1 mutation is potentially associated with motor neuron
degeneration (Zuo et al., 2015b). In addition, elevated OS
can inhibit neuroprotective IGF-I/AKT pathways, resulting in
neuron cell dysfunction (Davila and Torres-Aleman, 2008).
Furthermore, marked mitochondrial alterations caused by OS
have been suggested to be involved in the development of SCA
(Stucki et al., 2016).
Considering the complex roles of OS in neurodegenerative
disorders, the regulation of cellular ROS levels may represent
a potential treatment to impede neurodegeneration and
alleviate associated symptoms (Uttara et al., 2009). Clinical
evidence indicates that neurodegenerations can be ameliorated
upon proper intake of natural or supplementary antioxidants
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Liu et al. Nutritional Antioxidants in Oxidative Diseases
(Zandi et al., 2004). On the other hand, a lack of major
antioxidants due to malnutrition, which is implicated in
various neurodegenerative diseases, can worsen the progress of
neurological conditions (Brambilla et al., 2008;Tsagalioti et al.,
2016). For example, vitamin D deficiency has recently emerged as
one of the contributing factors leading to aberrant neurological
development. Vitamin D is an essential antioxidant that regulates
calcium-mediated neuronal excitotoxicity and the induction of
neurotransmitters and synaptic structural proteins (Mpandzou
et al., 2016;Wang et al., 2016). Wang et al. (2016) suggested
that inadequate vitamin D in serum is highly associated with
the loss of dopaminergic neurons in PD brains and increased
risk of PD. Neurological impairments have also been manifested
in individuals with a vitamin B deficiency. Multiple vitamin
B (e.g., B1, B3, and folate) deficiencies are implicated in the
pathophysiology of numerous neurodegenerative diseases such
as PD and AD (Sechi et al., 2016).
Rutin, resveratrol, and vitamin E, which target ROS-mediated
cascades such as JNK and NF-κB, have yielded some positive
outcomes in improving neurodegeneration both in vitro and
in vivo (Zuo et al., 2015a). In a rat brain, vitamin E was found
to be more effective in modulating OS than vitamins A and C
(Zaidi and Banu, 2004). Accordingly, a 2-year administration
of vitamin E at a dose of 2000 IU per day has been shown
to reduce the functional decline associated with AD (Sano
et al., 1997). The combination of vitamin E and coenzyme Q10
improves energy generation in some cases of Friedreich ataxia by
attenuating OS and restoring mitochondrial function (Lodi et al.,
2001). In addition to vitamins, phytochemicals, another type of
bioactive compounds that can be found in fruits and vegetables,
exhibit high antioxidant capacity with potential neuroprotective
effects against PD (Mazo et al., 2017). Anthocyanin derived
from strawberries possesses anti-oxidative, anti-inflammatory,
and anti-apoptotic abilities. It has been reported to alleviate
astrogliosis and preserve neuromuscular junctions and muscle
function, serving as a possible therapeutic agent for ALS and
other neurodegenerative diseases (Winter et al., 2017). During
AD progression, resveratrol’s potential in protecting neurons
from Aβand OS-induced toxicity shows promising therapeutic
applications (Anekonda, 2006;Bellaver et al., 2014). Lipoic
acid (LA) is shown to enhance GSH generation and deplete
lipid peroxide, thus protecting neurons against OS-induced
mitochondrial dysfunction (Table 1) (Moreira et al., 2010;Zuo
and Motherwell, 2013). Long-term administration of MitoQ,
a mitochondria-target antioxidant, also significantly restores
mitochondrial functions in Purkinje cells and alleviates SCA1-
related symptoms such as motor incoordination (Stucki et al.,
Numerous studies have been performed to investigate the
therapeutic effects of natural antioxidants on neurodegenerative
disorders; however, mixed results have been yielded (Dias et al.,
2013;Yan et al., 2013). For instance, despite the seeming
effectiveness of vitamin E, a study has showed that vitamin
E intake for 5 months failed to elevate vitamin E levels in
ventricular cerebrospinal fluid of PD patients (Pappert et al.,
1996). ROS formation is subtly regulated by antioxidant defense
systems within the human body (Zuo et al., 2015b). Hence,
single antioxidant intake could not be sufficient to resist
OS under pathophysiological conditions and could result in
cellular damage (Murphy, 2014). In this regard, a combined
use of various nutritional antioxidants should be considered.
Importantly, the simple dichotomy in redox biology comprised
of good antioxidants and bad ROS is regarded as untenable. It
is now well accepted that a small amount of ROS is essential
to activate redox-sensitive signaling pathways, while excessive
ROS can lead to detrimental effects (Margaritelis et al., 2016).
The different characteristics and sources of ROS may define their
specific roles in regulating cellular activities (Winterbourn and
Hampton, 2008;Margaritelis et al., 2016). Numerous studies
have stressed the need for a more precise description of the
metabolism of ROS in aspects of quantity, reactivity, location,
and reaction kinetics (Winterbourn and Hampton, 2008;Forman
et al., 2014;Margaritelis et al., 2016). However, most of the
exogenously administrated antioxidants are non-selective and
distributed uniformly across various parts of the cells or tissues
(Margaritelis et al., 2016). The lack of specificity of antioxidants
may account for their inefficacy in treating OS-related diseases.
It is thus imperative that researchers focus on developing novel
and targeted antioxidants such as mitoQ and Nox inhibitors to
improve the precise therapeutic effects of antioxidants in future
studies (Altenhofer et al., 2015;Margaritelis et al., 2016).
ROS are involved in all three stages of cancer development,
namely initiation, promotion, and progression (Khandrika et al.,
2009;Wells et al., 2009;Katakwar et al., 2016). In the initiation
stage, ROS-induced DNA mutations can accumulate if they
are not repaired in cancerous tissues (Poulsen et al., 1998).
Excessive ROS production may lead to oncogenic mutation of
DNA, potentially contributing to the onset of cancer (Valko et al.,
2006). In addition, cancer cells are characterized by more ROS
production than normal cells due to an altered metabolism and
increased energy demand (Sosa et al., 2013). ROS-induced OS
in carcinoma cells may promote cancer growth by triggering
cell growth signaling, enhancing tumor resistance to therapies,
increasing blood supply to tumors, and promoting metastasis
(Brown and Bicknell, 2001). ROS promote the expansion of
cancerous cells by modifying the genes related to apoptosis,
cell proliferation and transcription factors (Trueba et al., 2004).
ROS also upregulate antiapoptotic genes and downregulate
proapoptotic proteins via PI3K/AKT and ERK/MEK pathways
(McCubrey et al., 2007). In the progression stage of cancer
development, ROS contribute to the upregulation of matrix
metalloproteinases, inhibiting the action of anti-proteases and
angiogenesis, eventually leading to metastasis (Maulik, 2002;
Mori et al., 2004;Shinohara et al., 2010).
A depletion of endogenous antioxidants or a disruption of
redox equilibrium may lead to cancer development. Research
has shown that 35% of cancer can be prevented by dietary
modifications (Doll and Peto, 1981;Rayman, 2005). Fruits and
vegetables, which are rich in antioxidants, exert a protective
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Liu et al. Nutritional Antioxidants in Oxidative Diseases
effect against several different types of cancers (Soerjomataram
et al., 2010;Turati et al., 2015). Plant foods that contain
polyphenols have proven to be effective antioxidant agents for
the body (Barrajon-Catalan et al., 2010;Paredes-Lopez et al.,
2010;Sreelatha et al., 2012;Cordero-Herrera et al., 2013). They
have been shown to possess anti-cancer activity which is effective
against lung, breast, tongue, gastric, larynx, colon, and prostate
cancers (Table 1) (Manikandan et al., 2012;Sak, 2014). Fruits
containing higher phenolic content have stronger antioxidant
properties since they can induce hydroxyl group substitution
in the aromatic rings of phenol compounds (Sun et al., 2002;
Rokayya et al., 2014). Polyphenols induce apoptosis of cancer
cells, inhibit proliferation of mutated cells, reduce production
of cyclooxygenase-2 (COX-2), and downregulate cancer gene
expression (Gloria et al., 2014;Li et al., 2014;Xie et al., 2014;
Zhang et al., 2015). Moreover, nutrients such as vitamins and
minerals can reduce cancer risk by eliciting antioxidant action,
inhibiting proliferation of cancerous cells, maintaining DNA
methylation, and promoting cell-cycle arrest (Pathak et al., 2003;
Rayman, 2005). In individuals previously treated for cancer, a
healthy diet rich in fruits and vegetables can modify biologic
markers of cancer progression (Jones and Demark-Wahnefried,
2006). Healthy plant foods have shown to reduce the risk of death
after being diagnosed with breast (Vrieling et al., 2013;George
et al., 2014), head and neck (Arthur et al., 2013), and rectal
cancers (Pelser et al., 2014). A high vegetable diet has been shown
to be effective in reducing breast cancer recurrence for patients
on tamoxifen (Gold et al., 2009;Thomson et al., 2011).
Vitamins such as Vitamin A and E have a preventive effect
against oral cancer (Garewal, 1995). Selected micronutrients
(vitamin D, carnitine, and selenium) have been shown to
improve compliance and prognosis, patients’ quality of life,
and reduced adverse effects of cancer treatments (Block et al.,
2008;Grober et al., 2015). However, limited evidence supports
the effectiveness of vitamins and minerals in cancer prevention
(Fortmann et al., 2013), and such nutritional regimens are
not currently recommended for practice in healthy individuals
(World Cancer Research Fund/American Institute for Cancer
Research, 2007). Additionally, there is a lack of randomized
control trials investigating diets and cancer due to difficulty in
whole diet interventions as well as ethical issues in the proposed
research (Norat et al., 2015). Hence, current recommendations
are based on the effectiveness of a healthy diet (rich in fruits,
vegetables, and grains, and low on red meat and alcohol) and
lifestyle on reducing cancer risk (Norat et al., 2015).
It is well established that intestinal inflammation-associated
OS plays an essential role in the pathophysiology of various
gastrointestinal (GI) diseases, such as inflammatory bowel
diseases (IBD) (Balmus et al., 2016). Although the exact etiology
of IBD remains unclear, the underlying pathologies can be
partially attributed to excess ROS formation (Zhu and Li, 2012;
Bhattacharyya et al., 2014). Due to the presence of food particles,
pathogens, or microbiota imbalance, the GI tract may become
irritated, generating excess ROS and compromising endogenous
antioxidant defenses (Moura et al., 2015). OS disrupts the
intestinal epithelial barrier and increases intestinal permeability,
further exacerbating inflammation (Figure 2) (Balmus et al.,
2016). IBD, which is comprised of CD and ulcerative colitis
(UC), is characterized by chronic and prominent inflammation
associated with OS in the GI tract (Balmus et al., 2016).
Elevated levels of pro-inflammatory mediators such as platelet
activating factor (PAF) and leukotriene B4(LTB4) observed
in the mucosal samples from active IBD patients have been
shown to trigger the release of cytotoxic reactive oxygen
metabolites by overstimulating phagocytes (Ingraham et al.,
1982;Sharon and Stenson, 1984;Wallace and Chin, 1997).
Moreover, myeloperoxidases are released during the massive
infiltration of polymorphonuclear neutrophils and macrophages
into the inflamed mucosa, producing hypochlorous acid, a potent
oxidizing agent, via the metabolism of H2O2. Other sources
of ROS include enzymes such as cyclooxygenase, xanthine
oxidase, and 5-lipoxygenase that reside in the intestinal mucosa
(Alzoghaibi, 2013).
Despite ROS overproduction, a deficiency in dietary and
enzymatic antioxidants also contributes to the development of
OS (Alzoghaibi, 2013). For example, low levels of enzymatic
antioxidants and vitamins have been observed in patients with
CD, which is partly due to malnutrition (Buffinton and Doe,
1995;Alzoghaibi, 2013). In malnourished IBD patients, the
reduced dietary intakes of fruits and vegetables greatly influence
the concentration of carotenoid (vitamin A) (Balmus et al.,
2016). Vitamin C, which helps to repair and protect mucosal
lining against detrimental insults, is depleted in peptic ulcers
and gastritis (Aditi and Graham, 2012). Notably, the increased
incidence of vitamin D deficiency in CD patients is highly
associated with skeletal morbidity and a worsened quality of
life (Figure 2) (van Hogezand and Hamdy, 2006;Alastair et al.,
2011). Persistent OS can damage the intestinal barrier and
increase the permeability of GI epithelium via lipid peroxidation
and tight junction disruption. This alters the composition of
commensal microbiota in the GI tract and interrupts their ability
to establish colonization resistance, thus promoting the invasion
of pathogenic bacteria (Buffie and Pamer, 2013;Moura et al.,
2015). Such infections further aggravate ROS production and
inflammation and potentially increase the risk of inflammatory
bowel syndrome (Zhu and Li, 2012).
Considering a strong indication of ROS elevation in IBD
and other GI diseases, the adjuvant or treatment potential of
antioxidants are largely investigated. Antioxidant applications
have been shown to restore redox balance, thereby attenuating
intestinal damages and maintaining GI health (Bhattacharyya
et al., 2014). For example, studies have shown that CuZn-
SOD and 5-aminosalicylic acid effectively alleviate mucosal
injuries in CD by scavenging or inducing rapid decomposition
of ROS (Emerit et al., 1989;Couto et al., 2010;Alzoghaibi,
2013). In a randomized placebo-controlled study, 3 months of
oral antioxidant supplementation markedly improved the serum
antioxidant status in CD patients in remission. The combination
of antioxidants with n3 fatty acids further attenuated
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Liu et al. Nutritional Antioxidants in Oxidative Diseases
FIGURE 2 | Schematic illustrating the roles of OS and nutrient antioxidants in IBD. IBD, inflammatory bowel diseases; OS, oxidative stress; Se, selenium; Zn, zinc.
pro-inflammatory activities, thus serving as a potential treatment
for CD (Geerling et al., 2000). Compared to supplements, dietary
intakes of antioxidants from natural fruits and vegetables may
be a safer approach to avoid overconsumption. Inappropriate
antioxidant application can be harmful by scavenging of
physiological ROS (Bjelakovic et al., 2004;Poljsak et al., 2013).
Foods rich in micronutrients such as α-tocopherol (vitamin E)
and minerals have been reported to be beneficial in alleviating
ROS damage. For example, selenium and zinc interact with
GPx and SOD, respectively, to combat OS. The combination
of selenium and vitamin E has demonstrated protective effects
against oxidative damage in the colon of UC rats (Figure 2 and
Table 1) (Bitiren et al., 2010). Several functional foods may be
beneficial for IBD without undesirable effects.
Free radical theory, which was first proposed by Harman in
1956, suggests that aging is process related with progressive
and irreversible accumulation of oxidative damage in the cells
(Harman, 1956;Mariani et al., 2005). A shift of redox balance
toward a more oxidized status is noted in aging cells, as
indicated by decreased GSH/GSSG ratio. This alteration of
redox profile may blunt cellular capability of buffering ROS
produced both under physiological conditions and in response
to external stress (Kregel and Zhang, 2007). Excessive ROS
accumulation can directly damage DNA, protein, and lipids,
which disturbs normal cellular function (Zuo et al., 2015b).
Mitochondrial DNA (mtDNA) is particularly susceptible to OS
and the mutation of mtDNA has been closely linked with
the aging process (Trifunovic et al., 2004). It was reported
that mice with somatic mtDNA mutation exhibited an earlier
onset of aging-related features such as hair loss, osteoporosis,
and decreased subcutaneous fat as well as a shorter lifespan
(Trifunovic et al., 2004). Exposure to high levels of ROS can also
accelerate telomere shortening, which ultimately triggers cellular
senescence (Kregel and Zhang, 2007). For example, fibroblast
cells cultured under high OS showed increased rate of telomere
shortening and a reduced lifespan (Vonzglinicki et al., 1995).
Additionally, aging-associated OS could be responsible for the
chronic systematic inflammation as commonly seen in the elderly
via the activation of NF-κB (Chung et al., 2009). NF-κB is a
key regulator for inflammatory factors such as tumor necrosis
factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6 (Chung et al.,
2009). OS-induced NF-κB signaling is short-lived under normal
conditions in contrast to chronic activation during aging (Chung
et al., 2009). The persistent low-level inflammation could be
responsible for the development of age-related diseases such as
atherosclerosis, cancer, and dementia (Chung et al., 2009).
Aging population are at a higher risk of suffering from
malnutrition due to a general decline in body function
including decreased metabolic rate, digestive and absorptive
capability (Brownie, 2006). Therefore, the elderly are more
likely to be affected by diseases associated with nutritional
inadequacy. For example, aging-related vitamin D deficiency
has been shown to result in bone loss, susceptibility to
fracture, and hyperparathyroidism (Lips, 2001). Therefore,
appropriate supplementation with vitamin D can reduce
the risk of hip and other fractures in housebound elderly
(Table 1) (Lips, 2001). In recent years, focus on the diet
has increased due to the diet being an essential source of
exogenously obtained antioxidants. It appears that dietary
antioxidants have the anti-aging activity by their ability to
suppress the generation of free radicals (Kandola et al., 2015).
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Liu et al. Nutritional Antioxidants in Oxidative Diseases
Cognitive decline represents a major health concern in aging
population (Kang et al., 2005). A key study by Kang et al.
(2005) followed over ten thousand women from 1984–2003 to
investigate the relationship between their dietary pattern and
cognitive function. It was found that women who consumed
more green leafy or cruciferous vegetables demonstrated the
lowest cognitive decline; while fruit consumption did not affect
their cognitive function (Kang et al., 2005). Interestingly, higher
intake of green and yellow vegetables was also correlated with a
slower rate of skin aging in Japanese women after adjustment for
age, BMI, smoking status, and sun exposure (Nagata et al., 2010).
Energy restriction (ER) has recently been put up as a
potential way to extend life expectancy. This was partially
due to the favorable effects of ER on redox management.
In fruit flies, ER diet significantly increased the expression
of SOD1 and SOD2 as well as extended lifespan by 16%
(Peng et al., 2014). Various natural antioxidants, nutraceuticals,
and functional foods have been identified as free radical
or progressive oxygen hunters. Therefore, functional foods
and nutraceuticals which control the antioxidant activity may
represent an important role in slowing the aging process (Peng
et al., 2014). A diet rich in antioxidant has been shown
to increase lifespan in animal models (Miquel, 2002;Peng
et al., 2014). For instance, a diet supplemented blueberry
extract was found to markedly improve the lifespan in
fruit flies and Caenorhabditis elegans (Wilson et al., 2006;
Peng et al., 2014). This was accompanied by an increased
expression of SOD and catalase. The prolongevity induced
by blueberry extract was not observed in SOD or catalase-
mutated fruit flies. These results suggest that the beneficial
effects of blueberry to extend lifespan are potentially linked with
boosted endogenous antioxidant system (Peng et al., 2014). Other
nutritional antioxidants including apple polyphenols, black rice
anthocyanin extract, and black tea theaflavins all demonstrated
prominent prolongevity effects by upregulating the endogenous
antioxidant levels in animal models (Table 1) (Peng et al.,
2014). Further research is needed to evaluate the potential
effects of natural antioxidants on life expectancy in human
The implication of OS in the etiology of several chronic and
inflammatory diseases indicates that antioxidant-based therapy
could be promising for these disorders. A therapeutic strategy
that increases an individual’s antioxidant capacity may be useful
for a long-term treatment. However, many problems remain
elusive regarding antioxidant supplements in disease prevention.
It remains to be elucidated about the precise roles of ROS in the
pathogenesis of various diseases. Current recommendations are
based on the intake of a healthy diet (rich in fruits, vegetables,
and grains and low on red meat and alcohol) and healthy
lifestyle, which has demonstrated the ability to reduce the risk for
diseases. Further research is warranted before using antioxidant
supplements as an adjuvant therapy. In the meantime, avoiding
oxidant sources such as cigarette smoke and alcohol must be
considered when taking dietary antioxidants.
LZ conceptualized and designed the review. ZL, ZR, and JZ
summarized the literature and wrote the manuscript. LZ, EK,
C-CC, and TZ critically revised the manuscript. TZ prepared the
figures and abstract. All authors agreed to be accountable for the
content of this work.
This study was supported by 2016 American Physiology Society
S&R Foundation Ryuji Ueno Award.
We thank Paige Henry, Alicia Simpson, and Denethi
Wijegunawardana for their assistance during the manuscript
Aditi, A., and Graham, D. Y. (2012). Vitamin C, gastritis, and gastric disease: a
historical review and update. Dig. Dis. Sci. 57, 2504–2515. doi: 10.1007/s10620-
012-2203- 7
Alastair, F., Emma, G., and Emma, P. (2011). Nutrition in inflammatory
bowel disease. JPEN J. Parenter. Enteral Nutr. 35, 571–580. doi: 10.1177/
Allen, S., Britton, J. R., and Leonardi-Bee, J. A. (2009). Association
between antioxidant vitamins and asthma outcome measures: systematic
review and meta-analysis. Thorax 64, 610–619. doi: 10.1136/thx.2008.
Altenhofer, S., Radermacher, K. A., Kleikers, P. W., Wingler, K., and Schmidt, H. H.
(2015). Evolution of NADPH oxidase inhibitors: selectivity and mechanisms for
target engagement. Antioxid. Redox Signal. 23, 406–427. doi: 10.1089/ars.2013.
Alzoghaibi, M. A. (2013). Concepts of oxidative stress and antioxidant defense in
Crohn’s disease. World J. Gastroenterol. 19, 6540–6547. doi: 10.3748/wjg.v19.
Ambrose, J. A., and Barua, R. S. (2004). The pathophysiology of cigarette smoking
and cardiovascular disease: an update. J. Am. Coll. Cardiol. 43, 1731–1737.
doi: 10.1016/j.jacc.2003.12.047
Ames, B. N., and Wakimoto, P. (2002). Are vitamin and mineral deficiencies a
major cancer risk? Nat. Rev. Cancer 2, 694–704. doi: 10.1038/Nrc886
Anekonda, T. S. (2006). Resveratrol–a boon for treating Alzheimer’s disease? Brain
Res. Rev. 52, 316–326. doi: 10.1016/j.brainresrev.2006.04.004
Arab, L., and Steck, S. (2000). Lycopene and cardiovascular disease. Am. J. Clin.
Nutr. 71, 1691s–1695s. doi: 10.1093/ajcn/71.6.1691S
Arthur, A. E., Peterson, K. E., Rozek, L. S., Taylor, J. M., Light, E., Chepeha,
D. B., et al. (2013). Pretreatment dietary patterns, weight status, and head
and neck squamous cell carcinoma prognosis. Am. J. Clin. Nutr. 97, 360–368.
doi: 10.3945/ajcn.112.044859
Asplund, K. (2002). Antioxidant vitamins in the prevention of cardiovascular
disease: a systematic review. J. Intern. Med. 251, 372–392. doi: 10.1046/j.1365-
Azumi, H., Inoue, N., Ohashi, Y., Terashima, M., Mori, T., Fujita, H.,
et al. (2002). Superoxide generation in directional coronary atherectomy
specimens of patients with angina pectoris - Important role of NAD(P)H
Frontiers in Physiology | 9May 2018 | Volume 9 | Article 477
fphys-09-00477 May 16, 2018 Time: 17:2 # 10
Liu et al. Nutritional Antioxidants in Oxidative Diseases
oxidase. Arterioscler. Thromb. Vasc. Biol. 22, 1838–1844. doi: 10.1161/01.Atv.
Balmus, I. M., Ciobica, A., Trifan, A., and Stanciu, C. (2016). The implications
of oxidative stress and antioxidant therapies in inflammatory bowel disease:
clinical aspects and animal models. Saudi J. Gastroenterol. 22, 3–17.
doi: 10.4103/1319-3767.173753
Barrajon-Catalan, E., Fernandez-Arroyo, S., Saura, D., Guillen, E., Fernandez-
Gutierrez, A., Segura-Carretero, A., et al. (2010). Cistaceae aqueous extracts
containing ellagitannins show antioxidant and antimicrobial capacity, and
cytotoxic activity against human cancer cells. Food Chem. Toxicol. 48,
2273–2282. doi: 10.1016/j.fct.2010.05.060
Bellaver, B., Souza, D. G., Souza, D. O., and Quincozes-Santos, A. (2014).
Resveratrol increases antioxidant defenses and decreases proinflammatory
cytokines in hippocampal astrocyte cultures from newborn, adult and
aged Wistar rats. Toxicol. In Vitro 28, 479–484. doi: 10.1016/j.tiv.2014.
Bhattacharyya, A., Chattopadhyay, R., Mitra, S., and Crowe, S. E. (2014). Oxidative
stress: an essential factor in the pathogenesis of gastrointestinal mucosal
diseases. Physiol. Rev. 94, 329–354. doi: 10.1152/physrev.00040.2012
Bitiren, M., Karakilcik, A. Z., Zerin, M., Ozardali, I., Selek, S., Nazligul, Y.,
et al. (2010). Protective effects of selenium and vitamin E combination on
experimental colitis in blood plasma and colon of rats. Biol. Trace Elem. Res.
136, 87–95. doi: 10.1007/s12011-009- 8518-3
Bjelakovic, G., Nikolova, D., Simonetti, R. G., and Gluud, C. (2004). Antioxidant
supplements for prevention of gastrointestinal cancers: a systematic review and
meta-analysis. Lancet 364, 1219–1228. doi: 10.1016/S0140-6736(04)17138- 9
Blesa, J., Trigo-Damas, I., Quiroga-Varela, A., and Jackson-Lewis, V. R. (2015).
Oxidative stress and Parkinson’s disease. Front. Neuroanat. 9:91. doi: 10.3389/
Block, K. I., Koch, A. C., Mead, M. N., Tothy, P. K., Newman, R. A.,
and Gyllenhaal, C. (2008). Impact of antioxidant supplementation on
chemotherapeutic toxicity: a systematic review of the evidence from
randomized controlled trials. Int. J. Cancer 123, 1227–1239. doi: 10.1002/ijc.
Bonnefont-Rousselot, D., and Collin, F. (2010). Melatonin: action as antioxidant
and potential applications in human disease and aging. Toxicology 278, 55–67.
doi: 10.1016/j.tox.2010.04.008
Brambilla, D., Mancuso, C., Scuderi, M. R., Bosco, P., Cantarella, G., Lempereur, L.,
et al. (2008). The role of antioxidant supplement in immune system, neoplastic,
and neurodegenerative disorders: a point of view for an assessment of the
risk/benefit profile. Nutr. J. 7:29. doi: 10.1186/1475-2891- 7-29
Brown, N. S., and Bicknell, R. (2001). Hypoxia and oxidative stress in breast cancer
- Oxidative stress: its effects on the growth, metastatic potential and response to
therapy of breast cancer. Breast Cancer Res. 3, 323–327. doi: 10.1186/Bcr315
Browne, S. E., and Beal, M. F. (2006). Oxidative damage in Huntington’s disease
pathogenesis. Antioxid. Redox Signal. 8, 2061–2073. doi: 10.1089/ars.2006.8.
Brownie, S. (2006). Why are elderly individuals at risk of nutritional deficiency?
Int. J. Nurs. Pract. 12, 110–118. doi: 10.1111/j.1440-172X.2006.00557.x
Buffie, C. G., and Pamer,E. G. (2013). Microbiot a-mediated colonization resistance
against intestinal pathogens. Nat. Rev. Immunol. 13, 790–801. doi: 10.1038/
Buffinton, G. D., and Doe, W. F. (1995). Altered ascorbic acid status in the
mucosa from inflammatory bowel disease patients. Free Radic. Res. 22, 131–143.
doi: 10.3109/10715769509147535
Cachofeiro, V., Goicochea, M., De Vinuesa, S. G., Oubina, P., Lahera, V., and
Luno, J. (2008). Oxidative stress and inflammation, a link between chronic
kidney disease and cardiovascular disease. Kidney Int. 74, S4–S9. doi: 10.1038/
Cho, Y. S., and Moon, H. B. (2010). The role of oxidative stress in the pathogenesis
of asthma. Allergy Asthma Immunol. Res. 2, 183–187. doi: 10.4168/aair.2010.
Chung, H. Y., Cesari, M., Anton, S., Marzetti, E., Giovannini, S., Seo, A. Y.,
et al. (2009). Molecular inflammation: underpinnings of aging and age-related
diseases. Ageing Res. Rev. 8, 18–30. doi: 10.1016/j.arr.2008.07.002
Comhair, S. A., and Erzurum, S. C. (2010). Redox control of asthma: molecular
mechanisms and therapeutic opportunities. Antioxid. Redox Signal. 12, 93–124.
doi: 10.1089/ARS.2008.2425
Cordero-Herrera, I., Martin, M. A., Bravo, L., Goya, L., and Ramos, S. (2013).
Epicatechin gallate induces cell death via p53 activation and stimulation of
p38 and JNK in human colon cancer SW480 cells. Nutr. Cancer 65, 718–728.
doi: 10.1080/01635581.2013.795981
Couto, D., Ribeiro, D., Freitas, M., Gomes, A., Lima, J. L., and Fernandes, E. (2010).
Scavenging of reactive oxygen and nitrogen species by the prodrug sulfasalazine
and its metabolites 5-aminosalicylic acid and sulfapyridine. Redox Rep. 15,
259–267. doi: 10.1179/135100010X12826446921707
Covarrubias-Pinto, A., Moll, P., Solis-Maldonado, M., Acuna, A. I., Riveros, A.,
Miro, M. P., et al. (2015). Beyond the redox imbalance: oxidative stress
contributes to an impaired GLUT3 modulation in Huntington’s disease.
Free Radic. Biol. Med. 89, 1085–1096. doi: 10.1016/j.freeradbiomed.2015.
Davila, D., and Torres-Aleman, I. (2008). Neuronal death by oxidative stress
involves activation of FOXO3 through a two-arm pathway that activates stress
kinases and attenuates insulin-like growth factor I signaling. Mol. Biol. Cell 19,
2014–2025. doi: 10.1091/mbc.E07-08- 0811
Dias, V., Junn, E., and Mouradian, M. M. (2013). The role of oxidative stress in
Parkinson’s disease. J. Parkinsons Dis. 3, 461–491. doi: 10.3233/JPD-130230
Doll, R., and Peto, R. (1981). The causes of cancer: quantitative estimates of
avoidable risks of cancer in the United States today. J. Natl. Cancer Inst. 66,
1191–1308. doi: 10.1093/jnci/66.6.1192
Emerit, J., Pelletier, S., Tosoni-Verlignue, D., and Mollet, M. (1989). Phase II trial of
copper zinc superoxide dismutase (CuZnSOD) in treatment of Crohn’s disease.
Free Radic. Biol. Med. 7, 145–149. doi: 10.1016/0891-5849(89)90005-1
Evatt, M. L., Delong, M. R., Khazai, N., Rosen, A., Triche, S., and Tangpricha, V.
(2008). Prevalence of vitamin D insufficiency in patients with Parkinson disease
and Alzheimer disease. Arch. Neurol. 65, 1348–1352. doi: 10.1001/archneur.65.
Ferreira, I. M., Brooks, D., White, J., and Goldstein, R. (2012). Nutritional
supplementation for stable chronic obstructive pulmonary disease. Cochrane
Database Syst. Rev. 12:CD000998. doi: 10.1002/14651858.CD000998.pub3
Ferreira, I. M., Verreschi, I. T., Nery, L. E., Goldstein, R. S., Zamel, N., Brooks, D.,
et al. (1998). The influence of 6 months of oral anabolic steroids on body mass
and respiratory muscles in undernourished COPD patients. Chest 114, 19–28.
doi: 10.1378/chest.114.1.19
Fitzpatrick, A. M., Teague, W. G., Holguin, F., Yeh, M., Brown, L. A., and Severe
Asthma Research Program (2009). Airway glutathione homeostasis is altered
in children with severe asthma: evidence for oxidant stress. J. Allergy Clin.
Immunol. 123, 146.e8–152.e8. doi: 10.1016/j.jaci.2008.10.047
Forman, H. J., Ursini, F., and Maiorino, M. (2014). An overview of mechanisms of
redox signaling. J. Mol. Cell Cardiol. 73, 2–9. doi: 10.1016/j.yjmcc.2014.01.018
Fortmann, S. P., Burda, B. U., Senger, C. A., Lin, J. S., and Whitlock, E. P. (2013).
Vitamin and mineral supplements in the primary prevention of cardiovascular
disease and cancer: an updated systematic evidence review for the U.S.
Preventive Services Task Force. Ann. Intern. Med. 159, 824–834. doi: 10.7326/
0003-4819- 159-12- 201312170-00729
Garewal, H. (1995). Antioxidants in oral cancer prevention. Am. J. Clin. Nutr. 62,
1410S–1416S. doi: 10.1093/ajcn/62.6.1410S
Geerling, B. J., Badart-Smook, A., Van Deursen, C., Van Houwelingen, A. C.,
Russel, M. G., Stockbrugger, R. W., et al. (2000). Nutritional supplementation
with N-3 fatty acids and antioxidants in patients with Crohn’s disease in
remission: effects on antioxidant status and fatty acid profile. Inflamm. Bowel
Dis. 6, 77–84. doi: 10.1097/00054725-200005000- 00002
George, S. M., Ballard-Barbash, R., Shikany, J. M., Caan, B. J., Freudenheim, J. L.,
Kroenke, C. H., et al. (2014). Better postdiagnosis diet quality is associated
with reduced risk of death among postmenopausal women with invasive breast
cancer in the women’s health initiative. Cancer Epidemiol. Biomarkers Prev. 23,
575–583. doi: 10.1158/1055-9965.EPI- 13-1162
Gilgun-Sherki, Y., Melamed, E., and Offen, D. (2001). Oxidative stress induced-
neurodegenerative diseases: the need for antioxidants that penetrate the blood
brain barrier. Neuropharmacology 40, 959–975. doi: 10.1016/S0028-3908(01)
Gloria, N. F., Soares, N., Brand, C., Oliveira, F. L., Borojevic, R., and Teodoro, A. J.
(2014). Lycopene and beta-carotene induce cell-cycle arrest and apoptosis in
human breast cancer cell lines. Anticancer Res. 34, 1377–1386.
Gold, E. B., Pierce, J. P., Natarajan, L., Stefanick, M. L., Laughlin, G. A., Caan,
B. J., et al. (2009). Dietary pattern influences breast cancer prognosis in women
Frontiers in Physiology | 10 May 2018 | Volume 9 | Article 477
fphys-09-00477 May 16, 2018 Time: 17:2 # 11
Liu et al. Nutritional Antioxidants in Oxidative Diseases
without hot flashes: the women’s healthy eating and living trial. J. Clin. Oncol.
27, 352–359. doi: 10.1200/JCO.2008.16.1067
Goodman, M., Bostick, R. M., Kucuk, O., and Jones, D. P. (2011). Clinical trials of
antioxidants as cancer prevention agents: past, present, and future. Free Radic.
Biol. Med. 51, 1068–1084. doi: 10.1016/j.freeradbiomed.2011.05.018
Grober, U., Kisters, K., and Adamietz, I. A. (2015). Vitamin D in oncology: update
2015. Med. Monatsschr. Pharm. 38, 512–516.
Gumral, N., Naziroglu, M., Ongel, K., Beydilli, E. D., Ozguner, F., Sutcu, R.,
et al. (2009). Antioxidant enzymes and melatonin levels in patients with
bronchial asthma and chronic obstructive pulmonary disease during stable and
exacerbation periods. Cell Biochem. Funct. 27, 276–283. doi: 10.1002/cbf.1569
Hakonen, A. H., Goffart, S., Marjavaara, S., Paetau, A., Cooper, H., Mattila, K.,
et al. (2008). Infantile-onset spinocerebellar ataxia and mitochondrial recessive
ataxia syndrome are associated with neuronal complex I defect and mtDNA
depletion. Hum. Mol. Genet. 17, 3822–3835. doi: 10.1093/hmg/ddn280
Harman, D. (1956). Aging - a theory based on free-radical and radiation-chemistry.
J. Gerontol. 11, 298–300. doi: 10.1093/geronj/11.3.298
Harman, D. (2006). Alzheimer’s disease pathogenesis: role of aging. Ann. N. Y.
Acad. Sci. 1067, 454–460. doi: 10.1196/annals.1354.065
Heidenreich, P. A., Trogdon, J. G., Khavjou, O. A., Butler, J., Dracup, K.,
Ezekowitz, M. D., et al. (2011). Forecasting the future of cardiovascular
disease in the United States a policy statement from the American
heart association. Circulation 123, 933–944. doi: 10.1161/CIR.0b013e31820
Holick, M. F., Binkley, N. C., Bischoff-Ferrari, H. A., Gordon, C. M., Hanley, D. A.,
Heaney, R. P., et al. (2011). Evaluation, treatment, and prevention of vitamin D
deficiency: an endocrine society clinical practice guideline. J. Clin. Endocrinol.
Metab. 96, 1911–1930. doi: 10.1210/jc.2011-0385
Hoppe, P. P., and Krennrich, G. (2000). Bioavailability and potency of natural-
source and all-racemic alpha-tocopherol in the human: a dispute. Eur. J. Nutr.
39, 183–193. doi: 10.1007/s003940070010
Hornikx, M., Van Remoortel, H., Lehouck, A., Mathieu, C., Maes, K., Gayan-
Ramirez, G., et al. (2012). Vitamin D supplementation during rehabilitation
in COPD: a secondary analysis of a randomized trial. Respir. Res. 13:84.
doi: 10.1186/1465-9921- 13-84
Ignarro, L. J., Balestrieri, M. L., and Napoli, C. (2007). Nutrition, physical
activity, and cardiovascular disease: an update. Cardiovasc. Res. 73, 326–340.
doi: 10.1016/j.cardiores.2006.06.030
Ingraham, L. M., Coates, T. D., Allen, J. M., Higgins, C. P., Baehner, R. L.,
and Boxer, L. A. (1982). Metabolic, membrane, and functional responses of
human polymorphonuclear leukocytes to platelet-activating factor. Blood 59,
Jenner, P. (2003). Oxidative stress in Parkinson’s disease. Ann. Neurol. 53, S26–S36.
doi: 10.1002/ana.10483
Jiang, L., Diaz, P. T., Best, T. M., Stimpfl, J. N., He, F., and Zuo, L. (2014). Molecular
characterization of redox mechanisms in allergic asthma. Ann. Allergy Asthma
Immunol. 113, 137–142. doi: 10.1016/j.anai.2014.05.030
Jones, L. W., and Demark-Wahnefried, W. (2006). Diet, exercise, and
complementary therapies after primary treatment for cancer. Lancet Oncol. 7,
1017–1026. doi: 10.1016/S1470-2045(06)70976- 7
Kandola, K., Bowman, A., and Birch-Machin, M. A. (2015). Oxidative stress–a key
emerging impact factor in health, ageing, lifestyle and aesthetics. Int. J. Cosmet
Sci. 37(Suppl. 2), 1–8. doi: 10.1111/ics.12287
Kang, J. H., Ascherio, A., and Grodstein, F. (2005). Fruit and vegetable
consumption and cognitive decline in aging women. Ann. Neurol. 57, 713–720.
doi: 10.1002/ana.20476
Katakwar, P., Metgud, R., Naik, S., and Mittal, R. (2016). Oxidative stress marker in
oral cancer: a review. J. Cancer Res. Ther. 12, 438–446. doi: 10.4103/0973-1482.
Khandrika, L., Kumar, B., Koul, S., Maroni, P., and Koul, H. K. (2009). Oxidative
stress in prostate cancer. Cancer Lett. 282, 125–136. doi: 10.1016/j.canlet.2008.
King, D. A., Cordova, F., and Scharf, S. M. (2008). Nutritional aspects of chronic
obstructive pulmonary disease. Proc. Am. Thorac. Soc. 5, 519–523. doi: 10.1513/
Kohlmeier, L., and Hastings, S. B. (1995). Epidemiologic evidence of a role
of carotenoids in cardiovascular-disease prevention. Am. J. Clin. Nutr. 62,
1370–1376. doi: 10.1093/ajcn/62.6.1370S
Kohlmeier, L., Kark, J. D., Gomezgracia, E., Martin, B. C., Steck, S. E., Kardinaal,
A. F., et al. (1997). Lycopene and myocardial infarction risk in the EURAMIC
Study. Am. J. Epidemiol. 146, 618–626. doi: 10.1093/oxfordjournals.aje.a009327
Kregel, K. C., and Zhang, H. J. (2007). An integrated view of oxidative stress in
aging: basic mechanisms, functional effects, and pathological considerations.
Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R18–R36. doi: 10.1152/ajpregu.
Kris-Etherton, P. M., Lichtenstein, A. H., Howard, B. V., Steinberg, D., Witztum,
J. L., et al. (2004). Antioxidant vitamin supplements and cardiovascular disease.
Circulation 110, 637–641. doi: 10.1161/01.Cir.0000137822.39831.F1
Li, Y., Ma, C., Qian, M., Wen, Z., Jing, H., and Qian, D. (2014). Butein
induces cell apoptosis and inhibition of cyclooxygenase2 expression in
A549 lung cancer cells. Mol. Med. Rep. 9, 763–767. doi: 10.3892/mmr.2013.
Lin, M. T., and Beal, M. F. (2006). Mitochondrial dysfunction and oxidative stress
in neurodegenerative diseases. Nature 443, 787–795. doi: 10.1038/nature05292
Lips, P. (2001). Vitamin D deficiency and secondary hyperparathyroidism in the
elderly: consequences for bone loss and fractures and therapeutic implications.
Endocr. Rev. 22, 477–501. doi: 10.1210/edrv.22.4.0437
Lodi, R., Hart, P. E., Rajagopalan, B., Taylor, D. J., Crilley, J. G., Bradley, J. L., et al.
(2001). Antioxidant treatment improves in vivo cardiac and skeletal muscle
bioenergetics in patients with Friedreich’s ataxia. Ann. Neurol. 49, 590–596.
doi: 10.1002/ana.1001
Madamanchi, N. R., Vendrov, A., and Runge, M. S. (2005). Oxidative stress and
vascular disease. Arterioscler. Thromb. Vasc. Biol. 25, 29–38. doi: 10.1161/01.
Manikandan, R., Beulaja, M., Arulvasu, C., Sellamuthu, S., Dinesh, D., Prabhu, D.,
et al. (2012). Synergistic anticancer activity of curcumin and catechin: an
in vitro study using human cancer cell lines. Microsc. Res. Tech. 75, 112–116.
doi: 10.1002/jemt.21032
Margaritelis, N. V. (2016). Antioxidants as therapeutics in the intensive care unit:
Have we ticked the redox boxes? Pharmacol. Res. 111, 126–132. doi: 10.1016/j.
Margaritelis, N. V., Cobley, J. N., Paschalis, V., Veskoukis, A. S., Theodorou,
A. A., Kyparos, A., et al. (2016). Principles for integrating reactive species into
in vivo biological processes: examples from exercise physiology. Cell. Signal. 28,
256–271. doi: 10.1016/j.cellsig.2015.12.011
Mariani, E., Polidori, M. C., Cherubini, A., and Mecocci, P. (2005). Oxidative
stress in brain aging, neurodegenerative and vascular diseases: an overview.
J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 827, 65–75. doi: 10.1016/j.
Masoli, M., Fabian, D., Holt, S., Beasley, R., and Global Initiative for Asthma
(GINA) Program (2004). The global burden of asthma: executive summary of
the GINA Dissemination Committee report. Allergy 59, 469–478. doi: 10.1111/
Maulik, N. (2002). Redox signaling of angiogenesis. Antioxid. Redox Signal. 4,
805–815. doi: 10.1089/152308602760598963
Mazo, N. A., Echeverria, V., Cabezas, R., Avila-Rodriguez, M., Aliev, G.,
Leszek, J., et al. (2017). Medicinal plants as protective strategies against
Parkinson’s Disease. Curr. Pharm. Des. 23, 4180–4188 doi: 10.2174/
McCubrey, J. A., Steelman, L. S., Chappell, W. H., Abrams, S. L., Wong, E. W.,
Chang, F., et al. (2007). Roles of the Raf/MEK/ERK pathway in cell growth,
malignant transformation and drug resistance. Biochim. Biophys. Acta 1773,
1263–1284. doi: 10.1016/j.bbamcr.2006.10.001
Miquel, J. (2002). Can antioxidant diet supplementation protect against age-related
mitochondrial damage? Ann. N. Y. Acad. Sci. 959, 508–516. doi: 10.1111/j.1749-
Moreira, P. I., Zhu, X., Wang, X., Lee, H. G., Nunomura, A., Petersen, R. B.,
et al. (2010). Mitochondria: a therapeutic target in neurodegeneration.
Biochim. Biophys. Acta 1802, 212–220. doi: 10.1016/j.bbadis.2009.
Moreno-Macias, H., and Romieu, I. (2014). Effects of antioxidant supplements and
nutrients on patients with asthma and allergies. J. Allergy Clin. Immunol. 133,
1237–1244; quiz 1245. doi: 10.1016/j.jaci.2014.03.020
Mori, K., Shibanuma, M., and Nose, K. (2004). Invasive potential induced
under long-term oxidative stress in mammary epithelial cells. Cancer Res. 64,
7464–7472. doi: 10.1158/0008-5472.CAN- 04-1725
Frontiers in Physiology | 11 May 2018 | Volume 9 | Article 477
fphys-09-00477 May 16, 2018 Time: 17:2 # 12
Liu et al. Nutritional Antioxidants in Oxidative Diseases
Moura, F. A., De Andrade, K. Q., Dos Santos, J. C., Araujo, O. R., and Goulart,
M. O. (2015). Antioxidant therapy for treatment of inflammatory bowel
disease: Does it work? Redox Biol. 6, 617–639. doi: 10.1016/j.redox.2015.
Mpandzou, G., Ait Ben Haddou, E., Regragui, W., Benomar, A., and
Yahyaoui, M. (2016). Vitamin D deficiency and its role in neurological
conditions: a review. Rev. Neurol. 172, 109–122. doi: 10.1016/j.neurol.2015.
Muller, O., and Krawinkel, M. (2005). Malnutrition and health in developing
countries. CMAJ 173, 279–286. doi: 10.1503/cmaj.050342
Murphy, M. P. (2014). Antioxidants as therapies: can we improve on
nature? Free Radic. Biol. Med. 66, 20–23. doi: 10.1016/j.freeradbiomed.2013.
Nagata, C., Nakamura, K., Wada, K., Oba, S., Hayashi, M., Takeda, N., et al.
(2010). Association of dietary fat, vegetables and antioxidant micronutrients
with skin ageing in Japanese women. Br. J. Nutr. 103, 1493–1498. doi: 10.1017/
Navarro-Alarcon, M., and Cabrera-Vique, C. (2008). Selenium in food and the
human body: a review. Sci. Total Environ. 400, 115–141. doi: 10.1016/j.
Norat, T., Scoccianti, C., Boutron-Ruault, M. C., Anderson, A., Berrino, F.,
Cecchini, M., et al. (2015). European code against cancer 4th edition: diet and
cancer. Cancer Epidemiol. 39(Suppl. 1), S56–S66. doi: 10.1016/j.canep.2014.
Pappert, E. J., Tangney, C. C., Goetz, C. G., Ling, Z. D., Lipton, J. W.,
Stebbins, G. T., et al. (1996). Alpha-tocopherol in the ventricular cerebrospinal
fluid of Parkinson’s disease patients: dose-response study and correlations
with plasma levels. Neurology 47, 1037–1042. doi: 10.1212/WNL.47.4.
Paredes-Lopez, O., Cervantes-Ceja, M. L., Vigna-Perez, M., and Hernandez-
Perez, T. (2010). Berries: improving human health and healthy aging, and
promoting quality life–a review. Plant Foods Hum. Nutr. 65, 299–308.
doi: 10.1007/s11130-010- 0177-1
Pathak, S. K., Sharma, R. A., and Mellon, J. K. (2003). Chemoprevention of
prostate cancer by diet-derived antioxidant agents and hormonal manipulation
(Review). Int. J. Oncol. 22, 5–13. doi: 10.3892/ijo.22.1.5
Patten, D. A., Germain, M., Kelly, M. A., and Slack, R. S. (2010). Reactive
oxygen species: stuck in the middle of neurodegeneration. J. Alzheimers Dis.
20(Suppl. 2), S357–S367. doi: 10.3233/JAD-2010-100498
Pauwels, R. A., and Rabe, K. F. (2004). Burden and clinical features of chronic
obstructive pulmonary disease (COPD). Lancet 364, 613–620. doi: 10.1016/
S0140-6736(04)16855- 4
Pelser, C., Arem, H., Pfeiffer, R. M., Elena, J. W., Alfano, C. M., Hollenbeck,
A. R., et al. (2014). Prediagnostic lifestyle factors and survival after colon
and rectal cancer diagnosis in the National Institutes of Health (NIH)-
AARP Diet and Health Study. Cancer 120, 1540–1547. doi: 10.1002/cncr.
Peng, C., Wang, X., Chen, J., Jiao, R., Wang, L., Li, Y. M., et al. (2014). Biology
of ageing and role of dietary antioxidants. Biomed Res. Int. 2014:831841.
doi: 10.1155/2014/831841
Pham-Huy, L. A., He, H., and Pham-Huy, C. (2008). Free radicals, antioxidants in
disease and health. Int. J. Biomed. Sci. 4, 89–96.
Pimplikar, S. W., Nixon, R. A., Robakis, N. K., Shen, J., and Tsai, L. H.
(2010). Amyloid-independent mechanisms in Alzheimer’s disease pathogenesis.
J. Neurosci. 30, 14946–14954. doi: 10.1523/Jneurosci.4305-10.2010
Poljsak, B., Suput, D., and Milisav, I. (2013). Achieving the balance between ROS
and antioxidants: when to use the synthetic antioxidants. Oxid. Med. Cell.
Longev. 2013:956792. doi: 10.1155/2013/956792
Poulsen, H. E., Prieme, H., and Loft, S. (1998). Role of oxidative DNA
damage in cancer initiation and promotion. Eur. J. Cancer Prev.
7, 9–16.
Proteggente, A. R., Pannala, A. S., Paganga, G., Van Buren, L., Wagner, E.,
Wiseman, S., et al. (2002). The antioxidant activity of regularly consumed fruit
and vegetables reflects their phenolic and vitamin C composition. Free Radic.
Res. 36, 217–233. doi: 10.1080/10715760290006484
Quinones, M., Miguel, M., and Aleixandre, A. (2013). Beneficial effects
of polyphenols on cardiovascular disease. Pharmacol. Res. 68, 125–131.
doi: 10.1016/j.phrs.2012.10.018
Rao, A. V., and Agarwal, S. (2000). Role of antioxidant lycopene in cancer and
heart disease. J. Am. Coll. Nutr. 19, 563–569. doi: 10.1080/07315724.2000.107
Rayman, M. P. (2005). Selenium in cancer prevention: a review of the evidence
and mechanism of action. Proc. Nutr. Soc. 64, 527–542. doi: 10.1079/Pns200
Reboul, E., Richelle, M., Perrot, E., Desmoulins-Malezet, C., Pirisi, V., and
Borel, P. (2006). Bioaccessibility of carotenoids and vitamin E from their
main dietary sources. J. Agric. Food Chem. 54, 8749–8755. doi: 10.1021/jf061
Rego, A. C., and Oliveira, C. R. (2003). Mitochondrial dysfunction and
reactive oxygen species in excitotoxicity and apoptosis: implications for the
pathogenesis of neurodegenerative diseases. Neurochem. Res. 28, 1563–1574.
doi: 10.1023/A:1025682611389
Rogers, N. M., Seeger, F., Garcin, E. D., Roberts, D. D., and Isenberg, J. S. (2014).
Regulation of soluble guanylate cyclase by matricellular thrombospondins:
implications for blood flow. Front. Physiol. 5:134. doi: 10.3389/fphys.2014.
Rokayya, S., Li, C. J., Zhao, Y., Li, Y., and Sun, C. H. (2014). Cabbage
(Brassica oleracea L. var. capitata) phytochemicals with antioxidant and anti-
inflammatory potential. Asian Pac. J. Cancer Prev. 14, 6657–6662. doi: 10.7314/
Romieu, I. (2005). Nutrition and lung health. Int. J. Tuberc. Lung Dis. 9, 362–374.
Rotunno, M. S., and Bosco, D. A. (2013). An emerging role for misfolded
wild-type SOD1 in sporadic ALS pathogenesis. Front. Cell. Neurosci. 7:253.
doi: 10.3389/fncel.2013.00253
Sak, K. (2014). Site-specific anticancer effects of dietary flavonoid
quercetin. Nutr. Cancer 66, 177–193. doi: 10.1080/01635581.2014.
Sano, M., Ernesto, C., Thomas, R. G., Klauber, M. R., Schafer, K., Grundman, M.,
et al. (1997). A controlled trial of selegiline, alpha-tocopherol, or both as
treatment for Alzheimer’s disease. N. Engl. J. Med. 336, 1216–1222. doi: 10.1056/
Schols, A. M., Ferreira, I. M., Franssen, F. M., Gosker, H. R., Janssens, W.,
Muscaritoli, M., et al. (2014). Nutritional assessment and therapy in COPD:
a European respiratory society statement. Eur. Respir. J. 44, 1504–1520.
doi: 10.1183/09031936.00070914
Sechi, G., Sechi, E., Fois, C., and Kumar, N. (2016). Advances in clinical
determinants and neurological manifestations of B vitamin deficiency in adults.
Nutr. Rev. 74, 281–300. doi: 10.1093/nutrit/nuv107
Sesso, H. D., Buring, J. E., Zhang, S. M., Norkus, E. P., and Gaziano, J. M.
(2005). Dietary and plasma lycopene and the risk of breast cancer. Cancer
Epidemiol. Biomarkers Prev. 14, 1074–1081. doi: 10.1158/1055-9965.EPI-04-
Sharon, P., and Stenson, W. F. (1984). Enhanced synthesis of leukotriene
B4 by colonic mucosa in inflammatory bowel disease. Gastroenterology 86,
Shay, K. P., Moreau, R. F., Smith, E. J., Smith, A. R., and Hagen, T. M.
(2009). Alpha-lipoic acid as a dietary supplement: molecular mechanisms and
therapeutic potential. Biochim. Biophys. Acta 1790, 1149–1160. doi: 10.1016/j.
Shinohara, M., Adachi, Y., Mitsushita, J., Kuwabara, M., Nagasawa, A., Harada, S.,
et al. (2010). Reactive oxygen generated by NADPH oxidase 1 (Nox1)
contributes to cell invasion by regulating matrix metalloprotease-9 production
and cell migration. J. Biol. Chem. 285, 4481–4488. doi: 10.1074/jbc.M109.
Sies, H., Stahl, W., and Sevanian, A. (2005). Nutritional, dietary and
postprandial oxidative stress. J. Nutr. 135, 969–972. doi: 10.1093/jn/135.
Soerjomataram, I., Oomen, D., Lemmens, V., Oenema, A., Benetou, V.,
Trichopoulou, A., et al. (2010). Increased consumption of fruit and vegetables
and future cancer incidence in selected European countries. Eur. J. Cancer 46,
2563–2580. doi: 10.1016/j.ejca.2010.07.026
Sosa, V., Moline, T., Somoza, R., Paciucci, R., Kondoh, H., and Me, L. L.
(2013). Oxidative stress and cancer: an overview. Ageing Res. Rev. 12, 376–390.
doi: 10.1016/j.arr.2012.10.004
Sreelatha, S., Dinesh, E., and Uma, C. (2012). Antioxidant properties of Rajgira
(Amaranthus paniculatus) leaves and potential synergy in chemoprevention.
Frontiers in Physiology | 12 May 2018 | Volume 9 | Article 477
fphys-09-00477 May 16, 2018 Time: 17:2 # 13
Liu et al. Nutritional Antioxidants in Oxidative Diseases
Asian Pac. J. Cancer Prev. 13, 2775–2780. doi: 10.7314/APJCP.2012.13.6.
Stephens, N. G., Parsons, A., Schofield, P. M., Kelly, F., Cheeseman, K.,
and Mitchinson, M. J. (1996). Randomised controlled trial of vitamin
E in patients with coronary disease: Cambridge heart antioxidant
study (CHAOS). Lancet 347, 781–786. doi: 10.1016/S0140-6736(96)
Stucki, D. M., Ruegsegger, C., Steiner, S., Radecke, J., Murphy, M. P., Zuber, B., et al.
(2016). Mitochondrial impairments contribute to Spinocerebellar ataxia type 1
progression and can be ameliorated by the mitochondria-targeted antioxidant
MitoQ. Free Radic. Biol. Med. 97, 427–440. doi: 10.1016/j.freeradbiomed.2016.
Sun, J., Chu, Y. F., Wu, X., and Liu, R. H. (2002). Antioxidant and antiproliferative
activities of common fruits. J. Agric. Food Chem. 50, 7449–7454. doi: 10.1021/
Tang, G. W. (2010). Bioconversion of dietary provitamin A carotenoids to vitamin
A in humans. Am. J. Clin. Nutr. 91, 1468s–1473s. doi: 10.3945/ajcn.2010.
Tecklenburg, S. L., Mickleborough, T. D., Fly, A. D., Bai, Y., and Stager,
J. M. (2007). Ascorbic acid supplementation attenuates exercise-induced
bronchoconstriction in patients with asthma. Respir. Med. 101, 1770–1778.
doi: 10.1016/j.rmed.2007.02.014
Thomson, C. A., Rock, C. L., Thompson, P. A., Caan, B. J., Cussler, E., Flatt,
S. W., et al. (2011). Vegetable intake is associated with reduced breast cancer
recurrence in tamoxifen users: a secondary analysis from the Women’s Healthy
Eating and Living Study. Breast Cancer Res. Treat. 125, 519–527. doi: 10.1007/
s10549-010- 1014-9
Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio,
A. T., Bruder, C. E., et al. (2004). Premature ageing in mice expressing
defective mitochondrial DNA polymerase. Nature 429, 417–423. doi: 10.1038/
Trueba, G. P., Sanchez, G. M., and Giuliani, A. (2004). Oxygen free radical
and antioxidant defense mechanism in cancer. Front. Biosci. 9, 2029–2044.
doi: 10.2741/1335
Tsagalioti, E., Trifonos, C., Morari, A., Vadikolias, K., and Giaginis, C.
(2016). Clinical value of nutritional status in neurodegenerative
diseases: What is its impact and how it affects disease progression and
management? Nutr. Neurosci. 21, 162–175. doi: 10.1080/1028415X.2016.
Turati, F., Rossi, M., Pelucchi, C., Levi, F., and La Vecchia, C. (2015).
Fruit and vegetables and cancer risk: a review of southern European
studies. Br. J. Nutr. 113(Suppl. 2), S102–S110. doi: 10.1017/S00071145150
Uttara, B., Singh, A. V., Zamboni, P., and Mahajan, R. T. (2009). Oxidative
stress and neurodegenerative diseases: a review of upstream and downstream
antioxidant therapeutic options. Curr. Neuropharmacol. 7, 65–74. doi: 10.2174/
Valko, M., Rhodes, C. J., Moncol, J., Izakovic, M., and Mazur, M.
(2006). Free radicals, metals and antioxidants in oxidative stress-
induced cancer. Chem. Biol. Interact. 160, 1–40. doi: 10.1016/j.cbi.2005.
van Eeden, S. F., and Sin, D. D. (2013). Oxidative stress in chronic obstructive
pulmonary disease: a lung and systemic process. Can. Respir. J. 20, 27–29.
doi: 10.1155/2013/509130
van Hogezand, R. A., and Hamdy, N. A. (2006). Skeletal morbidity in inflammatory
bowel disease. Scand. J. Gastroenterol. Suppl. 41, 59–64. doi: 10.1080/
Varraso, R., Chiuve, S. E., Fung, T. T., Barr, R. G., Hu, F. B., Willett, W. C., et al.
(2015). Alternate Healthy Eating Index 2010 and risk of chronic obstructive
pulmonary disease among US women and men: prospective study. BMJ
350:h286. doi: 10.1136/bmj.h286
Vita, J. A. (2005). Polyphenols and cardiovascular disease: effects on endothelial
and platelet function. Am. J. Clin. Nutr. 81, 292s–297s. doi: 10.1093/ajcn/81.1.
Vivekananthan, D. P., Penn, M. S., Sapp, S. K., Hsu, A., and Topol, E. J. (2003).
Use of antioxidant vitamins for the prevention of cardiovascular disease:
meta-analysis of randomised trials. Lancet 362, 922–922. doi: 10.1016/S0140-
Vonzglinicki, T., Saretzki, G., Docke, W., and Lotze, C. (1995). Mild
hyperoxia shortens telomeres and inhibits proliferation of fibroblasts - a
model for senescence. Exp. Cell Res. 220, 186–193. doi: 10.1006/excr.1995.
Vrieling, A., Buck, K., Seibold, P., Heinz, J., Obi, N., Flesch-Janys, D.,
et al. (2013). Dietary patterns and survival in German postmenopausal
breast cancer survivors. Br. J. Cancer 108, 188–192. doi: 10.1038/bjc.
Wallace, J. L., and Chin, B. C. (1997). Inflammatory mediators in gastrointestinal
defense and injury. Proc. Soc. Exp. Biol. Med. 214, 192–203. doi: 10.3181/
00379727-214- 44087
Wang, J., Yang, D., Yu, Y., Shao, G., and Wang, Q. (2016). Vitamin D and sunlight
exposure in newly-diagnosed Parkinson’s disease. Nutrients 8:142. doi: 10.3390/
Wang, X., Ouyang, Y. Y., Liu, J., Zhu, M. M., Zhao, G., Bao, W., et al.
(2014a). Fruit and vegetable consumption and mortality from all causes,
cardiovascular disease, and cancer: systematic review and dose-response meta-
analysis of prospective cohort studies. BMJ 349:g4490. doi: 10.1136/bmj.
Wang, X., Wang, W., Li, L., Perry, G., Lee, H. G., and Zhu, X. W.
(2014b). Oxidative stress and mitochondrial dysfunction in Alzheimer’s
disease. Biochim. Biophys. Acta 1842, 1240–1247. doi: 10.1016/j.bbadis.2013.
Wells, P. G., Mccallum, G. P., Chen, C. S., Henderson, J. T., Lee, C. J., Perstin, J.,
et al. (2009). Oxidative stress in developmental origins of disease: teratogenesis,
neurodevelopmental deficits, and cancer. Toxicol. Sci. 108, 4–18. doi: 10.1093/
Wilson, M. A., Shukitt-Hale, B., Kalt, W., Ingram, D. K., Joseph, J. A., and Wolkow,
C. A. (2006). Blueberry polyphenols increase lifespan and thermotolerance
in Caenorhabditis elegans.Aging Cell 5, 59–68. doi: 10.1111/j.1474- 9726.2006.
Winter, A. N., Ross, E. K., Wilkins, H. M., Stankiewicz, T. R., Wallace, T., Miller, K.,
et al. (2017). An anthocyanin-enriched extract from strawberries delays disease
onset and extends survival in the hSOD1G93A mouse model of amyotrophic
lateral sclerosis. Nutr. Neurosci. doi: 10.1080/1028415X.2017.1297023 [Epub
ahead of print].
Winterbourn, C. C., and Hampton, M. B. (2008). Thiol chemistry and specificity
in redox signaling. Free Radic. Biol. Med. 45, 549–561. doi: 10.1016/j.
Wood, L. G., Garg, M. L., Smart, J. M., Scott, H. A., Barker, D., and Gibson, P. G.
(2012). Manipulating antioxidant intake in asthma: a randomized controlled
trial. Am. J. Clin. Nutr. 96, 534–543. doi: 10.3945/ajcn.111.032623
World Cancer Research Fund/American Institute for Cancer Research (2007).
Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global
Perspective. Washington, DC: AICR.
Xie, Q., Bai, Q., Zou, L. Y., Zhang, Q. Y., Zhou, Y., Chang, H., et al. (2014).
Genistein inhibits DNA methylation and increases expression of tumor
suppressor genes in human breast cancer cells. Genes Chromosomes Cancer 53,
422–431. doi: 10.1002/gcc.22154
Yan, M. H., Wang, X., and Zhu, X. (2013). Mitochondrial defects and oxidative
stress in Alzheimer disease and Parkinson disease. Free Radic. Biol. Med. 62,
90–101. doi: 10.1016/j.freeradbiomed.2012.11.014
Zaidi, S. M., and Banu, N. (2004). Antioxidant potential of vitamins A, E and
C in modulating oxidative stress in rat brain. Clin. Chim. Acta 340, 229–233.
doi: 10.1016/j.cccn.2003.11.003
Zandi, P. P., Anthony, J. C., Khachaturian, A. S., Stone, S. V., Gustafson, D.,
Tschanz, J. T., et al. (2004). Reduced risk of Alzheimer disease in users of
antioxidant vitamin supplements: the Cache County Study. Arch. Neurol. 61,
82–88. doi: 10.1001/archneur.61.1.82
Zhang, Y. J., Gan, R. Y., Li, S., Zhou, Y., Li, A. N., Xu, D. P., et al. (2015).
Antioxidant phytochemicals for the prevention and treatment of chronic
diseases. Molecules 20, 21138–21156. doi: 10.3390/molecules201219753
Zhou, T., Prather, E. R., Garrison, D. E., and Zuo, L. (2018). Interplay
between ROS and antioxidants during ischemia-reperfusion injuries in
cardiac and skeletal muscle. Int. J. Mol. Sci. 19:E417. doi: 10.3390/ijms190
Zhu, H., and Li, Y. R. (2012). Oxidative stress and redox signaling
mechanisms of inflammatory bowel disease: updated experimental and
Frontiers in Physiology | 13 May 2018 | Volume 9 | Article 477
fphys-09-00477 May 16, 2018 Time: 17:2 # 14
Liu et al. Nutritional Antioxidants in Oxidative Diseases
clinical evidence. Exp. Biol. Med. 237, 474–480. doi: 10.1258/ebm.2011.
Zino, S., Skeaff, M., Williams, S., and Mann, J. (1997). Randomised controlled trial
of effect of fruit and vegetable consumption on plasma concentrations of lipids
and antioxidants. BMJ 314, 1787–1791. doi: 10.1136/bmj.314.7097.1787
Zuo, L., Hemmelgarn, B. T., Chuang, C. C., and Best, T. M. (2015a). The role of
oxidative stress-induced epigenetic alterations in amyloid-beta production in
Alzheimer’s disease. Oxid. Med. Cell. Longev. 2015:604658. doi: 10.1155/2015/
Zuo, L., and Motherwell, M. S. (2013). The impact of reactive oxygen species
and genetic mitochondrial mutations in Parkinson’s disease. Gene 532, 18–23.
doi: 10.1016/j.gene.2013.07.085
Zuo, L., Pannell, B. K., and Liu, Z. (2016). Characterization and redox mechanism
of asthma in the elderly. Oncotarget 7, 25010–25021. doi: 10.18632/oncotarget.
Zuo, L., Zhou, T., Pannell, B. K., Ziegler, A. C., and Best, T. M. (2015b). Biological
and physiological role of reactive oxygen species–the good, the bad and the ugly.
Acta Physiol. 214, 329–348. doi: 10.1111/apha.12515
Conflict of Interest Statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Copyright © 2018 Liu, Ren, Zhang, Chuang, Kandaswamy, Zhou and Zuo. This is an
open-access article distributed under the terms of the Creative Commons Attribution
License (CC BY). The use, distribution or reproduction in other forums is permitted,
provided the original author(s) and the copyright owner are credited and that the
original publication in this journal is cited, in accordance with accepted academic
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with these terms.
Frontiers in Physiology | 14 May 2018 | Volume 9 | Article 477
... Our study found that the number of damaged mitochondria in IECs of UC patients increased with disease severity, and the level of mtROS in intestinal mucosa increased continuously, which was consistent with previous studies (Liu et al., 2018), further proving the correlation between the level of damaged mitochondria and mtROS and the severity of UC. Therefore, timely removal of damaged mitochondria may be an important way to inhibit the inflammation of intestinal mucosa. ...
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The overactivation of NLRP3 inflammasome in intestinal epithelial cells (IECs) is among the important reasons for severe inflammation in ulcerative colitis (UC). We found that heat shock transcription factor 2 (HSF2), which is highly expressed in UC, could inhibit the activation of NLRP3 inflammasome and reduce IL-1β in IECs, but the mechanisms were still not clear. It has been reported that HSP72 regulated by HSF2 can enhance the mitophagy mediated by Parkin. The number of damaged mitochondria and the mitochondrial derived ROS (mtROS) can be reduced by mitophagy, which means the activity of NLRP3 inflammasome is inhibited. Therefore, we speculate that HSF2 might regulate the activation of NLRP3 inflammasome of IECs in UC through the mitophagy mediated by Parkin. This study proves that the number of damaged mitochondria in IECs, the level of mitophagy, and the level of ROS in intestinal mucosa are positively correlated with the severity of UC. In mice and cells, mitophagy was promoted by HSF2 through the PARL/PINK1/Parkin pathway. This study reveals the potential mechanisms of HSF2 decreasing mtROS of IECs in UC.
... Aging and many human diseases, such as cancer, inflammatory disorder, and neurodegenerative and digestive diseases, are associated with the overproduction of reactive oxygen species (ROS) or other free radicals [65][66][67]. These molecules are very reactive because of their unpaired electrons and, as a result, can cause cellular damage. ...
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Ziziphus nummularia, a small bush of the Rhamnaceae family, has been widely used in traditional folk medicine, is rich in bioactive molecules, and has many reported pharmacological and therapeutic properties. Objective: To gather the current knowledge related to the medicinal characteristics of Z. nummularia. Specifically, its phytochemical contents and pharmacological activities in the treatment of various diseases such as cancer, diabetes, and cardiovascular diseases, are discussed. Methods: Major scientific literature databases, including PubMed, Scopus, ScienceDirect, SciFinder, Chemical Abstracts, Medicinal and Aromatic Plants Abstracts, Henriette′s Herbal Homepage, Dr. Duke′s Phytochemical and Ethnobotanical Databases, were searched to retrieve articles related to the review subject. General web searches using Google and Google scholar were also utilized. The search period covered articles published between 1980 and the end of October 2021.The search used the keywords ‘Ziziphus nummularia’, AND (‘phytochemical content’, ‘pharmacological properties, or activities, or effects, or roles’, ‘anti-inflammatory’, ‘anti-drought’, ‘anti-thermal’, ‘anthelmintic’, ‘antidiabetic’,’ anticancer’, ‘anticholinesterase’, ‘antimicrobial’, ‘sedative’, ‘antipyretic’, ‘analgesic’, or ‘gastrointestinal’). Results: This plant is rich in characteristic alkaloids, especially cyclopeptide alkaloids such as nummularine-M. Other phytochemicals, including flavonoids, saponins, glycosides, tannins, and phenolic compounds, are also present. These phytochemicals are responsible for the reported pharmacological properties of Z. nummularia, including anti-inflammatory, antioxidant, antimicrobial, anthelmintic, antidiabetic, anticancer, analgesic, and gastrointestinal activities. In addition, Z. nummularia has anti-drought and anti-thermal characteristics. Conclusion: Research into the phytochemical and pharmacological properties of Z. nummularia has demonstrated that this plant is a rich source of novel bioactive compounds. So far, Z. nummularia has shown a varied pharmacological profile (antioxidant, anticancer, anti-inflammatory, and cardioprotective), warranting further research to uncover the therapeutic potential of the bioactives of this plant. Taken together, Z. nummularia may represent a new potential target for the discovery of new drug leads.
... Apple fruit juice is rich in many potential health-promoting properties, including high phenolic compounds, vitamins, minerals, and good antioxidant capacity, and is widely consumed in many temperate countries [20]. Star fruit is also a tropical fruit containing many beneficial properties such as polyphenols and ascorbic acid, which is helpful in preventing cancer, immune dysfunction, cardiovascular diseases aging, and neural diseases [21]. Thus, with their added nutritional value, apple and star fruit juices are likely to be the food media, where the healthy bacteria can also make their mark on the well-being of the consumers. ...
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In this study, two probiotic lactobacillus strains, such as Lactobacillus fermentum and Lactobacillus plantarum, were inoculated in apple and star fruit juices to develop probiotic juices. The main aim of this study was to test the suitability of these two strains in the fruit juices, and also assess the change of biochemical and sensory properties under chill (4 °C) storage. For each fruit juice, three probiotic juice samples were prepared by inoculating with 1 % L. plantarum, 1 % L. fermentum, and the mixture of both L. fermentum and L. plantarum (0.5 % each) and compared with the control sample (juice with no lactobacillus strain). The changes in pH, acidity, protein, total soluble solid, total cell count, and sensory properties of samples were studied at every seven-day interval at 4 °C for three weeks. The results revealed that the pH, protein, and total soluble solids (TSS) of both probiotic juices, decreased slightly with increasing storage time. At the same time, acidity contents showed a reverse trend. It was found that both L. fermentum and L. plantarum sustained well in fruit juices, though the highest bacterial cell count was found on 7 th day of storage for both probiotic juices. Notably fruits juices with L. fermentum supported more cell growth than the juice samples with L. plantarum. Regarding organoleptic analysis, overall sensory scores of fermented apple and star fruit juices including control samples slightly decreased with increasing storage duration. Overall, the study insinuated that two lactobacilli did not put forth any inferior properties of fruit juice samples compared to the control samples regarding physicochemical and sensory properties. Therefore, apple and star fruit juices could be viable media for the growth of L. fermentum and L. plantarum as potential probiotics.
Rheumatoid arthritis (RA) has plagued physicians and patients for years due to the lack of targeted treatment. In this study, inspired by the commonality between Rheumatoid Arthritis fibroblast‐like synoviocytes (RA‐FLS) and cancer cells, the therapeutic effects of cold air plasma (CAP) on RA are studied systematically and thoroughly. In/ex vivo results show that CAP with the proper dosage significantly relieves symptoms including synovial hyperplasia, inflammatory infiltration and angiogenesis and eliminates the root cause by triggering the self‐antioxidant capability of the surrounding tissue. The mechanism on the molecular and cellular level is also revealed that the spontaneous reactive oxygen species (ROS) cascade induces the mitochondrial apoptosis pathway on RA‐FLS. This study reveals a new strategy for targeted treatment of rheumatoid arthritis (RA) and the mechanistic study provides the theoretical foundation for future development of plasma medicine. This article is protected by copyright. All rights reserved.
The present study investigated the potential antioxidant applications of Humulus lupulus L. as raw extract and nanoformulated in liposomes. H. lupulus is commonly used as a food ingredient, but it is also a promising source of specialized metabolites with health-promoting effects. In the extract obtained by hydroalcoholic maceration, 24 compounds were characterized using liquid chromatography-mass spectrometry analyses. The extract exhibited an interesting antioxidant activity in in vitro spectrophotometric and cell assays. The extract was nanoformulated into liposomes to exploit and improve its beneficial proprierties. The in vitro assays revealed that, after incorporation into liposomes, the extract’s antioxidant activity was preserved and even improved. Moreover, a lower dose of the extract was required to prevent reactive oxygen species overproduction when included in the nanoformulation. These results confirm the advantages of nanoformulating herbal extract to maximize its health-promoting effects for a potential pharmaceutical application.
La phytothérapie et le recours aux plantes médicinales pour prévenir ou traiter diverses maladies remontent à l’antiquité. De nos jours, les industries pharmaceutiques et cosmétiques sont constamment à la recherche de molécules bioactives naturelles pour diverses applications. Ce travail de thèse a consisté à rechercher des composés à intérêt thérapeutiques dans les parties aériennes d’Astragalus emarginatus Labill. (AEL) et d’Astragalus coluteoides Will. (ACW), deux plantes utilisées dans la médecine traditionnelle libanaise. En utilisant les essais TEAC, ORAC et DPPH il a été possible de montrer un pouvoir anti-radicalaire dans divers extraits des deux plantes préparés avec des solvants de polarités différentes (eau, méthanol, éthanol, chloroforme et acétate d’éthyle). Les extraits hydroéthanoliques, EtOH 30% pour AEL (AEEt30) et EtOH 50% pour ACW (ACEt50) ont montré l’activité anti-radicalaire la plus importante. Une analyse CLHP-ABTS•+ a déterminé précisément les molécules antioxydantes dans chacun de ces extraits. Ensuite, une analyse CLUHP-DAD-SMHR a mené à l’identification de ces molécules, ainsi que d’autres constituants de ces deux extraits. Ces identifications ont montré d’une part, la présence de deux catégories de composés dans l’extrait AEEt30, les flavonoïdes et les hydroxycinnamates, et d’autre part que les dérivés de l’acide caféique et les dérivés glycosilés de quercétine sont à l’origine de l’action antioxydante. L’extrait ACEt50 a révélé quant à lui une composition chimique différente de celle de l’extrait AEEt30 surtout s’agissant des composés non flavonoïques. La rutine y a été identifiée comme l’antioxydant principal. Ces résultats ont l’intérêt d’AEL et d’ACW comme une source des antioxydants naturels. Des tests cellulaires d’activités anticancéreuse, anti-inflammatoire et antibactérienne n’ont par contre pas permis de mettre en évidence de telles activités à l’exception de l’activité anti-inflammatoire dans l’extrait ACEt50.
Les accidents vasculaires cérébraux (AVC) constituent la 2ème cause de mortalité dans le monde et la 1ère chez les femmes en France. Pour les AVC ischémiques (AVCi), seules des stratégies de recanalisation pharmacologique ou mécanique ont été approuvées mais aucune stratégie protectrice n'est aujourd'hui disponible. Bien que le rôle délétère du stress oxydant ait été clairement établi dans les lésions neuronales et vasculaires à la suite d'une ischémie cérébrale (IC) dans les études précliniques, aucune stratégie anti-oxydante n'a démontré d'efficacité clinique à ce jour. Or, les nanoparticules d'oxyde de cérium (NPC) possèdent de multiples capacités antioxydantes (enzymatique et non enzymatique). Afin d'améliorer la biocompatibilité des NPC, la société Specific Polymers® a développé des copolymères de polyéthylène glycol (PEG)/ polyméthacrylate de méthyle/ phosphonate pour recouvrir leur surface. De plus, ces polymères peuvent être fonctionnalisés avec un peptide ciblant l'endothélium ce qui permettrait d'y concentrer l'effet antioxydant des NPC, afin de réduire la survenue d'hémorragies cérébrales, complications graves chez les patients victimes d'AVCi. L'objectif de cette thèse est d'évaluer l'impact du recouvrement des NPC sur leur potentiel thérapeutique dans l'IC. Les études ont été menées in vitro pour établir la toxicité, l'effet antioxydant et l'internalisation cellulaire des NPC et in vivo, pour examiner leur biodistribution et leur toxicité, ainsi que leur potentiel thérapeutique dans un modèle d'IC. Les études in vitro ont été effectuées sur des cellules endothéliales cérébrales murines de la lignée b.End3. Nous avons démontré que les NPC n'induisaient ni mortalité, ni perturbation de l'activité métabolique jusqu'à 100µg/ml. A 1000µg/mL, les NPC nues augmentent la mortalité, contrairement aux NPC PEGylées. Nous avons modélisé l'excitotoxicité survenant lors d'une IC et qui contribue au stress oxydant, grâce à un traitement des cellules par le glutamate. L'augmentation de la production d'espèces réactives de l'oxygène par les cellules b.End3 et l'oxydation des acides nucléiques dans ces conditions ont été réduites par les NPC, démontrant que leur recouvrement n'interfère pas avec leurs propriétés anti-oxydantes. La fonctionnalisation des NPC a permis le greffage d'un fluorophore pour suivre leur internalisation par cytométrie en flux et microscopie confocale. Nous avons ainsi mis en évidence que les NPC étaient rapidement internalisées dans les cellules b.End3. Des études de microscopie électronique ont ensuite montré que les NPC sont principalement localisées dans des endosomes périnucléaires. Enfin, nous avons réalisé le greffage sur les NPC d'un peptide ciblant une protéine d'adhésion vasculaire surexprimée lors de l'IC. La suite de ces études consistera à vérifier l'interaction spécifique de ces NPC avec la molécule d'adhésion. Les études in vivo ont permis d'établir la biodistribution des NPC chez des souris Swiss : des NPC sont retrouvées durant les premières heures suivant leur injection, avant leur élimination par voie rénale. L'histopathologie n'a révélé aucune toxicité des NPC sur le foie, les reins, la rate, les poumons et le cerveau de ces souris et aucune modification de leur numération sanguine n'a été observée. Les NPC ont ensuite été administrées dans un modèle murin d'IC, mais n'ont pas réduit le volume de la lésion dans nos conditions. En conclusion, le recouvrement des NPC par des polymères innovants a réduit leur toxicité sans altérer leurs capacités antioxydantes et leur internalisation dans des cellules endothéliales cérébrales. L'absence d'accumulation à long terme et de toxicité in vivo sont encourageantes quant à leur biocompatibilité. Bien que les NPC n'aient pas montré d'effet protecteur in vivo, celles ciblant l'endothélium pourraient réduire les lésions vasculaires et le risque hémorragique consécutif à une IC.
In the present study, we developed new functional food materials from chickpea (Cicer arietinum) milk (CM) with desirable nutritional value, health functions, and rheology to mitigate lifestyle and age-related diseases. The anti-oxidant, anti-glycation, and bile acid-lowering properties of CM fermented with the lactic acid bacteria Lactiplantibacillus pentosus Himuka-SU5 (LpFCM) and Lactococcus lactis subsp. lactis Amami-SU1 (LcFCM) were determined in vitro. L. pentosus Himuka-SU5 and L. lactis Amami-SU1 were found to lower the pH from 6.4 to 4.7 at 12 and 48 h, respectively. The lactic acid concentration in LpFCM and LcFCM was 6.9 and 4.4 mg/mL, respectively. Both starters were found to degrade the dissolved proteins in CM, and L. lactis Amami-SU1 produced ammonia. Though the total phenolic content was slightly lower in LpFCM and LcFCM than in unfermented CM, O2⁻ radical-scavenging capacity, 1,1-diphenyl-2-picrylhydrazyl radical-scavenging capacity, and Fe-reducing power were high in both LpFCM and LcFCM. Anti-glycation in a bovine serum albumin-fructose model and the bile acid-lowering capacities of CM were distinctly increased following fermentation. Based on the results of the present study, we inferred that fermented CM can be considered a desirable food material to prevent and ameliorate chronic lifestyle diseases, particularly in the elderly.
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Ischemia reperfusion (IR), present in myocardial infarction or extremity injuries, is a major clinical issue and leads to substantial tissue damage. Molecular mechanisms underlying IR injury in striated muscles involve the production of reactive oxygen species (ROS). Excessive ROS accumulation results in cellular oxidative stress, mitochondrial dysfunction, and initiation of cell death by activation of the mitochondrial permeability transition pore. Elevated ROS levels can also decrease myofibrillar Ca2+ sensitivity, thereby compromising muscle contractile function. Low levels of ROS can act as signaling molecules involved in the protective pathways of ischemic preconditioning (IPC). By scavenging ROS, antioxidant therapies aim to prevent IR injuries with positive treatment outcomes. Novel therapies such as postconditioning and pharmacological interventions that target IPC pathways hold great potential in attenuating IR injuries. Factors such as aging and diabetes could have a significant impact on the severity of IR injuries. The current paper aims to provide a comprehensive review on the multifaceted roles of ROS in IR injuries, with a focus on cardiac and skeletal muscle, as well as recent advancement in ROS-related therapies.
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Parkinson´s disease is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra pars compacta region. An important mechanism contributing to its development is oxidative stress, induced by the imbalance between the endogenous antioxidant defenses and free radicals production. Naturally occurring bioactive compounds exhibit high antioxidant capacity that may help reducing oxidative stress and even reverse the damage induced by ROS. Fruits are particularly rich in phytochemicals with antioxidant effect, and their properties against the development of neurodegenerative diseases are of great interest. This review discusses how the fruits bioactive compounds and synthetic analogs have been assessed for their ability to regulate molecular pathways involved in neuronal survival such as MAPK, Nrf2, and NF-B, thus elucidating the possible therapeutic and neuroprotective actions of these compounds.
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Oxygen derived species such as hydrogen peroxide, superoxide anion radical, hydroxyl radical (OH-), and singlet oxygen are well known to be cytotoxic and have been implicated in the etiology of a wide array of human diseases, including cancer. Various carcinogens may also partly exert their effect by generating reactive oxygen species (ROS) during their metabolism. Oxidative damage to cellular DNA can lead to mutations and may, therefore, play an important role in the initiation and progression of multistage carcinogenesis. ROS influences central cellular processes such as proliferation, apoptosis, and senescence which are implicated in the development of cancer. Understanding the role of ROS as key mediators in signaling cascades may provide various opportunities for pharmacological intervention.
The phospholipid mediator of anaphylaxis, platelet-activating factor (PAF) is chemotactic for polymorphonuclear leukocytes (PMN). We have examined this agent's effects on several other PMN functions. Human PMN were prepared from heparinized venous blood by Ficoll gradient. Metabolic burst was examined by measurement of O2 use and O2.- production in the presence or absence of PAF (10(-6)--10(-9) M). Unless cells were treated with cytochalasin-B (5 micrograms/ml), no significant respiratory burst was demonstrated. However, pretreatment with PAF (10(-7) M) enhanced approximately threefold the O2 utilization found when cells were subsequently stimulated with 10(-7) M FMLP. PAF also stimulated arachidonic acid metabolism in 14C-arachidonic acid- labeled PMN. Thin-layer chromatography analysis of chloroform-methanol extracts showed substances that comigrated with authentic 5- hydroxyeicosatetraenoic acid had a marked increase in radioactivity following PAF stimulation at 10(-7) M. PAF failed to stimulate release of granule enzymes, B-glucuronidase, lysozyme, or myeloperoxidase unless cytochalasin-B were added. PAF from 10(-6) M to 10(-10) M affected PMN surface responses. PMN labeled with the fluorescent dye, chlorotetracycline, showed decreased fluorescence upon addition of PAF, suggesting translocation of membrane-bound cations. Further, the rate of migration of PMN in an electric field was decreased following PAF exposure, a change consistent with reduced cell surface charge. PMN self-aggregation and adherence to endothelial cells were both influenced by PAF (10(-6) M--10(-9) M). Aggregation was markedly stimulated by the compound, and the percent PMN adhering to endothelial cell monolayers increased almost twofold in the presence of 10(-8) M PAF. Thus, PAF promotes a variety of PMN responses: enhances respiratory burst, stimulates arachidonic acid turnover, alters cell membrane cation content and surface charge, and promotes PMN self- aggregation as well as adherence to endothelial cells.
Objective: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting from the death of motor neurons in the brain, brain stem, and spinal cord. Several processes such as oxidative stress, neuroinflammation, and neuronal apoptosis, contribute to disease progression. Anthocyanins are flavonoid compounds derived from fruits and vegetables that possess antioxidant, anti-inflammatory, and anti-apoptotic abilities. Thus, these unique compounds may provide therapeutic benefit for the treatment of ALS. Methods: We used the G93A mutant human SOD1 (hSOD1G93A) mouse model of ALS to assess the effects of an anthocyanin-enriched extract from strawberries (SAE) on disease onset and progression. Mice were administered SAE orally beginning at 60 days of age until end-stage such that mice received 2 mg/kg/day of the extract's primary anthocyanin constituent. Clinical indices of disease were assessed until mice were sacrificed at end-stage. Histopathological indices of disease progression were also evaluated at 105 days of age. Results: hSOD1G93A mice supplemented with SAE experienced a marked (∼17 day) delay in disease onset and a statistically significant (∼11 day) extension in survival in comparison to their untreated mutant counterparts. Additionally, SAE-treated hSOD1G93A mice displayed significantly preserved grip strength throughout disease progression. Histopathological analysis demonstrated that SAE supplementation significantly reduced astrogliosis in spinal cord, and preserved neuromuscular junctions (NMJs) in gastrocnemius muscle. Discussion: These data are the first to demonstrate that anthocyanins have significant potential as therapeutic agents in a preclinical model of ALS due to their ability to reduce astrogliosis in spinal cord and preserve NMJ integrity and muscle function. Therefore, further study of these compounds is warranted in additional preclinical models of ALS and other neurodegenerative diseases.
Neurodegenerative diseases constitute a major problem of public health that is associated with an increased risk of mortality and poor quality of life. Malnutrition is considered as a major problem that worsens the prognosis of patients suffering from neurodegenerative diseases. In this aspect, the present review is aimed to critically collect and summarize all the available existing clinical data regarding the clinical impact of nutritional assessment in neurodegenerative diseases, highlighting on the crucial role of nutritional status in disease progression and management. According to the currently available clinical data, the nutritional status of patients seems to play a very important role in the development and progression of neurodegenerative diseases. A correct nutritional evaluation of neurodegenerative disease patients and a right nutrition intervention is essential in monitoring their disease.
Spinocerebellar ataxia type 1 (SCA1), due to an unstable polyglutamine expansion within the ubiquitously expressed Ataxin-1 protein, leads to the premature degeneration of Purkinje cells (PCs), decreasing motor coordination and causing death within 10-15 years of diagnosis. Currently, there are no therapies available to slow down disease progression. As secondary cellular impairments contributing to SCA1 progression are poorly understood, here, we focused on identifying those processes by performing a PC specific proteome profiling of Sca1(154Q/2Q) mice at a symptomatic stage. Mass spectrometry analysis revealed prominent alterations in mitochondrial proteins. Immunohistochemical and serial block-face scanning electron microscopy analyses confirmed that PCs underwent age-dependent alterations in mitochondrial morphology. Moreover, colorimetric assays demonstrated impairment of the electron transport chain complexes (ETC) and decrease in ATPase activity. Subsequently, we examined whether the mitochondria-targeted antioxidant MitoQ could restore mitochondrial dysfunction and prevent SCA1-associated pathology in Sca1(154Q/2Q) mice. MitoQ treatment both presymptomatically and when symptoms were evident ameliorated mitochondrial morphology and restored the activities of the ETC complexes. Notably, MitoQ slowed down the appearance of SCA1-linked neuropathology such as lack of motor coordination as well as preventing oxidative stress-induced DNA / RNA damage and PC loss. Our work identifies a central role for mitochondria in PC degeneration in SCA1 and provides evidence for the supportive use of mitochondria-targeted therapeutics in slowing down disease progression.
Critically ill patients are under oxidative stress and antioxidant administration reasonably emerged as a promising approach to combat the aberrant redox homeostasis in this patient cohort. However, the results of the antioxidant treatments in the intensive care unit are conflicting and inconclusive. The main objective of the present review is to highlight some inherent, yet widely overlooked redox-related issues about the equivocal effectiveness of antioxidants in the intensive care unit, beyond methodological considerations. In particular, the discrepancy in the literature partially stems from: (1) the largely unspecified role of reactive species in disease onset and progression, (2) our fragmentary understanding on the interplay between inflammation and oxidative stress, (3) the complex spatiotemporal specificity of in vivo redox biology, (4) the pleiotropic effects of antioxidants and (5) the divergent effects of antioxidants according to the temporal administration pattern. In addition, two novel and sophisticated practices with promising pre-clinical results are presented: (1) the selective neutralization of reactive species in key organelles after they are formed (i.e., in mitochondria) and (2) the targeted complete inhibition of dominant reactive species sources (i.e., NADPH oxidases). Finally, the reductive potential of NADPH as a key pharmacological target for redox therapies is rationalized. In light of the above, the recontextualization of knowledge from basic redox biology to translational medicine seems imperative to perform more realistic in vivo studies in the fast-growing field of critical care pharmacology.