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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
REVIEW
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,
Greece
Mutay Aslan,
Akdeniz University, Turkey
*Correspondence:
Li Zuo
zuo.4@osu.edu
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
Citation:
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,
vitamins
INTRODUCTION
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.
OXIDATIVE STRESS AND NUTRITIONAL
STATUS IN RESPIRATORY DISEASES
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.,
2012).
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,
2016).
OXIDATIVE STRESS AND NUTRITIONAL
STATUS IN CARDIOVASCULAR
DISEASES
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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Liu et al. Nutritional Antioxidants in Oxidative Diseases
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.,
2013).
OXIDATIVE STRESS AND NUTRITIONAL
STATUS IN NEURODEGENERATIVE
DISORDERS
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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(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.,
2016).
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).
OXIDATIVE STRESS AND NUTRITIONAL
STATUS IN CANCER
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).
OXIDATIVE STRESS AND NUTRITIONAL
STATUS IN DIGESTIVE DISEASES
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.
OXIDATIVE STRESS AND NUTRITIONAL
STATUS IN AGING
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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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
beings.
SUMMARY AND PROSPECTIVE
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.
AUTHOR CONTRIBUTIONS
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.
FUNDING
This study was supported by 2016 American Physiology Society
S&R Foundation Ryuji Ueno Award.
ACKNOWLEDGMENTS
We thank Paige Henry, Alicia Simpson, and Denethi
Wijegunawardana for their assistance during the manuscript
preparation.
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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
practice. No use, distribution or reproduction is permitted which does not comply
with these terms.
Frontiers in Physiology | www.frontiersin.org 14 May 2018 | Volume 9 | Article 477
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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.
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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.
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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.