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Nutrients and Oxidative Stress: Friend or Foe?

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There are different types of nutritionally mediated oxidative stress sources that trigger inflammation. Much information indicates that high intakes of macronutrients can promote oxidative stress and subsequently contribute to inflammation via nuclear factor-kappa B-(NF-κB-) mediated cell signaling pathways. Dietary carbohydrates, animal-based proteins, and fats are important to highlight here because they may contribute to the long-term consequences of nutritionally mediated inflammation. Oxidative stress is a central player of metabolic ailments associated with high-carbohydrate and animal-based protein diets and excessive fat consumption. Obesity has become an epidemic and represents the major risk factor for several chronic diseases, including diabetes, cardiovascular disease (CVD), and cancer. However, the molecular mechanisms of nutritionally mediated oxidative stress are complex and poorly understood. Therefore, this review aimed to explore how dietary choices exacerbate or dampen the oxidative stress and inflammation. We also discussed the implications of oxidative stress in the adipocyte and glucose metabolism and obesity-associated noncommunicable diseases (NCDs). Taken together, a better understanding of the role of oxidative stress in obesity and the development of obesity-related NCDs would provide a useful approach. This is because oxidative stress can be mediated by both extrinsic and intrinsic factors, hence providing a plausible means for the prevention of metabolic disorders.
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Review Article
Nutrients and Oxidative Stress: Friend or Foe?
Bee Ling Tan,
1
Mohd Esa Norhaizan ,
1,2,3
and Winnie-Pui-Pui Liew
1
1
Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang,
Selangor, Malaysia
2
Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
3
Research Centre of Excellent, Nutrition and Non-Communicable Diseases (NNCD), Faculty of Medicine and Health Sciences,
Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
Correspondence should be addressed to Mohd Esa Norhaizan; nhaizan@upm.edu.my
Received 14 August 2017; Revised 24 November 2017; Accepted 4 December 2017; Published 31 January 2018
Academic Editor: Rodrigo Valenzuela
Copyright © 2018 Bee Ling Tan et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
There are dierent types of nutritionally mediated oxidative stress sources that trigger inammation. Much information indicates
that high intakes of macronutrients can promote oxidative stress and subsequently contribute to inammation via nuclear factor-
kappa B- (NF-κB-) mediated cell signaling pathways. Dietary carbohydrates, animal-based proteins, and fats are important to
highlight here because they may contribute to the long-term consequences of nutritionally mediated inammation. Oxidative
stress is a central player of metabolic ailments associated with high-carbohydrate and animal-based protein diets and excessive
fat consumption. Obesity has become an epidemic and represents the major risk factor for several chronic diseases, including
diabetes, cardiovascular disease (CVD), and cancer. However, the molecular mechanisms of nutritionally mediated oxidative
stress are complex and poorly understood. Therefore, this review aimed to explore how dietary choices exacerbate or dampen
the oxidative stress and inammation. We also discussed the implications of oxidative stress in the adipocyte and glucose
metabolism and obesity-associated noncommunicable diseases (NCDs). Taken together, a better understanding of the role of
oxidative stress in obesity and the development of obesity-related NCDs would provide a useful approach. This is because
oxidative stress can be mediated by both extrinsic and intrinsic factors, hence providing a plausible means for the prevention of
metabolic disorders.
1. Introduction
There are dierent types of nutritionally mediated oxidative
stress sources that trigger inammation. Oxidative stress
plays a crucial role in the development of numerous human
diseases [1]. Reactive oxygen species (ROS) and reactive
nitrogen species (RNS) are produced continuously in the
body via oxidative metabolism, mitochondrial bioenergetics,
and immune function [2]. The most frequent forms of ROS
include superoxide anion, hyphochlorous acid, hydrogen
peroxide, singlet oxygen, hypochlorite, hydroxyl radical,
and lipid peroxides, which are involved in the progression,
growth, death, and dierentiation of cells. They can bind
with nucleic acids, enzymes, membrane lipids, proteins, and
other small molecules [1]. Short-term postprandial mito-
chondrial oxidative stress causes inammation, which is
mainly mediated by nuclear factor-kappa B (NF-κB) [3].
Conversely, long-term chronic overconsumption contributes
to obesity, which induces permanent states of inammation
via the generation of white adipose tissue which secretes
proinammatory factors [4]. Extensive research has shown
that high-glucose and a high-fat diet mediate inammation,
which suggests that oxidative stress may alter cellular physi-
ological processes [5, 6].
Substantial evidence highlights the detrimental impact of
diets high in rened carbohydrates and saturated fat [7].
Cardiovascular disease (CVD), obesity, type 2 diabetes, and
nonalcoholic fatty liver disease are attributed to the overcon-
sumption of foods high in carbohydrates and saturated fats,
the saturation of nutrient storage, and sedentary lifestyles
[8, 9]. Studies exploring the inuence of a Westernized
dietary pattern on inammatory diseases, such as colorectal
cancer [10], have consistently shown a similar trend. Such
ndings highlight the fundamental idea that diet quality
Hindawi
Oxidative Medicine and Cellular Longevity
Volume 2018, Article ID 9719584, 24 pages
https://doi.org/10.1155/2018/9719584
can impact immune function and systematic inammation.
In a study by Song et al. [11] focusing on carbohydrate and
rened-grain intake and metabolic syndrome outcome in
Korean men and women, women were shown to have a
greater likelihood of metabolic syndrome with rened-grain
consumption compared to the men, suggesting that rened-
grain intakes are linked to a high level of inammation.
The prevalence of obesity has doubled from 1980 to 2008
worldwide. In 2008, more than 50% of men and women in
the WHO European Region were overweight, and nearly
20% of men and 23% of women were obese [12]. Nearly 1.5
billion people worldwide are obese or overweight which
increases their risk of developing inammatory disturbances,
CVD, nonalcoholic fatty liver disease, coronary heart disease,
and type 2 diabetes [13, 14].
The eects of oxidative stress are related to the type of
macronutrients consumed and their absolute quantity [15];
both of these aspects contribute to oxidative stress and may
favor the development of obesity and obesity-related non-
communicable diseases (NCDs) [16]. However, the molecu-
lar mechanisms of nutritionally mediated oxidative stress
are complex and poorly understood. Therefore, this review
aimed to explore how dietary choices exacerbate or dampen
oxidative stress and inammation. We also discussed the
implications of oxidative stress in the adipocyte and glucose
metabolism and obesity-associated NCDs. A better under-
standing of the role of oxidative stress in obesity and the
development of obesity-related NCDs would provide a useful
approach. This is because oxidative stress can be mediated by
both extrinsic and intrinsic factors, hence providing a plausi-
ble means for the prevention of metabolic disorders.
2. Oxidative Stress
The harmful eects of free RNS and ROS radicals cause a
potential biological damage, namely, nitrosative stress and
oxidative stress, respectively [17]. ROS are generated in
normal aerobic metabolism as a by-product; however, when
the level is increased under stress, it may cause basic health
hazard [18]. The mitochondrion is the predominant cell
organelle in ROS production [19]. It generates adenosine
triphosphate (ATP) via a series of oxidative phosphorylation
processes [19]. During this process, one or two electron
reductions instead of four electron reductions of oxygen have
occurred, which subsequently leads to the formation of
H
2
O
2
or O
2
, and convert to other ROS [19]. The major
form of RNS includes nitric oxide (NO) and peroxynitrite
(ONOO) [17]. When excess NO is present, this reaction
leads to the formation of nitrogen dioxide radical [17].
Higher NO concentration leads to the formation of N
2
O
3
and this usually results in nitrosation [17].
Oxygen free radicals, including alkyl peroxyl radical
(
OOCR), hydroxyl radical (OH
), and superoxide anion
radical (O
2
), are potent initiators in lipid peroxidation,
the role of which is well-established in the pathogenesis of
diseases [18]. Once lipid peroxidation is initiated, a propaga-
tion of chain reactions will take place until termination
products are produced [18]. Thus, end products of lipid
peroxidation, for example, F2-isoprostanes, 4-hydroxy-2-
nonenol (4-HNE), and malondialdehyde (MDA), are
accumulated in biological systems [18]. DNA bases are very
susceptible to ROS oxidation, and the major detectable oxi-
dation product of DNA bases is 8-hydroxy-2-deoxyguano-
sine [18]. Oxidation of DNA bases can cause mutations and
deletions in both nuclear and mitochondrial DNA. Mito-
chondrial DNA is relatively prone to oxidative damage due
to its proximity to ROS and its decient repair capacity
compared to that of the nuclear DNA [18]. These oxidative
modications cause functional changes in structural and
enzymatic proteins, which may lead to substantial physiolog-
ical impact [18]. In addition, redox modulations of transcrip-
tion factors also increase or decrease their specic DNA
binding activities and thereby altering gene expression [18].
3. Nutritionally Mediated Oxidative Stress
3.1. High Carbohydrates. Much information indicates that
high intakes of macronutrients can promote oxidative stress
and subsequently contribute to inammation via NF-κB-
mediated cell signaling pathways [20]. Dietary carbohydrates
are important to highlight here because they may contribute
to the long-term consequences of nutritionally mediated
inammation [21]. Dietary carbohydrate intake has gained
attention among researchers because of the associations
between a high glycemic index (GI) or glycemic load (GL)
diet with diabetes, obesity, cancer, and coronary heart disease
[22, 23]. High GL diets have been characterized as a common
feature of Western culture; they are heavy in added sugars
and rened carbohydrates [24]. By contrast, low GI foods
were found to decrease postprandial glycemia in over-
weight/obese [23] and type 2 diabetes patients [25]. Consis-
tent relationships between high GI and diabetes have been
demonstrated in observational and cohort studies [2628].
The high GI of white rice may lead to high oxidative
stress [29]. Most Asian populations consume large amounts
of rice as a staple food; thus, dietary carbohydrate intake
plays a substantial role in the development of metabolic
diseases in Asian populations. In support of this, a positive
relationship between rice intake or total carbohydrates
and diabetes has been demonstrated in Japanese women
[30, 31]. In addition to diabetes outcome, a high intake
of rened-grain was also positively linked to fasting blood
glucose and triglyceride levels and negatively associated
with high-density lipoprotein (HDL) cholesterol in Asian
Indian and Korean populations [11, 32], indicating that a
high GI diet may negatively impact health.
The elevation of oxidative stress is linked to chronic
inammation [33]; other sources may also further increase
the accumulation of proinammatory cytokines in a vicious
cycle[34]. In cultured adipocytes, ROS promotes the pro-
duction of cytokine interleukin-6 (IL-6) and proinamma-
tory monocyte chemotactic protein-1 (MCP-1) expression
[35, 36]. In the adipose tissue, this can activate macrophage
inltration and subsequently result in a proinammatory
environment [37, 38]. ROS can also stimulate signal trans-
duction pathways (mainly via NF-κB), which activates the
production of tumor necrosis factor-α(TNF-α) and IL-6
[35, 39, 40]. Further, oxidative stress can also promote cells
2 Oxidative Medicine and Cellular Longevity
into cellular senescence, particularly adipocyte senescence,
partly via cellular oxidation damage [41, 42]. Adipocyte
senescence may recruit macrophages and elevates the
production of proinammatory cytokines [42, 43].
Excessive high caloric intake from either a high-
carbohydrate or high-fat diet will cause more substrates
to enter into mitochondrial respiration [44]. Subsequently,
the number of electrons donated to the electron transport
chain may increase [45]. Upon reaching a threshold
voltage, extra electrons might back up at complex III with
further donations to molecular oxygen, which produces
high levels of superoxide [45].
Intriguingly, extremely high amounts of carbohydrates
may lead to the reduction of insulin binding and the
downregulated transcription of insulin receptor expression
in the skeletal muscle [46]. High insulin and glucose levels
may decrease insulin binding to the insulin receptor in
adipocytes [47], negatively aecting Akt activity. The accumu-
lation of ROS/RNS or a reduction of antioxidant capacity due
to increased carbohydrate metabolism in insulin target tissues
may change the phosphorylation status of these signaling
pathways, subsequently resulting in deactivation. Indeed,
exposure to hydrogen peroxide (H
2
O
2
) promotes a signicant
loss in distal and proximal insulin signaling and decreased
glucose transport in muscles and adipocytes in vitro [48].
Evidence from an epidemiological study demonstrated
that the consumption of rened carbohydrates, such as
fructose-rich syrups, potentially leads to the epidemics of type
2 diabetes and obesity [49, 50]. Indeed, fructose-rich syrups
may potentially pose a risk of diabetes and CVD [49]. Animal
model studies further demonstrate that feeding normal rats
fructose-rich diets may induce several endocrine and meta-
bolic derangements, interfering with many organs and tissues
[51, 52]. Because the liver is predominantly responsible for
fructose metabolism and uptake, several studies are focusing
on hepatic glucose metabolism [53]. Although the molecular
link underlying fructose detrimental eects and carbohydrate
metabolism requires further elucidation, most of the experi-
mental studies indicate that oxidative stress could play a cen-
tral role [54, 55]. In this regard, a key mode of action to
explain this relationship is via fructose-induced oxidative
stress which subsequently leads to impaired carbohydrate
metabolism. Data from animal experiments have shown a
greater likelihood of inammation after the administration
of fructose [51]. Such ndings highlight the association of
insulin resistance and fructose and its role in hepatic metabo-
lism and carbohydrate metabolism against the anabolic path-
way and impaired glucose tolerance [52, 55, 56]. Castro et al.
[53] further demonstrated that fructose may modulate the
liver glucokinase activity via the production of ROS. These
data imply that numerous metabolic changes induced by
fructose in the liver are more likely initiated by an increase of
fructose phosphorylation by fructokinase, followed by adap-
tive changes that attempt to switch the substrate ow from
mitochondrial metabolism to energy storage [53].
3.2. High Animal-Based Proteins. In developed countries,
meat composes a signicant proportion of the normal diet
and consists of 15% of the daily energy intake, 40% of daily
protein, and 20% of daily fat [57]. Meat is high in dietary
protein and saturated fatty acids (SFAs). Fermentation of
the excessive proteins in the gut produces metabolites such
as ammonia (NH3) and hydrogen sulde (H2S), which are
compounds known to trigger the toxicity of the mucosa
[58]. Meat can be marketed fresh or processed, the latter of
which includes curing, salting, stung, smoking, drying,
and fermentation [59]. Although meat contains high amounts
of dietary protein, it can also be a source of mutagens due to
the presence of N-nitroso compounds (NOC) in processed
meats and heterocyclic amines (HCA) and polycyclic
aromatic hydrocarbons (PAH) during high-temperature
cooking and grilling [60].
Research has shown an association between the intake of
well-done red meat and colorectal cancer, which could be
partially explained by the formation of carcinogenic HCA
and PAH. Although meat is high in SFAs, a study evaluating
the mechanisms behind this nding suggests that these
associations are more likely caused by something other than
SFA content. However, the formation of cyto and genotoxic
lipid oxidation products, such as malondialdehyde (MDA),
4-hydroxy-2- nonenal (4-HNE), and N-nitroso compounds
(NOC) catalyzed by heme-Fe during digestion, is regarded
as the most plausible determinant that contributes to the
increased risk of colorectal cancer [61, 62]. A high intake of
red meat has been demonstrated to increase NOC formation
in humans, which is related to the colonic development of
the NOC-specic DNA adduct O6-carboxymethylguanine
(O6-C-MeG) [63].
Free Fe
2+
markedly increases during the cooking of
uncured meats [63]. Conversely, nitrite curing prevents
the degradation of heme-Fe through the stabilization of
the porphyrin ring [63]. Heat treatment also causes a
reduction of antioxidant enzymes, such as glutathione
peroxidase [64, 65], and generates oxygen from oxymyo-
globin, which contributes to the production of H
2
O
2
[66]. Further, free Fe
2+
catalyzes the Fenton reaction when
oxidative processes are initiated [67]. Through this reactive
nature, ROS results in oxidative damage to meat proteins,
which further explains the high formation of 4-HNE and
MDA when uncured pork is heated [68]. Compared to
cooked meat, a slightly lower concentration of simple alde-
hydes was observed in overcooked uncured pork. This could
be explained by the evaporation of aldehydes caused by the
reduction of the prooxidant eect of oxymyoglobin when
heated to above 75
°
C or intense heating [69]. Rather, when
meats are nitrite-cured, less degradation of the heat-stable
NO-heme may contribute to a reduced release of Fe
2+
to
initiate oxidation processes, which subsequently results in a
reduction of lipid oxidation. Because the Fenton reaction is
a chain reaction, a higher dosage of oxidation products after
digestion was expected [70]. A further study reported by Van
Hecke et al. [63] showed that the antioxidant eect of nitrite-
curing during digestion was signicantly reduced in over-
cooked nitrite-cured pork. Consistent with the study
reported by Van Hecke et al. [63], Okayama et al. [71] also
found that a prolonged cooking time or a temperature reach-
ing 80
°
C increased the decomposition of nitrite. A 1 : 1 ratio
of nitric oxide (
NO) to ROS activates lipid oxidation
3Oxidative Medicine and Cellular Longevity
whereas
NO >ROS suppresses this process [72]. Accord-
ingly, low residual nitrite caused by intense heating is more
likely to alter the
NO : ROS ratio; thus, nitrite could change
from an antioxidant to prooxidant behavior, which might
explain the increased formation of oxidation products in
overcooked nitrite-cured meats. In an earlier study by Ayala
et al. [73], MDA was shown to be absorbed in the blood-
stream and produce lipid oxidation products that could reach
tissues and cause DNA damage. Low lipid oxidation product
levels in colonic digests are attributed to Schibase forma-
tion with proteins, which thus binds with bacterial DNA
[74] or is oxidized by bacterial aldehyde dehydrogenase
activity. Collectively, the eect of nitrite curing of meat in
the colonic step was predominant since it was linked to a
low level of MDA but proportionally increased 4-HNE levels
and doubled heptanal amounts in the overcooked and
cooked meats [63].
In addition, the nitrite-curing of beef and pork also
caused a twofold dierence in heptanal levels in stimulated
colonic digests compared to their counterparts [70]. Lipid
aldehydes, such as 4-HNE and MDA, react with protein
chains leading to protein aggregation, causing the protein
to be less susceptible to pepsin activity [70]. Overcooked
nitrite-cured pork has low concentrations of protein
carbonyl compounds and lipid oxidation products before
digestion; this likely occurs because the meat proteins are
initially well-digested in the stomach, after which the low
levels of residual protein bind with 4-HNE and MDA, which
subsequently form in a later phase of digestion [70]. The rate
of protein digestibility is vitally important in association to
colorectal cancer because higher levels of residual protein
reaching the colon could result in the formation of
potentially harmful protein fermentation products, such as
p-cresol, ammonia, indole, and phenol [75]. NOC can be
stimulated either enzymatically or nonenzymatically via
oxidation [76, 77]. This nonenzymatic stimulation of NOC
can be generated by a hydroxyl radical-generating system
containing H
2
O
2
,Cu
2+
,Fe
2+
, and ascorbic acid. All these
compounds are present in meat. When H
2
O
2
,Cu
2+
,orFe
2+
was eliminated from a reaction mixture with N-nitroso-N-
methylpentylamine, the mutagenicity of these mixtures was
reduced [76].
3.3. Excessive Consumption of Fats. An extensive body of sys-
tematic reviews of randomized trials [78, 79] and prospective
cohort studies [78, 80] has urged for a reevaluation of dietary
guidelines for consumption and a reappraisal of the impact of
SFAs on health. Although research has demonstrated an
association between SFAs and CVD [81], not all data demon-
strated such a link. De Souza et al. [82] did not identify an
association of SFA intake and CVD, coronary heart disease,
ischemic stroke, or type 2 diabetes. Interestingly, a study
has reported that the total fat and types of fat were inversely
associated with total mortality [83]. Additionally, no associa-
tion was reported between the total fat and types of fat with
CVD mortality and myocardial infarction [83].
Substantial evidence has suggested that SFAs can boost
proinammatory signaling. The lengths of SFA chains can
produce dierent physiological responses [84, 85], but many
mechanisms are still debated. Long-chain SFAs including
palmitate and myristate acids are typically known for their
harmful eects against endothelial cells, which can induce
apoptosis through the induction of NF-κB in human
coronary artery endothelial cells (HCAECs) [86, 87]. Harvey
et al. [86] showed that long-chain SFAs can promote proin-
ammatory endothelial cell phenotypes through the incorpo-
ration into endothelial cell lipids. Conversely, short- and
medium-chain SFAs do not incorporate or contribute to
lipotoxicity. Particularly, stearic acid stimulates the upregula-
tion of ICAM-1 human aortic endothelial cells (HAECs) via
an NF-κB dependent manner [86].
Murumalla and Gunasekaran [88] reported that SFAs
(lauric acid and palmitic acid) did not stimulate Toll-like
receptors 4 (TLR4) or 2 (TLR2) in HEK-Blue cells transfected
with TLR2 and TLR4. Despite the inverse association
between SFAs and TLR4 or TLR2, not all studies agreed.
Huang et al. [84] found that palmitic acid and lauric acid
activated TLR2 and TLR4 in RAW264.7 macrophages and
transiently transfected human monocytic (THP-1) mono-
cytes. Data from human studies exploring the impact of SFAs
on gene expression are limited, but evidence from epidemio-
logical studies indicates the association between SFA
consumption and CVD. Nonetheless, the meta-analyses of
prospective studies exploring the relationship between CVD
and SFA showed a consistent poor association. From the
study reviewed, metaregressions conducted in randomized
trials demonstrated that polyunsaturated fatty acids
(PUFAs) replacing SFAs did not lead to any changes in
CVD risk [89]. Inconclusive ndings suggest that SFAs are
generally grouped together although medium-chain SFAs
may provide benecial health eects such as preventing
obesity and the inhibition of body fat accumulation [90].
The impact of high-SFA diet on gene expression in adipose
tissue was also presented by Youseef-Elabd et al. [91]. In
particular, an SFA diet led to an upregulation of genes such
as integrin beta 2 (ITGB2), cathepsin S (CTSS), and
interleukin-8 (IL-8) in moderately overweight individuals,
suggesting that these changes were linked to diet-induced
changes rather than obesity.
A high-fat diet (HFD) was demonstrated to be a signi-
cant risk factor for health. Animals feeding a long-term
HFD show increased oxidative stress and dysfunctional
mitochondria in several organs [9294]. Several research
studies have also indicated that high-fat consumption causes
a signicant reduction in auditory function [95, 96]. This
study demonstrated that long-term HFD reduced auditory
function and promoted age-related hearing loss [97]. From
the study reviewed, feeding rats with a HFD for a period of
12 months may increase plasma triglycerides, total choles-
terol, and nonesteried fatty acid levels, causing an increase
in blood oxidative stress parameters. A HFD was shown to
not only aggravate the lipid prole it also further enhanced
ROS accumulation and triggered mitochondrial damage in
the inner ear [97], suggesting enormous detrimental impacts
of a HFD on health.
Several studies have corroborated this nding and
found that increased caloric intake or obesity is associated
with increased mitochondrial superoxide production. Data
4 Oxidative Medicine and Cellular Longevity
reported by Anderson et al. [98] have shown that feeding a
HFD to both mice and humans causes a signicant elevation
of H
2
O
2
from the mitochondria isolated from the skeletal
muscle. From the study reviewed, H
2
O
2
emission was used
as a surrogate of superoxide emission as mitochondrial
superoxide and is converted to H
2
O
2
by superoxide dismut-
ase 2 (SOD 2). Further, ROS accumulation has also been
found in mitochondria isolated from adipose [99], liver
[100], and kidney [101] tissue in high-fat or obese-treated
animals. In another study, Valenzuela et al. [102] found that
liver enzyme activity such as superoxide dismutase (SOD),
catalase, glutathione peroxidase, and glutathione reductase
was signicantly reduced by a HFD diet-fed mice.
Additionally, an adipogenic diet and the accumulation of
adipose tissue can trigger oxidative stress in mammalian
tissues. Some studies supported the hypothesis that HFD
promotes inammation in the intestine, particularly in the
small intestine. This observation may represent an early
event that precedes and predisposes the individual to insulin
resistance and obesity [103]. de La Serre et al. [104] reported
that HFD activates myeloperoxidase activity, an inamma-
tion marker, in the ileum of obesity-prone Sprague-Dawley
rats. A study by de Wit et al. [105] further supported that
HFD activates macrophage migration inhibitory factor
expression in the ileum of obesity-prone C57BL/6J mice.
Consistent with studies reported by de La Serre et al. [104]
and de Wit et al. [105], Ding et al. [106] and Cortez et al.
[107] also found that TNF-αexpression was activated after
2 to 6 weeks of HFD administration and led to weight gain
and an increased body fat mass. High-fat consumption also
stimulates Kuper cells (the resident macrophages of the liver)
in mice and causes an elevation of the M1-polarized popula-
tion, which is linked to the pathogenesis of obesity-induced
fatty liver disease and insulin resistance [108]. Consequently,
obesity is associated with a marked increase in oxidative
damage to all cellular macromolecules [14, 109, 110].
The mechanisms underlying the elevation of oxidative
stress in metabolic disorders are not fully understood, but it
is hypothesized that mitochondrial dysfunction [16], aug-
mented by NADPH oxidase activity [111], and increased
fatty acid oxidation [112] contribute to these phenomena.
Most of the studies so far addressed abnormal gene expres-
sion in the adipose tissues and liver, accompanied by upreg-
ulated NADPH oxidase expression and downregulated
antioxidative enzyme expression [113, 114]. HFD promotes
dyslipidemia, which is associated with oxidative stress, an
accumulation of some transition metals and elevated free
radicals [115]. Fat accumulation has also been linked to
systemic oxidative stress in mice and humans via the
increased accumulation of ROS, accompanied by the
improved expression of NADPH oxidase and the decreased
expression of antioxidative enzymes [114]. Moreover, HFD
provokes lipid peroxidation and oxidative stress, whereas
NADPH oxidase activation deregulates the production of
redox-sensitive transcription mRNA such as NF-κB and
adipocytokines (fat-derived hormones) including plasmino-
gen activator inhibitor-1, monocyte chemotactic protein-1
(MCP-1), IL-6, adiponectin, and other inammatory cyto-
kines form dierent metabolic tissues [116].
Additionally, HFD raises the level of chylomicrons in the
intestine. These chylomicrons enter circulation and cause the
generation of free fatty acids (FFAs), which are taken up
by the liver. These hepatic FFAs may either enter the
mitochondria for β-oxidation or be esteried into triglyc-
erides [117, 118]. Triglycerides are either accumulated in
hepatocytes as small droplets or generate very low-density
lipoprotein (VLDL) which is thereby converted into low-
density lipoprotein (LDL) [118]. An excessive LDL burden
in the blood due to its excessive accumulation or lack of
LDL-receptors in hepatocytes may form oxidized-LDL
(Ox-LDL), which in turn is engulfed by macrophages to
become foam cells. Subsequently, foam cells accumulate
in the arterial endothelium to form plaque. Ultimately,
these lead to cardiovascular and circulatory disorders such
as thromboembolism, hypertension, atherosclerosis, and
heart block [119121]. Subsequently, the mitochondrial
β-oxidation of FFAs is linked to the conversion of oxi-
dized cofactors (NAD
+
and FAD) into reduced cofactors
NADH and FADH
2
and is thereby reoxidized and restored
back into NAD
+
and FAD by the mitochondrial respira-
tory chain. During reoxidation, NADH and FADH
2
trans-
fer electrons to the rst complexes of the respiratory
chain. Most of these electrons then migrate up to
cytochrome-c oxidase and thereby combine with protons
and oxygen to form water. These intermediates may inter-
act with oxygen and produce more and more superoxide
anion radicals and other ROS [122125]. Therefore, the
high consumption of fat-rich diets promotes mitochondrial
β-oxidation of FFAs and subsequently leads to an excess
electron ow using cytochrome-c oxidase, which elevates
the accumulation of ROS. Mitochondria are a vitally
important cellular source of ROS; they oxidize the unsatu-
rated lipids of fat deposits to cause lipid peroxidation. ROS
and lipid peroxidation can consume vitamins and antioxi-
dant enzymes [125, 126]. The depletion of these protective
substances may hamper ROS inactivation and promote
ROS-mediated damage and lipid peroxidation [114]. This
HFD-induced ROS may stimulate the proinammatory
state and thereby activate the NF-κB transcription factor.
Further, HFD also may trigger ROS or NF-κB, which
induces NF-κB-dependent proinammatory agents such
as TNF-α, inducible nitric oxide synthase (iNOS), and
interferon-γ(IFN-γ) [101, 127, 128]. These data converge
to provide evidence supporting the role of oxidative stress
induced by HFD in metabolic disorders. Surprisingly, an
in vitro study showed that free fatty acids increased ROS
accumulation, indicating that increased fatty acids in obe-
sity may provide an extra source of additional electron
transport chain substrates via the oxidation of fatty acids
[111, 129]. In addition to the generation of ROS, the over-
production of nitric oxide (NO) through the activation of
iNOS also causes an accumulation of RNS [130, 131].
Taken together, chronic consumption of high GI foods
may cause oxidative stress via the formation of free radi-
cals that are capable in destroying biological molecules
and initiate abnormal cell growth through gene mutation
[132]. Further, HCA formed during high-temperature
cooking and grilling of meat may cause oxidation of
5Oxidative Medicine and Cellular Longevity
proteins and lipids, thereby resulting in oxidative stress and
may subsequently increase the risk of chronic diseases
[133], while the HFD may serve as a stimulus to elevate the
systemic inammatory response in the development of
obesity, CVD, diabetes, and cancers [134137]. Overall, these
data imply that high-carbohydrate/high-calorie/high-fat
diets stimulate oxidative stress by augmenting the inamma-
tory response and elevating inammatory markers.
4. Molecular Connectivity of Oxidative
Stress-Induced Diseases
4.1. Obesity and Adipocyte Dysfunction. Obesity has been
recognized as a heritable disorder in recent decades [138].
It has become increasingly clear that sedentary lifestyles
and an increased availability of inexpensive calorie-dense
foods have played a pivotal role in creating an obesogenic
environment, which has contributed to the obesity epidemic
[139141]. The individual heritability of obesity susceptibil-
ity genes and interaction of the nutrients in the obesogenic
environment, particularly dietary macronutrients, including
rened carbohydrates and saturated fats, are linked to weight
gain and may subsequently contribute to obesity [142, 143].
Thus, the functions of obesity susceptibility genes may be
associated with this major health concern.
Obesity is considered a chronic low-grade inammatory
stress condition modulated by immune cells via the inltra-
tion of adipose tissue, along with metabolic stress when over-
supplied with glucose and lipids in adipocytes [144, 145].
Inammatory cytokines have been observed in many fat cells;
they are involved in fat metabolism and are associated with
all indices of obesity, particularly abdominal obesity [146].
The alterations of leptin and hypothalamic pituitary adrenal
(HPA) axis dysfunction, adipocyte function, and fatty acid
levels and oxidative stress have been suggested to play a
vitally important role in obesity-associated inammation
[146]. In general, the association between excessive nutrient
uptake (sugars, lipids, and fatty acids) and metabolic distur-
bances is modulated by several types of cells, such as adipo-
cytes and resident or inltrating immune cells including
monocytes, T cells, mast cells, and macrophages, which indi-
rectly modify adipocyte function and dysfunction [147, 148].
A study by Lim et al. [149] found that dietary fatty acids
activate protease-activated receptor 2 (PAR2) expression,
which is a new biomarker for obesity and a substantial con-
tributor in metabolic dysfunction and inammation.
Studies have shown that ROS is generated from hypertro-
phic adipocytes induced by a HFD. The expansion of fat mass
occurs via two concomitant processes in white adipose tissue
expansion: hyperplasia (increased numbers of fat cells associ-
ated with the dierentiation of adipocyte precursors) and
hypertrophy (increased size of fat cells) [150152]. Several
studies have shown a close relationship between ROS and
fat mass expansion [153, 154]. Fat accumulation parallels
with ROS, as demonstrated by an increase of ROS accumula-
tion during adipocyte 3T3-L1 alteration [155, 156]. Leptin, a
white adipose tissue-derived hormone, has been reported to
promote the elevation of ROS accumulation in endothelial
cells [157, 158]. NF-κB can be stimulated by leptin in an
oxidant-dependent manner. This nding is linked with an
increased expression of monocyte chemoattractant protein-
1 (MCP-1), which enhances atherosclerosis by supporting
the relocation of inammatory cells [152, 159]. Further,
leptin also activates ROS in vascular smooth muscle cells
via the protein kinase C-dependent activation of NAD(P)H
oxidase [160]. Leptin promotes the release of active macro-
phage lipoprotein lipase via an oxidative stress-dependent
pathway, signifying a proatherogenic eect of leptin on mac-
rophages in diabetes [157]. By contrast, the exposition of adi-
pocytes to high ROS levels suppresses the secretion and
expression of adiponectin [161], an adipokine that shows
anti-inammatory, antiatherogenic, and insulin-sensitizing
properties [162]. Collectively, systemic oxidative stress-
associated HFD and obesity may lead to insulin sensitivity
of metabolic organs, which thus promotes the inammatory
response [163].
Obesity has been demonstrated to drive the development
of insulin resistance. However, not all obese individuals
develop type 2 diabetes mellitus or insulin resistance, indicat-
ing that the biological mechanism underlying the association
between obesity and insulin resistance must be well-
controlled under certain circumstances [164]. Obesity has
become an epidemic and represents the major risk factor
for several chronic diseases, including diabetes, CVD, and
cancer [165]. Therefore, the present study focused on the
detrimental impact of oxidative stress on diabetes, CVD,
and cancer outcomes.
4.2. Diabetes. Type 2 diabetes is the most common metabolic
disorder, aecting 422 million people worldwide in 2014
[166], with nearly half of all deaths attributable to high blood
glucose [166]. Type 2 diabetes is currently the most common
form of the disease, representing nearly 9095% of diabetes
mellitus cases. Diabetes mellitus is a complex and progressive
disease that is accompanied by several complications such as
nephropathy, retinopathy, neuropathy, and micro- and
macrovascular damage [167].
Oxidative stress has been identied as a major risk factor
in the development of diabetes [168]. Numerous risk factors
including increased age, unhealthy dietary intake, and obe-
sity all lead to an oxidative environment that may modify
insulin sensitivity either via the elevation of insulin resistance
or the impairment of glucose tolerance [169]. The mecha-
nisms that implicate these diseases are complex and involve
several cell signaling pathways [170]. Hyperglycemia is
linked to diabetes and subsequently contributes to its
progression and an overall oxidative environment [171].
Macro- and microvascular complications contribute to the
morbidity and mortality of diabetic patients, and all these
factors are associated with oxidative stress [172].
The derangement of molecular and cellular processes is
common in type 2 diabetes, particularly in βcells. Pathophy-
siologically, ROS and RNS, such as H
2
O
2
, superoxide anion
(O
2
), NO, peroxynitrite (ONOO), and hydroxyl radical
(OH
), all contribute to primary physiologic and metabolic
processes. Mitochondrial function impairment leads to a
reduction in ATP generation capacity, which in turn leads
to βcell glucose-stimulated insulin secretion (GSIS), the
6 Oxidative Medicine and Cellular Longevity
NADPH complex, and Ca
2+
signaling related to neurotrans-
mission [173, 174].
Insulin resistance plays a predominant role in the devel-
opment and progression of metabolic dysfunction associated
with obesity. Insulin resistance refers to the impairment of
the cellular response in insulin-sensitive tissues such as skel-
etal muscle, adipose, liver, and brain tissues [175177]. Sub-
sequently, this may lead to a reduction of glucose uptake,
accompanied by the elevation of hepatic glucose output,
and thereby contribute to plasma glucose concentrations
[178]. The subsequent changes of glucose homeostasis may
place a burden on pancreatic βcells to secrete and produce
more insulin to restore normal blood carbohydrate levels
[179]. Nonetheless, this compensatory mechanism may ame-
liorate glucose levels in an early or prediabetes condition,
characterized by continuous insulin resistance and high
exposure of βcells to blood glucose and lipids [180]. This
may boost βcell failure and dysfunction and culminate in
overt diabetes [176].
Pancreatic islets are highly vascularized and specialized
structures that control the nutrient contents in the blood-
stream and are mainly comprised of ve cell types: αcells,
βcells, δcells, ghrelin cells (γcells), and pancreatic peptide-
(PP-) secreting cells [181]. Islets generate blood from the
splenic branches and pancreaticoduodenal arteries and inter-
act to increase dietary nutrients to secrete insulin from αand
βcells into glucagon and the bloodstream, respectively (dur-
ing nutrient-deprived conditions such as starvation and fast-
ing) [175]. The pancreatic βcell response to glucose depends
on the acute regulation of intracellular or extracellular ROS
and RNS [173, 174]. The elevation of glycolytic ux promotes
ATP production and oxidative phosphorylation, which sub-
sequently results in the formation of O
2
released from the
electron transport chain [182]. Additionally, an initial adap-
tive response is modulated through the pentose phosphate
pathway in which surfeit glucose is converted to pentose
and glucose carbon is deviated away from excessive oxidative
and glycolysis phosphorylation. However, shuttling glucose
in this direction may also increase NADPH oxidase (NOX)
activity and subsequently lead to increased O
2
synthesis.
Indeed, high glucose levels may increase ROS through other
possible mechanisms, such as the generation of advanced gly-
cation end products (AGEs) and glucose autoxidation [183].
Once insulin is released into the blood circulation by β
cells in response to increased blood glucose levels, insulin
exhibits its anabolic eects through the transmembrane insu-
lin receptor (IR) in target tissues. Interaction with insulin fos-
ters the autophosphorylation of the receptor with the
phosphorylation and recruitment of insulin receptor sub-
strate (IRS) proteins and the stimulation of other related
downstream signaling cascades, such as protein kinase B
(Akt) and phosphatidylinositol-3-kinase (PI3K) [184]. Akt
has been identied as a primary regulator in vesicle translo-
cation of glucose transporter type 4 (GLUT-4) to the plasma
membrane, which is crucial in the intracellular uptake of free
glucose in insulin-sensitive tissues [48].
Numerous studies have indicated that there is an associ-
ation between increased nitrosylation and carbonylation of
proteins in obese- or insulin-resistant phenotypes and
insulin-sensitive tissues [110, 185187]. This suggests that
an insulin-resistant phenotype may promote the reduction
of insulin receptor expression. Thus, prolonged hyperinsuli-
naemia and chronic hyperglycemia, along with increased
ROS and RNS levels, are hypothesized to inuence insulin
receptor gene expression through the derangement of key
transcription factors such as high mobility group AT-hook
1 (HMGA-1) [188]; they may also increase insulin recep-
tor-desensitization, which under normal circumstances is a
process under the negative-feedback control [189, 190].
Taken together, the development and progression of dia-
betes mellitus is associated with βcell dysfunction and insu-
lin resistance, and this phenomenon is normally related to
obesity [175].
4.3. Cardiovascular Disease. Oxidative stress is implicated in
the progression and development of cardiovascular disease
(CVD) [191]. Its burden is attributable to lifestyle factors,
particularly smoking, alcohol consumption, sedentary life-
styles, and dietary intake [192]. In Malaysia, western dietary
habits that are high in fat and low in dietary ber lead to
the increase in CVD incidence [193]. Chronic and low-
grade inammation has been suggested as a major patho-
physiology in obesity and its associated diseases such as
CVD [194]. C-reactive protein (CRP) has been shown to be
an independent risk factor for the development of CVD
[195, 196]. The elevation of CRP in obesity could be attrib-
uted to macrophage inltration into the expanded adipose
tissue and subsequently leads to the production and release
of macrophage-derived proinammatory cytokines such as
IL-6 and TNF-α[197, 198].
One common feature of CVD is increased oxidative
stress in the heart [199]. Specically, systemic oxidative dam-
age in patients with CVD was due to ROS accumulation and
reduced antioxidant defense [200]. A HFD increased ROS
accumulation and reduced antioxidant capacity, thus causing
a variety of disorders including endothelial dysfunction,
which is characterized by a decreased bioavailability of vaso-
dilators, namely, NO, and promotes endothelium-derived
contractile factors causing atherosclerotic disease [201].
One potential biological mechanism linking cardiac oxidative
stress has been described by Ilkun and Boudina [201] and
includes mitochondrial dysfunction, increased fatty acid oxi-
dation, and increased NADPH oxidase activity. Ilkun and
Boudina [201] demonstrated that the modes of action under-
lying cardiac pathology are complex and might include
altered calcium homeostasis, lipid accumulation, abnormal
autophagy, increased brosis and stiness, increased oxida-
tive stress, and mitochondrial dysfunction. Collectively,
mitochondrial and extramitochondrial sources of ROS and
a reduction of antioxidant defense mechanisms have
occurred in the myocardium of human and animals [201].
4.4. Cancer. Research has demonstrated that high oxidative
stress leads to cancer, including colorectal cancer [202]. Oxi-
dative stress is hypothesized to be associated with obesity and
cancer. A study in an animal obese model of nonalcoholic
steatohepatitis supports these hypotheses, suggesting that
the absence of adiponectin promotes hepatic tumor
7Oxidative Medicine and Cellular Longevity
formation and elevates oxidative stress [203]. Indeed, ROS
plays a crucial role in cancer development [204, 205]. The
elevation of ROS leads to increased mutation rates or suscep-
tibility to mutagenic agents and thus contributes to DNA
damage during the early stages of carcinogenesis [205]. The
elevation of ROS has also been demonstrated in tumor prolif-
eration via the ligand-independent transactivation of recep-
tor tyrosinekinase [204], which can promote metastasis and
the invasion of cancer cells [206]. Semenza [207] observed
that ROS can promote the stabilization of hypoxia-
inducible factor 1, a transcription factor of vascular endothe-
lial growth factor, which facilitates tumor angiogenesis.
Intriguingly, data from a previous study have shown that
insulin is a proliferation factor for prostate cancer; thus, the
reduction of carbohydrates may subsequently decrease
serum insulin and slow down prostate cancer proliferation
[208]. Epidemiological studies have shown that patients with
type 2 diabetes and obesity have a greater likelihood of hav-
ing liver, colorectal, breast, and pancreatic cancers [209,
210]. These ndings suggest that leptin [203, 211], insulin/
insulin-like growth factor-1 [212, 213], adiponectin [203,
211], and inammation [214, 215] are additive between type
2 diabetes or obesity and cancers. Fat accumulation is often
linked with systemic oxidative stress via elevation of ROS
[114]. A previous study stated that increased oxidative stress
can lead to chronic inammation, which in turn could mod-
ulate chronic diseases such as cancer [216]. Oxidative stress
can trigger a wide range of transcription factors such as
Wnt/β-catenin, NF-κB, and nuclear factor E2-related factor
2(Nrf2) and thereby activates inammatory pathways
[216]. Taken together, these ndings suggest that increased
circulating or local ROS levels derived from the expansion
of the adipose tissue in a tumor environment provoke
oxidative stress within tumor cells and thereby lead to an
increased risk for cancer progression in patients with type
2 diabetes or obesity.
5. Diet Ameliorates Oxidative
Stress-Induced Diseases
Oxidative stress is increased in diabetic patients and cancer
cells [217, 218]. Higher intracellular glucose concentrations
can generate ROS via several pathways [219], and the pro-
gression and development of these diseases could be pre-
vented by changing dietary habits [220]. It was evident that
high-glucose and an animal-based protein diet and excessive
fat consumption can promote oxidative stress [221], for
example, excessive omega-6 stimulates inammation [222];
however, there are other dietary choices (the Mediterranean
and Okinawan diets of the Greek and Japanese populations)
that can reduce inammation [223]. Figure 1 summarizes the
dietary intake pattern in relation to human health.
5.1. Whole Grains. Numerous components of the diet may
promote inammation. Whole grains comprised of germ,
endosperm, and bran are rich in vitamins, bers, minerals,
and phytochemicals such as carotenoids, lignans, vitamin E,
inulin, β-glucan, sterols, and resistant starch [224]. As an
example, the ber found in whole grain foods appears to play
a role in immune-modulating functions [225, 226]. Fiber
aects microbiota in the gut [227], which aects immune
function [228]. In support of this, the intake of whole grains
such as sorghum benets the gut microbiota and indices
associated with oxidative stress, obesity, inammation,
hypertension, and cancer [229]. Whole grain foods are rich
in phytochemicals and provide protection against oxidative
stress, which can result in inammation. Polyphenol com-
pounds present in wheat sprouts may benet a certain group
of the population because they appear to combat oxidative
stress associated with obesity [230] and enhance glucose
metabolism [231].
Data from a meta-analysis have demonstrated that a high
intake of whole grain products is associated with a reduction
of total cancer risk [232]. In a Scandinavian HELGA cohort
study, intakes of whole grains were found to be inversely
associated with colorectal cancer incidence [233]. A study
by Tan et al. [202] and Tan et al. [234] further supported
the role of a unique complex of bioactive constituents in
brewersrice, which is a rice by-product in the rice industry
that exerts signicant nutritional value to combat colon car-
cinogenesis. Anti-inammatory eects of brewersrice pro-
tect against oxidative stress and free radical damage by
improved antioxidant enzymes such as MDA, SOD, and
NO. They also inhibit DNA damage caused by ROS via the
upregulation of the Nrf2 signaling pathway. Several studies
have also reached a similar nding, in which rice by-
products have an antiproliferative activity against cancer
[235, 236]. Strikingly, feeding with brewersrice not only
reduced the number of aberrant crypt foci (ACF) [237]; in
fact, the relative proportions of natural antioxidant com-
pounds in brewersrice have also been reported to attenuate
liver and kidney damage in azoxymethane-induced oxidative
stress in rats, as reported by Tan et al. [238], suggesting that
bioactive constituents present in whole grains may amelio-
rate oxidative stress.
In addition to the eects observed on cancer, germinated
brown rice has been extensively studied in the past few
decades. Germinated brown rice has a signicant nutritional
value. In addition to containing high amounts of minerals,
vitamins, and ber, germinated brown rice is also rich in a
variety of bioactive compounds and has drawn a great deal
of interest in the prevention of CVD risk. These bioactive
compounds were demonstrated to have antioxidant activities
that are suggested to alleviate CVD risk via the modula-
tion of hepatic cholesterol metabolism and oxidative stress
[239, 240]. Accordingly, germinated brown rice modulates
lipid metabolism via the transcriptional regulation of per-
oxisome proliferator-activated receptor gamma (PPARγ),
hepatic lipoprotein lipase (LPL), ATP-binding cassette,
subfamily A (ABCA), v-akt murine thymoma viral onco-
gene homologue 1 and homologue 3 (AKT1 and AKT3),
and adiponectin [239]. In this regard, natural components
present in whole grain such as polyphenolic compounds
have the potential to suppress proinammatory immune
signaling and subsequently improve lipid metabolism and
inhibit cancer development [241].
Notably, the nutritional values of ber components such
as arabinoxylans and β-glucans are also found in whole
8 Oxidative Medicine and Cellular Longevity
grains. Studies have revealed a positive association between
wheat and rye arabinoxylans and water-soluble maize on
caecal fermentation, the reduction of serum cholesterol, and
the production of short-chain fatty acids [242, 243]. Dietary
bers present in whole grain also play a central role to
enhance immune function through the production of short-
chain fatty acids, suggesting that increasing the intake of
fermentable dietary ber may be vitally important in reduc-
ing inammation [244, 245]. Short-chain fatty acids may
promote T helper cells, neutrophils, macrophages, and
cytotoxic activity in natural killer cells [246]. Further, the
fermentation of dietary ber in the colon and changes in
gut microbiota are associated with impaired gastrointestinal
tolerance [247]. Together with the gut immune system,
mucosal and colonic microora prevent pathogenic bacteria
from invading the gastrointestinal tract [248]. The intestinal
ora salvages energy via the fermentation of undigested
carbohydrates in the upper gut [246]. The predominant sub-
strates are dietary carbohydrates and mucus, which escape
digestion in the upper gastrointestinal tract [246]. These
include nonstarch polysaccharides (such as hemicelluloses,
celluloses, gums, and pectins), resistant starch, sugar alco-
hols, and nondigestible oligosaccharides [246]. The primary
fermentation pathway produces pyruvate from hexoses in
undigested carbohydrates [246]. Colonic bacteria use a wide
range of carbohydrates to hydrolyze enzymes and produce
methane, hydrogen, short-chain fatty acids (primarily buty-
rate, propionate, and acetate), carbon dioxide, and lactate
[249]. In this regard, these components activate fermenta-
tion, increase bacterial and fecal mass, and ultimately lead
to a stool bulking eect [246]. Overall, this suggests that the
protective eect of whole grains on oxidative stress may be
Cancer Diabetes
Cardiovascular
disease
Obesity
(i) Inammation
(ii) Insulin sensitivity
(iii) -amylase and -glucosidase
activity
Fruits and
vegetables
(i) Vitamins C
and E
(ii) -carotene
(iii) Flavonoids
(iv) Lipolysis genes
(v) Lipogenesis genes
(vi) Oncogene
(vii) Cancer cell proliferation
Fish
(i) n-3 PUFA
(ii) Protein
(iii) Bioactive
peptides
Legumes
(i) Protein
(ii) Amylose
starch
(iii) Phyto
chemicals
Whole
grains
(i) Fiber
Nuts
(i) Fiber
(ii) n-3 PUFA
Healthy
High protein
(i) Red meat
High carbohydrate
Glucose
Fructose
(i)
(ii)
High fat
(i) Saturated fat
(i)
(ii)
(iii)
(iv)
(v)
(vi)
Inammation
Insulin sensitivity
Cancer cell proliferation
Lipogenesis genes
Oncogene
Healthy cell apoptosis
Oxidative
stress
Oxidative
stress
Oxidative stress
Oxidative stress
Figure 1: Dietary intake patterns aect human health state. High-carbohydrate and an animal-based protein diet and excessive fat
consumption will eventually lead to obesity as well as other obesity-related diseases such as cardiovascular diseases (CVD), diabetes,
and cancer. The key pathway involved in the pathogenesis is via the elevation of oxidative stress. Subsequently, inammation occurs
resulting in the reduction of insulin sensitivity, increased cancer cell proliferation, involvement of gene in lipogenesis, and cancer
development of which is activated and accompanied by apoptosis of healthy cells. To revert these unhealthy conditions,
consumption of healthy diet is essential. Healthy diet includes whole grains, nuts, fruits and vegetables, sh, and legumes. In
general, a healthy diet contains dietary ber, unsaturated fatty acids like monounsaturated fatty acid (MUFA) and n-3
polyunsaturated fatty acid (n-3 PUFA), protein, vitamins, minerals, and others health-promoting components. All these components
exhibit antioxidant ability thereby reduce oxidative stress. The healthy diet could reduce inammation, cancer development, and
lipogenesis transcriptional expression. It also increases insulin sensitivity accompanied by the reduction of α-amylase and α-
glucosidase activity. A healthy dietary pattern is crucial for maintaining good health.
9Oxidative Medicine and Cellular Longevity
mediated partly via the synergistic/additive eects of these
bioactive components.
5.2. Nuts. When a landmark epidemiological study found
that a high frequency of nut consumption was related to a
reduction of CVD [250], nuts were brought from obscurity
to prominence as a crucial health food. In the last 15 years
since this rst epidemiological study, scientic research on
the health eects of nuts has not only focused on the area
of coronary heart disease and its risk factors but has also
extended to other areas of health. In addition, clinical trials
have found that diets enriched with nuts reduce oxidative
stress and inammation [251] and alleviate endothelial
dysfunction or insulin resistance [252]. Another clinical
study consistently reported a hypocholesterolemic potential
of regular nut consumption, which partly explains how
walnuts reduce the risk of CVD [253].
Nuts are not only a high-fat and energy-dense food but
they are also rich in bioactive constituents [254] that are
believed to have anti-inammatory and anticarcinogenic
properties including folic acids and several phytochemicals
[255, 256]. Notably, collective ndings suggest that a protec-
tive role of nuts on colorectal and endometrial cancer
prevention is possible [257259].
A crucial underlying mechanism of action that has been
proposed to explain an inverse relationship between the fre-
quency of nut-enriched consumption and risk of obesity is
unsaturated fatty acids. Healthy fats (unsaturated fatty acids)
in nuts contribute to the prevention of diabetes and CVD
risk. By contrast, nuts are complex food matrices that are also
a source of other bioactive constituents, namely, tocopherols
and phenolic compounds [260]. Compelling evidence
suggests that monounsaturated fatty acids (MUFAs) and
polyunsaturated fatty acids (PUFAs) are more readily oxi-
dized [261] and have a greater thermogenic eect [262]
than do saturated fatty acids, which might contribute to
less fat accumulation. Due to their unique fat and nonfat
composition, nuts are more likely to mediate inammation
and oxidative stress.
Because nuts contain the abundance of unsaturated fatty
acids, protein, and ber, they are a highly satiating food
[263]. Thereby, after consuming nuts, hunger is reduced
and subsequent food intake is curtailed [264]. The physical
structure of nuts may also lead to their satiety eect because
they must be masticated, small enough for swallowing.
Mastication stimulates nutrient, mechanical, and sensory sig-
naling systems that may alter appetitive sensations [265].
Additionally, a small degree of fat absorption may occur after
nut consumption because fat is found within the wall cellular
structures that are not fully digested in the gut [266], which
could be compounded by incomplete mastication [267]. Data
from population-based studies indicate an inverse relation-
ship between nut intake, such as almonds and CRP [268,
269]. Plasma IL-6 levels were reduced after a Mediterranean
diet with nuts compared to a control diet [270, 271].
Similarly, previous studies reported by Zhao et al. [272] and
Zhao et al. [273] also evaluated walnuts rich in PUFAs and,
in particular, alpha-linolenic acid (ALA), in relation to proin-
ammatory cytokine production [273] and inammatory
markers [272] by blood mononuclear cells. The data showed
that compared to the average American diet, the CRP levels
were reduced by 75% in subjects consuming an ALA diet;
conversely, levels in subjects consuming the linoleic acid
(LA) diet decreased by 45% [272]. Indeed, reductions in mul-
tiple inammatory markers such as IL-6, IL-1β, and TNF-α
produced by cultured mononuclear cells were observed from
subjects who consumed an ALA-enriched diet [273].
Based on the ndings for marine-derived omega-3
PUFA, ALA would be expected to have anti-inammatory
properties. This was evaluated in a clinical study with a
relatively small observed eect [274]. However, an in vitro
study in which THP-1 cells were supplemented with LA,
ALA, docosahexaenoic acid (DHA), and palmitic acid in
the presence of lipopolysaccharide [275] showed a signicant
reduction in TNF-α, IL-1β, and IL-6 after treatment with
DHA, ALA, and LA compared to palmitic acid, indicating
that ALA present in walnuts elicits an anti-inammatory
response. Notably, cellular adhesion molecules are biochem-
ical markers of endothelial dysfunction concomitantly with
inammation. In a further study focused on CVD outcomes,
Zhao et al. [273] compared hypercholesterolemic subjects
who consumed a diet high in ALA, a diet high in LA, and
an American diet, respectively. The data showed that partici-
pants who consumed 15 g of walnut oil along with 37 g of
walnuts/daily for 6 weeks demonstrated a reduction in CRP,
cellular adhesion molecule soluble intercellular adhesion
molecule (sICAM) 1, and E-selectin. Importantly, some
research has emerged to suggest that CVD risk factors nega-
tively aect endothelial function and are involved in the mod-
ulation of LDL cholesterol [276, 277]. In support of this, the
acute consumption of walnuts oils is favorably aected and
shows a better endothelial function [278]. Further, walnuts
and walnut oil may inuence inammation, at least in part,
via the elevation of cholesterol eux, which is a reverse choles-
terol transport that is crucial for the removal of cholesterol
from peripheral tissues and indicates cardioprotective eects
[253]. Taken together, nuts seem a good dietary choice for
providing nutrients and preventing obesity and other chronic
diseases. However, the bioactive components responsible for
the eects that we stated above require further elucidation.
5.3. Fruits and Vegetables. Fruits and vegetables are rich in
minerals, vitamins, and dietary ber. High intakes of fruits
and vegetables are inversely associated with mortality and
the incidence of obesity-related diseases such as CVD, type
2 diabetes, and cancer [279]. Such protection has been accre-
dited to antioxidant vitamins such as β-carotene, vitamin E,
and vitamin C [280]. In general, more than 85% of the total
antioxidants in fruits and vegetables are hydrophilic antioxi-
dants [281]. Beta-carotene and vitamins E and C are vitally
important for the proper regulation of physiological function
[282]. The essential role of vitamin E in maintaining the
oxidative-antioxidant balance is well-recognized, yet vitamin
C can enhance the antioxidant protection [282]. Beta-
carotene is usually found in bright-colored fruits and vegeta-
bles [283]. It has been demonstrated to maintain the immune
system and exert an ability to decrease LDL-cholesterol
oxidation through the modulation of antioxidant enzymes
10 Oxidative Medicine and Cellular Longevity
[283]. In addition to the vitamin antioxidants stated above,
other dietary components such as avonoids may protect
against oxidative stress. Flavonoids are plant polyphenolic
compounds ubiquitous in fruits and vegetables. Flavonoids
exert multiple biological activities such as antitumor eects,
anti-inammatory activity, antioxidant activity, and antimi-
crobial action, and they suppress platelet aggregation [284].
An animal study has demonstrated that a diet supple-
mented with β-carotene from fruit signicantly downregu-
lated the expression of fatty acid synthase, acetyl-CoA
carboxylase, and fat synthesis-related genes [285]. Findings
from a population-based study mirror some of those from
preclinical data obtained from an in vivo study. Data from a
population-based study reported that high intakes of fruits
and vegetables signicantly decreased energy consumption,
waist circumference, body weight, and sagittal abdominal
diameter in overweight and obese men and women [286].
Compelling epidemiological studies have revealed that
intakes of fruits and vegetables induce protective cardiomet-
abolic eects. A study showed that encapsulated fruit and
vegetable-concentrated juice decreased total cholesterol,
LDL-cholesterol, plasma TNF-α, and systolic blood pressure,
in addition to increasing total lean mass [287]. The improve-
ments in these indices could be attributed to the alteration of
gene expression via several signaling pathways such as AMP-
activated protein kinase (AMPK) and NF-κB associated
genes [287]. Body composition, blood lipids, and systemic
inammation were improved in obese subjects after consum-
ing fruits and vegetables and thus provide a useful approach
for reducing the obesity-induced chronic diseases risk [288].
Further, fruits and vegetables can also prevent CVDs or assist
with the restoration of function and morphology of vessels
and the heart after injury. Fruits and vegetables are thought
to protect against CVD by regulating lipid metabolism,
protecting vascular endothelial function, suppressing platelet
function, modulating blood pressure, inhibiting thrombosis,
attenuating inammation, alleviating ischemia/reperfusion
injury, and reducing oxidative stress [289, 290].
In addition to the eects observed in obesity and CVD, a
benecial eect of fruit and vegetable consumption in human
has also been reported on the incidence of type 2 diabetes.
Data from a meta-analysis included a study from 1966 to
2014 that demonstrated that a high intake of fruit, particu-
larly berries, and yellow, cruciferous, green leafy vegetables
or their bers, is negatively linked to type 2 diabetes [291].
As an example, lactucaxanthin (Lxn), a carotenoid in lettuce
(Lactuca sativa), suppresses α-amylase and α-glucosidase
activity both in vitro and in diabetic rats [292]. Such ndings
highlight the role of unique complexes of bioactive compo-
nents in fruits and vegetables.
Fruits and vegetables not only reduce obesity, CVD, and
diabetes but they also inhibit several cancers, demonstrating
the numerous functional potentials of fruits and vegetables.
Epidemiological studies have shown an inverse relationship
between fruit and vegetable intakes and cancer risks such as
colon, breast, and prostate cancers. This suppressive eect
was mainly observed in cruciferous and green-yellow vegeta-
bles [293] via the modulation of genes involved in prolifera-
tion and glucose metabolism and the induction of several
antioxidant genes [294]. Notably, dietary ber in fruits and
vegetables will undergo fermentation by gut microbiota,
which may lead to the production of short-chain fatty acids.
Short-chain fatty acids such as acetate [295], butyrate [296],
and propionic acids [297] may have protective eects against
cancers. It is possible that only certain types of fruits and
vegetables confer protection against oxidative stress [283].
Since some bioactive compounds regulate the same gene
expression and pathways targeted by drugs, diets high in
fruits and vegetables in combination with medical therapies
are being considered as a novel treatment strategy [298].
Overall, bioactive constituents in fruits and vegetables might
be promising tools for the alleviation of a wide range of
diseases [299].
5.4. Fish. Fish is an essential source of dietary protein, omega-
3 fatty acids, and minerals. Nakamura et al. [300] demon-
strated that individuals who consume sh daily were
inversely associated with obesity compared to those with
normal weight or underweight. The intake of sh has been
linked to a reduced risk of obesity [301], yet the composition
of sh often includes representative PUFA amounts, such as
n-3 fatty acids, whose chemical structure makes them prone
to peroxidation and are found abundantly in fatty sh.
Therefore, our body becomes more susceptible to oxidative
stress and subsequently activates the lipid peroxidation
process [302]. Undoubtedly, PUFA intake is essential as they
have well-established health benets especially in preventing
heart disease [303]. However, it is recommended to have an
adequate vitamin E to match the increased of PUFA intake
[304]. This is because lipophilic antioxidant vitamin E plays
a vital role in protecting PUFA [305]. In addition, an animal
study has shown that the vitamin E requirement is increased
almost proportionally with the degree of unsaturation of the
PUFA [304].
The consumption of lean sh has a benecial impact on
insulin sensitivity, glucose homeostasis, and lipid metabolism
[306, 307]. Aadland et al. [306] further demonstrated that
intakes of lean sh for 4 weeks reduced the ratio of total to
HDL cholesterol in serum, decreased the VLDL concentra-
tion, and reduced fasting and postprandial triacylglycerol
(TAG) compared to those with a nonseafood diet, suggesting
the cardioprotective potential of lean-seafood intake. A sim-
ilar dietary intake was also found to reduce the urinary excre-
tion of metabolites involved in mitochondrial lipid and
energy metabolism, possibly facilitating a higher lipid catab-
olism [308]. Intriguingly, lean sh contains relatively low
amounts of marine n-3 fatty acids, and thereby the benecial
eects of sh are not solely ascribed to the lipid composition.
Dietary protein has been suggested as the most eective
food macronutrient to provide a satiating eect. Therefore,
protein-rich foods can facilitate in the modulation of food
intake, promoting body weight loss and maintaining body
weight thereafter. Glucagon-like peptide-1 (GLP-1) release
stimulated by a high-protein meal is evoked by carbohydrate
content. Indeed, cholecystokinin (CCK) and peptide YY
(PYY) release is activated by a high-protein meal [309].
Fish not only contains macronutrients but also has a sub-
stantial antioxidant source due to its composition and oers a
11Oxidative Medicine and Cellular Longevity
relatively low level of saturated fat compared to other food
items. Taurine, an amino acid that is abundantly found in
sh, is a vital antioxidant source. Studies have shown that
taurine can eectively combat metabolic syndrome by regu-
lating glucose metabolism, reducing triglycerides to prevent
obesity, regulating the renin-angiotensin-aldosterone and
kallikrein-kinin systems to decrease blood pressure, and low-
ering cholesterol (particularly reducing VLDL + LDL choles-
terol and promoting HDL cholesterol) to prevent diet-
induced hypercholesterolemia [310].
Notably, the production of sh protein peptides (hydro-
lysates) maximizes the usage of sh protein because peptides
have a health-promoting potential [311]. Techniques such as
autolysis, thermal hydrolysis, and enzymatic hydrolysis have
been developed to produce sh hydrolysates. The antiviral-,
cardioprotective- (antihypertensive, antiatherosclerotic, and
anticoagulant), analgesic-, antimicrobial-, antioxidative-,
antitumor-, immunomodulatory-, neuroprotective, and
appetite-suppressing activities have drawn attention from
the pharmaceutical industry, which attempts to design the
treatment and prevention of certain diseases [312]. Lassoued
et al. [313] and Razali et al. [314] reported that peptides
derived from sh proteins exhibit signicant antioxidative
activity in oxidative systems. The dietary intake of antioxi-
dant compounds can strengthen the bodys oxidant status
and facilitate a balanced condition in terms of oxidants/anti-
oxidants in the body.
In addition to sh and its protein peptides, neovastat
(AE-941), a liquid extract derived from the cartilage of
sharks, exerts antiangiogenic, anti-inammatory, and antitu-
mor properties both in vitro and in vivo [315]. These favor-
able eects are mediated via the suppression of matrix
metalloproteinases (MMP)-2, MMP-9, and MMP-12 and
the activation of tissue plasminogen activator enzymatic
activities [315].
Another metabolic disorder is hypertension, which
occurs when renin produces angiotensin I from angiotensino-
gen. The angiotensin I-converting enzyme (ACE) cleaves
angiotensin I to angiotensin II, which is a potent vasocon-
strictor [316]. Accordingly, Balti et al. [317] have sourced
bioactive constituents from dierent types of sh in ACE-
inhibitor activity studies with molecular weights of
<10 kDa. From a review study, Balti et al. [317] found that
bioactive peptides are suitable competitive inhibitors that
can bind to the active site of ACE and thereby block its activ-
ity. Collectively, it remains unknown whether PUFA content
or its antioxidant is responsible for its benecial eects; thus,
further study is necessary to conclusively resolve the question
behind the anti-inammatory eects of sh.
5.5. Legumes. Legumes are a primary component of the
Mediterranean diet. They are rich in ber and protein, which
can facilitate in lowering energy density and reducing the gly-
cemic response [318]. Legumes also contain B vitamins and
minerals, such as potassium, calcium, and iron. Most of the
nutritional value in legumes is contributed by their relative
proportions of protein, bers [319], and phytochemicals such
as isoavones, phytoestrogens, saponins, oligosaccharides,
lectins, and phenolic compounds [320]. Due to their high
nutritional values, legume intake has been demonstrated to
have benecial eects in the prevention of obesity and other
related disorders [321].
Compared to those who rarely or never consume
legumes, adults who consume legumes have a signicantly
lower body mass index and waist circumference. Children
who consume legumes had smaller waist circumferences
compared to those who never consume legumes [322]. Shi-
nohara et al. [323] further demonstrated that ethanol extracts
of chickpeas improved total lipid indices and gene expression
associated with fatty acid metabolism in adipocytes. Studies
have shown that enzymes involved in lipogenesis such as
AMPK, acetyl-CoA carboxylase (ACC), and liver kinase B1
(LKB1) were inactivated by phosphorylation. Further, lipoly-
sis was increased by the extract through the stimulation of
palmitoyltransferase 1 (CPT1) and uncoupling protein 2
(UCP2), which has been reported as a crucial protein in fatty
acid oxidation [323].
Starch digestibility and composition inuence glycemic
response. Legumes are high in amylose starch. Nonetheless,
the digestion of high amylose starch is signicantly lower
compared to that of high amylopectin starch [324]. Yang
et al. [325] reported a more sustainable plasma glucose level
after a high-amylose meal compared to a high-amylopectin
meal [325]. Furthermore, legumes have a high protein
content; thus, the interaction of protein-starch may further
hamper digestibility [326]. Moreover, high amounts of
dietary ber markedly reduced the extent and rate of legume
starch digestibility. A high intake of ber may promote
satiety, enhance insulin resistance, and decrease the glycemic
response [327]. Evidence from epidemiological studies shows
that legume intake is negatively associated with fasting
glucose levels [328].
Notably, data from large-scale epidemiological studies
found that legume consumption is negatively associated with
CVD mortality. Compared to the highest and lowest legume
consumption, high legume consumption showed a 6%
decreased risk of CVD [329]. Isoavones are believed to have
hypolipidemic activity by binding with estrogen receptors
when circulating estrogen is low and thereby translocating
to the nucleus, which interacts with a DNA sequence near
the promoter region of target genes and results in DNA
transcription [330]. Through this mechanism, isoavone
may act as a ligand for lipid-regulating proteins including
PPAR, farnesoid X receptor, and liver X receptor, which
facilitates cholesterol reabsorption, bile acid synthesis, and
hepatic lipid synthesis [331].
In addition to the eects mentioned above, legumes have
the potential to protect against cancers. For example, soy
food protects against estrogen receptor-negative breast
cancer [332]. A study reported by Guo et al. [332] demon-
strated that in women with high soy intakes, tumor suppres-
sor genes were upregulated (miR-29a-3p and IGF1R), and
oncogenes were downregulated (KRAS and FGFR4). Consis-
tent with the study reported by Guo et al. [332], green
pea- (Pisum sativum) extracted lectin has also been reported
to have antiproliferative activity against liver cancer cell lines
[333]. Despite the limited available evidence to draw a rm
conclusion, some studies suggest that legumes may be
12 Oxidative Medicine and Cellular Longevity
potentially benecial to some population segments. Collec-
tively, future studies may elucidate the role of legumes in
human health, yet their use within a balanced diet should
be considered in the absence of clear contraindications.
6. Summary and Future Prospects
This review has provided clear evidence of the identica-
tion of known sources of nutritionally mediated oxidative
stress as a mediating pathway for both risks of obesity
and other obesity-associated diseases. Oxidative stress is a
central player of metabolic ailments associated with high-
carbohydrate and animal-based protein diets and excessive
fat consumption. There is inconsistent research supporting
the clinical use of antioxidant agents in preventing or delay-
ing the onset and progression of metabolic disorders such as
diabetic complications and cancer [334337], and most clin-
ical studies are limited in their sample size and duration of
the study. Despite this, preclinical studies in vitro and animal
experiments have provided in-depth insight into the modula-
tion of these diseases. Several anti-inammatory dietary
sources such as whole grains, nuts, fruits and vegetables,
and others can delay the onset of insulin resistance, prevent
adipocyte and endothelial dysfunctions, and prevent tumor
proliferation by reacting with oxidizing free radicals and
inhibiting the inammatory response. Therefore, more
randomized clinical trials are warranted to evaluate the over-
all long-term eects of dietary intervention.
7. Conclusions
The available research strongly supports that a diet high in
carbohydrates and animal proteins and excessive fat con-
sumption produces ROS and subsequently leads to oxidative
stress. The best dietary advice for the prevention and
management of obesity and other metabolic disorders
includes replacing rened carbohydrates with whole grains,
increasing fruits and vegetables, substituting total and satu-
rated fat with MUFAs, and consuming a moderate amount
of calories with an ultimate goal of maintaining an ideal body
weight. Overall, further studies are warranted to gain a better
understanding of the types and the degree of ROS generation
in relation to diet-induced metabolic disorders.
Conflicts of Interest
The authors declare that there are no conicts of interests
regarding the publication of this article.
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