animals

Review
Research Progress on Oxidative Stress and Its Nutritional
Regulation Strategies in Pigs
Yue Hao, Mingjie Xing and Xianhong Gu *

State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural
Sciences, Beijing 100193, China; [email protected] (Y.H.); [email protected] (M.X.)
* Correspondence: [email protected]

Simple Summary: In the process of production, especially the modern intensive scale farming where
high quality and high efficiency are pursued, pigs are subjected to a series of adverse stimuli from
birth to slaughter (e.g., immunotherapy, environmental changes, uncomfortable temperature, feed
contamination, improper transportation, slaughter methods, etc.). These adverse stimuli eventually
translate into an imbalance in redox levels in the body, resulting in oxidative stress. The generation of
oxidative stress, in turn, eventually causes damage to the pigs. To eliminate/reduce this harmful effect
and counteract oxidative stress, pigs use part of the energy reserved for growth, which eventually
leads to a decrease in production performance and causes unnecessary economic losses.

Abstract: Oxidative stress refers to the dramatic increase in the production of free radicals in human
and animal bodies or the decrease in the ability to scavenging free radicals, thus breaking the
antioxidation–oxidation balance. Various factors can induce oxidative stress in pig production.
Oxidative stress has an important effect on pig performance and healthy growth, and has become



one of the important factors restricting pig production. Based on the overview of the generation


of oxidative stress, its effects on pigs, and signal transduction pathways, this paper discussed the
Citation: Hao, Y.; Xing, M.; Gu, X.
nutritional measures to alleviate oxidative stress in pigs, in order to provide ideas for the nutritional
Research Progress on Oxidative Stress
research of anti-oxidative stress in pigs.
and Its Nutritional Regulation
Strategies in Pigs. Animals 2021, 11,
Keywords: oxidative stress; pigs; performance; signaling pathways; nutritional additive modulation
1384. https://doi.org/10.3390/
ani11051384

Academic Editor: Peter F. Surai

1. Introduction
Received: 9 March 2021 The concept of oxidative stress was first mentioned by Helmut Sies in 1985 in his
Accepted: 3 May 2021 book titled Oxidative Stress: A disturbance in the prooxidant-antioxidant balance favors
Published: 13 May 2021 the former [1]. The prooxidant system has subsequently been developed for more than
30 years through continuous research and refinement. In a 2018 review, oxidative stress was
Publisher’s Note: MDPI stays neutral defined as a state of imbalance between excessive (free) oxidant radicals and insufficient
with regard to jurisdictional claims in degradation of these radicals by antioxidant systems as an in-house defense mechanism [2].
published maps and institutional affil- Free radicals in living organisms are intermediates of various biochemical reactions. These
iations. are small, unstable, and diffusible small molecules that are highly chemically active due to
the presence of unpaired electrons. Biological systems possess several types of radicals, the
most important of which are reactive oxygen species (ROS) and reactive nitrogen radicals
(RNS) [3].
Copyright: © 2021 by the authors. Redox homeostasis is important for the organism. Under the interaction of oxidants
Licensee MDPI, Basel, Switzerland. and antioxidants, ROS levels in organisms are in dynamic equilibrium, just like pH reg-
This article is an open access article ulation [4]. ROS is present at or below normal physiological concentrations and has a
distributed under the terms and physiological role in the cellular response to hypoxia [5]. According to the current research
conditions of the Creative Commons understanding, ROS play an important role in host defense, cell signaling, and biosynthetic
Attribution (CC BY) license (https://
processes [6]. When cells are stimulated by adverse factors in the internal and external envi-
creativecommons.org/licenses/by/
ronment, excessive ROS are produced, which, when not cleared in time, result in increased
4.0/).

Animals 2021, 11, 1384. https://doi.org/10.3390/ani11051384 https://www.mdpi.com/journal/animals

 understanding, ROS play an important role in host defense, cell signaling, and
Animals 2021, 11, 1384 2 of 21
thetic processes [6]. When cells are stimulated by adverse factors in the internal
ternal environment, excessive ROS are produced, which, when not cleared in tim
in increased concentrations and finally exceed the normal physiological range.
concentrations and finally exceed the normal physiological range. Abnormally high levels
mally high levels of ROS can cause harm to tissues and cells, such as abnormal si
of ROS can cause harm to tissues and cells, such as abnormal signaling pathways, energy
pathways, energy metabolism
metabolism disorders, gene mutations, disorders,
and proteingene mutations,
structure changes and protein
[7] (Figure structure
1), and
[7] (Figure
thus, 1),functions
affect the and thus, affect
of cells, the functions
tissues, organs, andof cells,
even tissues, organs, and even syst
systems.

Figure 1. When the oxidative system in the body is stronger than the antioxidant system, the
Figure 1. When the oxidative system in the body is stronger than the antioxidant system, t
generation of excess ROS cannot be scavenged in time. This disrupts the homeostasis of redox
eration of excess ROS cannot be scavenged in time. This disrupts the homeostasis of redox
balance in the body and causes oxidative stress, ultimately leading to DNA, membrane, protein, and
in the body and causes oxidative stress, ultimately leading to DNA, membrane, protein, an
lipid damage.
damage.
Various factors can induce oxidative stress in pig production. Oxidative stress is often
accompanied
Variousbyfactors
other pathological
can inducefactors, whichstress
oxidative has a in
direct
pignegative impactOxidative
production. on pig stre
performance and healthy growth. Therefore, studying the mechanism of oxidative stress in
ten accompanied by other pathological factors, which has a direct negative impac
animals and human intervention programs are of great significance to animal and human
performance andishealthy
health. This review planned togrowth. Therefore,
summarize studying
the generation the mechanism
of oxidative of oxidativ
stress, its effects
in
on animals and
pigs, signal human intervention
transduction programs
pathways of oxidative are
stress, andofthe
great significance
nutritional measurestotoanimal
man health. This review is planned to summarize the generation offor
alleviate oxidative stress in pigs. The aim is to provide alternative nutritional ideas the
oxidative st
research of anti-oxidative stress in pigs.
effects on pigs, signal transduction pathways of oxidative stress, and the nu
measures to alleviate oxidative stress in pigs. The aim is to provide alternative nu
ideas for the research of anti-oxidative stress in pigs.

2. Oxidative Stress in Pigs

Animals 2021, 11, 1384 3 of 21

2. Oxidative Stress in Pigs

In pig production, many factors can induce the body to produce a large number of free
radicals, which can cause oxidative damage in pigs (especially piglets). Swine intestinal
tract is a major target organ of free radical attack, which leads to intestinal structure
destruction, microbial disturbance, and nutrient absorption obstacles, and ultimately leads
to decreased feed intake and slowed down or negative weight gain of pigs, which has a
serious impact on the economic benefits of pig breeding. At present, domestic and foreign
studies have confirmed that there are five main factors in the pig production process that
induce oxidative stress and affect the healthy growth of pigs. These factors include birth,
weaning stress, mycotoxin pollution in feed, feeding environment, social factors, etc.

2.1. Oxidative Stress at Birth

The main changes during the sow parturition are from the fetal placenta mediated
passive respiration in the hypoxic environment of the sow uterus to the spontaneous
respiration in the hyperxic environment outside the uterus after parturition. At the same
time, the birth process also involves changes in ambient temperature, humidity, lighting,
and noise. The sudden change in these factors may cause the mitochondrial respiratory
system and other physiological metabolic system of newborn piglets to produce large
amounts of oxygen free radicals. However, the antioxidant system of newborn piglets is
very weak, which cannot remove excessive free radicals in time, resulting in an oxidative
stress reaction of newborn piglets [8]. Yin et al. (2013) studied the changes of blood
oxidation indexes and antioxidant indexes of newborn piglets during 21 days after birth [9].
It was found that the level of blood lipid oxidation product malondialdehyde (MDA) was
as high as 900 pmol/mg on birth, but decreased to about 200 pmol/mg on day 7 after
birth. At the same time, protein and nucleic acid oxidation products also showed a peak on
birth and significantly decreased on day 7. Moreover, the activities of antioxidant enzymes
including glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in piglets
were low after birth, but significantly increased after 7 days. These results further confirm
that large amounts of free radicals are produced during the birth process of piglets, and the
weak antioxidant system cannot timely clean up the free radicals induced by birth stress,
thus causing the oxidative stress response of piglets.

2.2. Oxidative Stress during Weaning

Previous study found that weaning stress in piglets was closely related to oxidative
stress. Blood malondialdehyde (MDA) increased significantly on the third day after wean-
ing, and protein hydroxyl, a marker of protein oxidative damage, significantly increased
on the first day after weaning. These results indicate that weaning induces the oxidative
stress response in piglets, the sensitivity of lipid and protein is different in the process
of weaning oxidative damage, and protein is more susceptible to the effects of weaning
oxidative stress [10]. Luo et al. (2016) further confirmed that the content of oxygen free
radical hydrogen peroxide (H2 O2 ) in liver significantly increased after weaning, while the
activities of antioxidant enzymes such as GSH-Px and SOD were significantly inhibited [11].
Weaning oxidative stress is affected by many factors, and its mechanism is a multi-factor
and multi-level complex process. Current studies have confirmed that multiple signaling
mechanisms are involved in weaning oxidative stress response, including nuclear factor
erythroid 2-related factor 2 (Nrf2) and mitogen-activated protein kinase (MAPK). More-
over, autophagy, nuclear factor kappa B (NF-κB) and intestinal microorganisms have been
reported to be involved in weaning stress in piglets. However, its role in weaning-induced
oxidative damage and its mechanism still need to be further studied.

2.3. Oxidative Stress Induced by Mycotoxins

A large number of studies have shown that ingestion of feed contaminated with
mycotoxin can induce systemic or tissue oxidative stress in pigs [12–14]. Treatment of
intestinal epithelial cells with deoxynivalenol (DON) can directly induce the production
Animals 2021, 11, 1384 4 of 21

of oxygen free radicals, and autophagy may be the underlying mechanism. In a previous
study, CRISPR-Cas9 gene editing technology was used to knock out key genes of autophagy,
and the results showed that the lack of autophagy affected the expression of stress-related
genes in cells [15]. Yin et al. (2015) established a H2 O2 -induced acute oxidative stress
model in piglets and further found that oxidative stress could induce autophagy and is
linked to the signaling pathways of the inhibitor of nuclear factor kappa-B kinase (IKK). It
mediates the expression of antioxidant genes (such as SOD and GSH-Px) in the body [16].
Feeding DON-contaminated feed induced oxidative stress in piglets and caused a
disturbance of the nutrient metabolism. However, the addition of functional amino acids
(such as glutamate and arginine) promoted the body’s antioxidant capacity and alleviated
oxidative stress injury [17–19]. Effects of mixed mycotoxins (including aflatoxin B1, DON,
ochratoxin, and fumatoxin) on piglets were studied by natural fermentation and mildewing.
The results showed that the mixed mycotoxin significantly reduced the performance and
blood SOD activity, and addition of arginine significantly increased blood glutathione
(GSH) content [20].

2.4. Oxidative Stress Caused by Environmental and Social Factors

Many environmental and social factors during pig production can also induce ox-
idative stress in pigs, including feeding density, fighting, pig house hygiene, heat and
cold stress, transportation stress, and E. coli infection. In the actual production process,
in order to save the feeding space, the feeding density of pigs is often greater than the
standard of piggery construction. However, high-density breeding often induces a series
of adverse health factors, including lack of space for activities, rising house temperature,
weakened ventilation effect, accumulation of harmful gases, large number of bacteria, food
and water shortage, too much fighting and biting behavior, etc. Studies have shown that
high-density feeding can significantly induce the production of free radicals in pigs at
different stages, thus destroying the antioxidation–oxidation balance and causing oxidative
damage [21]. By comparing markers of blood oxidative damage, it was found that the
blood protein hydroxyl group of high-density pigs was significantly increased, suggesting
that high-density feeding environment could cause an oxidative stress response and oxida-
tive damage of pigs [22]. There is no evidence that high-density feeding directly causes
oxidative stress in pigs. However, high-density feeding induces house temperature rise,
harmful gas accumulation, bacterial infection, and fighting, which can directly cause large
amounts of free radicals in pigs and lead to oxidative stress injury.
Pigs are very sensitive to heat stress, so high temperature is the most common source
of stress during pig production. Short-term heat stress tests (2 days) showed significant
increases in rectal temperature, respiratory metabolic rate, and intestinal permeability in
growing pigs, accompanied by oxidative stress responses [23]. Long-term heat stress tests
(3 weeks) identified 37 liver differential proteins, 10 of which are involved in the oxidative
stress response of pigs [24]. Porcine cell culture tests further confirmed that heat stress
induced oxidative stress in porcine muscle cells, but did not change the inflammatory
signals [25].
In addition, cold stress, transport stress, and infection can induce strong stress response
and affect the metabolism of pigs. However, there are few studies on the effects of these
stressors on the oxidative system of the body. Therefore, further studies on the effects of
these stressors on the production of free radicals and the antioxidant system of the body
are still needed.

3. Model of Oxidative Stress in Pigs

Research on pig oxidative stress models mainly includes the diquat model, hydrogen
peroxide model, lipopolysaccharide model, vomiting toxin model, etc. Different models
have different mechanisms, but they can all induce pigs to produce a large number of
free radicals, thereby destroying the body’s antioxidation–oxidation balance and causing
oxidative stress.
Animals 2021, 11, 1384 5 of 21

At present, the main way to establish oxidative stress in pigs is the diquat model,
by intraperitoneal injection of a certain dose of diquat (8–15 mg/kg). It can not only
decompose superoxide anion free radicals by itself, but also stimulate the generation of free
radicals by acting on the cellular respiratory cycle, causing the disorder of the antioxidation–
oxidation balance in the body environment and inducing the oxidative stress reaction in
animals [26,27]. Xu et al. (2008) evaluated the oxidative stress effect of diquat injection
in growing pigs, and found that diquat injection significantly induced oxidative stress
response in the pig systems 7 days after diquat injection, and the stress effect lasted for
28 days [28]. The study by Cao et al. (2018) showed that diquat-induced oxidative stress
increases intestinal permeability, impairs mitochondrial function, and triggers mitophagy
in piglets. At present, the diquat model has been widely used to study the effects of
nutritional intervention on the oxidative stress response in pigs [29].
Through gastric intubation, Yin et al. (2015) established an acute model of H2 O2
oxidative stress in piglets [16]. Injection of 5–10% H2 O2 significantly induced systemic
oxidative stress in piglets within 2 days, and at the same time, caused intestinal damage by
destroying the intestinal permeability and intestinal villus structure [16]. Although this
model is directly induced by H2 O2 , due to the need to perform surgery on pigs in advance
and the fact that H2 O2 can easily cause gastrointestinal ulcer in pigs, it has great limitations
in application. However, in cell experiments, H2 O2 is the most important and direct
inducer of oxidative stress, which is of great significance for the study of oxidative stress
mechanisms in cell models [30]. It was found that H2 O2 treatment could induce autophagy,
mitochondrial disorders, and apoptosis in piglets or a porcine intestinal epithelial cell
model, and NF-κB and Nrf2 signaling pathways were involved in H2 O2 -induced oxidative
stress [16,31].
The lipopolysaccharide model has been widely used as an inflammatory response
model in piglet studies [32–34], but the inflammatory response is closely related to oxidative
stress. The production of free radicals in the process of inflammatory reaction is also
stimulated, and oxidative stress reaction is also involved in the process of the inflammatory
response [35,36]. Tang et al. (2018) used LPS to establish a cell oxidative injury model in
IPEC-J2 cells [37].
Furthermore, a large number of in vivo and in vitro experiments have found that
DON can induce the generation of free radicals in addition to mycotoxins, so some studies
have also used DON to induce oxidative stress [15,38]. The results of Marin et al. (2018)
indicated that ochratoxin A (OTA) and aristolochic acid (AA) could induce inflammation
and oxidative stress in the liver and kidney of weanling piglets [39].
In addition, Li et al. (2020) established in a chronic oxidative stress pig model induced
by D-galactose [40]. The results demonstrated that administration of D-gal significantly
affected the growth performance and SOD and GSH-Px levels, including related mRNA
expression suppression, MDA levels enhancement, gut microbiota dysfunction, and serum
amino acid alteration in pigs.

4. Oxidative Stress Signal Pathways

Oxidative stress can disrupt intracellular reduction-oxidation (redox) levels, which
in turn inhibits/activates several signaling molecules and signaling pathways, such as
the Kelch-like ECH-associated protein 1 (Keap1)/Nrf2 signaling pathway [41–44], the
NF-κB signaling pathway (a key regulator of protein synthesis) [45,46], brain-derived
neurotrophic factor/tropomyosin-related kinase receptor type B signaling channel [47], the
phosphoinositide 3-kinase (PI3K)/Akt signaling pathway [48], protein kinase C [49,50],
MAPKs [51,52], adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK), etc.
These signaling molecules ultimately regulate the expression of relevant redox-related tar-
get genes to regulate redox levels. In this review, we discuss the effects of the Keap1/Nrf2,
MAPKs, and AMPK signaling pathways on oxidative stress.
 highly conserved regions, and these homologous structures are named Neh1-Neh6 (Nrf2-
ECH homology 1 to 6). The first conserved region is Neh1 that contains the CNC homol-
ogous region and the leucine zipper structure. The second and third regions are highly
conserved protein amino- and carboxy-termini called Neh2 and Neh3, respectively. Fur-
Animals 2021, 11, 1384 6 of 21
thermore, there are two conserved acidic regions (Neh4 and Neh5) and a conserved ser-
ine-rich region (Neh6) [53] (Figure 2). The Neh1 region contains a leucine zipper-like
structure with the small protein molecule Maf (including Maf F, Maf G, and Maf K) to
4.1. Keap1/Nrf2/ARE
form a heterodimer Signaling
that Pathway
recognizes and binds to a specific base sequence
(TGCTGA(G/C)TCAGCA)ofpresent
4.1.1. Structural Domains Keap1 and Nrf2antioxidant response element (ARE) to initiate
on the
Nrf2 is of
transcription a member
the targetof gene
the CNC[54].(cap’-n’-collar)
Nrf2 deficiency family of transcription
induces oxidative factors withand it
stress [55]
six highly conserved regions, and these homologous structures are named
essentially protects cells from damage by upregulating the expression of cytoprotective Neh1-Neh6
(Nrf2-ECH homology 1 to 6). The first conserved region is Neh1 that contains the CNC ho-
enzymes with ARE in a series of its promoter regions [56].
mologous region and the leucine zipper structure. The second and third regions are highly
Keap1 belongs
conserved to theand
protein amino- BTB-Kelch protein
carboxy-termini family
called Neh2and and consists of about Further-
Neh3, respectively. 50 members
named Kelch-like 1–42 or Kelch and BTB domain-containing 1–14 [57].
more, there are two conserved acidic regions (Neh4 and Neh5) and a conserved serine-rich Keap1 is a cyto-
plasmic
region protein of 624
(Neh6) [53] amino
(Figure acids
2). The Neh1and fivecontains
region distinctaregions, the amino-terminal
leucine zipper-like structure with region,
thethe
BTB/POZ (Bric-a-brac,
small protein tramtrac,
molecule Maf broad-complex/poxvirus
(including Maf F, Maf G, and Maf K) zinc finger)
to form domain, a cys-
a heterodimer
that recognizes
teine-rich and binds
intervening to a specific
region, base sequence (TGCTGA(G/C)TCAGCA)
the double-glycine repeat or Kelch domain, present
and on the car-
the antioxidant response element (ARE) to initiate transcription of the
boxy-terminal region [58] (Figure 2). Keap1 binds to the N-terminal Neh2 domain target gene [54]. Nrf2of Nrf2
deficiency induces oxidative stress [55] and it essentially protects cells
through common DLG and ETGE motifs. Upon oxidative stress, the DLG motif in Nrf2 is from damage by
upregulating the expression of cytoprotective enzymes with ARE in a series of its promoter
released from the DRG region of Keap1; thus, it blocks the ubiquitination and degradation
regions [56].
of Nrf2 [59].

Figure 2. The structural regions of Nrf2 and Keap1 proteins. A, Domains of Nrf2; B, Domains of
Figure 2. The structural regions of Nrf2 and Keap1 proteins. A, Domains of Nrf2; B, Domains of
Keap1.
Keap1.
Keap1 belongs to the BTB-Kelch protein family and consists of about 50 members
named Kelch-like
4.1.2. Signaling 1–42 or
Pathway inKelch and BTB domain-containing
Keap1/Nrf2/ARE Oxidative Stress1–14 [57]. Keap1 is a cyto-
State
plasmic protein of 624 amino acids and five distinct regions, the amino-terminal region,
Nrf2 is located in the cytoplasm and Keap1 is a pro-electron oxidative stress sensor
the BTB/POZ (Bric-a-brac, tramtrac, broad-complex/poxvirus zinc finger) domain, a
that acts as a stress
cysteine-rich receptorregion,
intervening and a the
splice component repeat
double-glycine of the Cullin3
or Kelch(Clu3)-based
domain, and ubiquitin
the
E3carboxy-terminal
ligase. Nrf2 andregion
Keap1[58]
bind to each other in a 1:2 ratio, in which
(Figure 2). Keap1 binds to the N-terminal Neh2 two Keap1
domainproteins
of
form
Nrf2a through
homodimer andDLG
common bindand
through
ETGE their
motifs.BTB structural
Upon oxidativedomains
stress, thetoDLG
the motif
Nrf2 in
protein
Nrf2 is released from the DRG region of Keap1; thus, it blocks the ubiquitination and
degradation of Nrf2 [59].

4.1.2. Signaling Pathway in Keap1/Nrf2/ARE Oxidative Stress State

Nrf2 is located in the cytoplasm and Keap1 is a pro-electron oxidative stress sensor
that acts as a stress receptor and a splice component of the Cullin3 (Clu3)-based ubiquitin
E3 ligase. Nrf2 and Keap1 bind to each other in a 1:2 ratio, in which two Keap1 proteins
form a homodimer and bind through their BTB structural domains to the Nrf2 protein [60].
Under normal (stress-free) conditions, Keap1 binds to ubiquitinated Nrf2, which leads to
rapid degradation of Nrf2 via the proteasome pathway, thus inhibiting the transcriptional
Animals 2021, 11, x 7 of 22

Animals 2021, 11, 1384 [60]. Under normal (stress-free) conditions, Keap1 binds to ubiquitinated 7Nrf2, of 21 which
leads to rapid degradation of Nrf2 via the proteasome pathway, thus inhibiting the tran-
scriptional activity of Nrf2 and maintaining it in a low and inactive steady state in the cell
[61]. Upon
activity cellular
of Nrf2 exposure ittoinoxidative
and maintaining or electrophilic
a low and inactive steady state stress,
in theelectrophilic
cell [61]. Uponreagents
modify
cellular the reactive
exposure cysteine residues
to oxidative of Keap1,
or electrophilic causing
stress, a loss of
electrophilic its ability
reagents to ubiquitinate
modify the
reactive
Nrf2 andcysteine residues
its activity ofE3
as an Keap1,
ligasecausing a loss ofNrf2
component. its ability to ubiquitinate
is stabilized Nrf2 and to the
and translocated
its activitywhere
nucleus, as an E3
it ligase component. Nrf2
heterodimerizes withissmall
stabilized
Mafandviatranslocated to the nucleus,
the antioxidant/electrophile re-
sponse element (ARE/EpRE), and activates protective cellular target geneselement
where it heterodimerizes with small Maf via the antioxidant/electrophile response for transcrip-
(ARE/EpRE), and activates protective cellular target genes for transcription [62]. These
tion [62]. These cytoprotective genes include: (1) two genes for detoxifying enzymes,
cytoprotective genes include: (1) two genes for detoxifying enzymes, NAD(P)H quinone
NAD(P)H quinone oxidoreductase (NQO1) and glutathione S-transferases and (2) antiox-
oxidoreductase (NQO1) and glutathione S-transferases and (2) antioxidant genes such
idant genes
as heme oxygenasesuch as1 and
heme oxygenase 1 andsynthase
γ-glutamylcysteine γ-glutamylcysteine
[63] (Figure 3).synthase [63] (Figure 3).
With continuous
With continuous
regulation regulation
in vivo, after in vivo,
redox levels reachafter redox levels
equilibrium, Keap1reach equilibrium,
translocates into the Keap1
nucleus translo-
cates intoNrf2
to escort the nucleus
out of theto escort
nucleusNrf2 out of the nucleus
for proteasomal for proteasomal
degradation degradation
in the cytoplasm, thus in the
cytoplasm, thus terminating Nrf2 activity [64].
terminating Nrf2 activity [64].

Figure 3. Signaling pathway of Keap1/Nrf2/ARE under oxidative stress.

Figure 3. Signaling pathway of Keap1/Nrf2/ARE under oxidative stress.
4.1.3. Keap1/Nrf2/ARE and Oxidative Stress
4.1.3.Keap1
Keap1/Nrf2/ARE and Oxidative
is activated during Stress
oxidative stress and has a huge role in bone remodeling and
inhibition of apoptosis. Nrf2, a regulator of bone healing, was found to play an important
Keap1 is activated during oxidative stress and has a huge role in bone remodeling
role in bone remodeling [65]. Nrf2 is activated during the remodeling of healthy bone
and inhibition of apoptosis. Nrf2, a regulator of bone healing, was found to play an im-
and fracture healing. In Nrf2-deficient mice, tissues for cartilage healing suffer high levels
portant role stress
of oxidative in bone remodeling
damage, resulting[65]. Nrf2 is activated
in reduced strength andduring the remodeling
stability of the fracturedof healthy
bone and fracture healing. In Nrf2-deficient mice, tissues for
bones and impeded bone formation and healing. In cardiomyocytes exposed to hypoxic cartilage healing suffer high
levels of oxidative
conditions, oxidative stress
stressdamage,
is induced resulting in reduced
in the cells strength andincrease
with a concomitant stabilityin of
thethe frac-
tured bones
forkhead boxand impeded
protein bone formation
O6 (FOXO6) expression. andDownregulation
healing. In cardiomyocytes exposed to hy-
of FOXO6 expression
by gene
poxic knockdown
conditions, promotes
oxidative sirtuin6
stress (SIRT6)in
is induced expression, which
the cells with ultimately enhances
a concomitant increase in the
forkhead box protein O6 (FOXO6) expression. Downregulation of[66].
Nrf2-mediated activation of antioxidant signaling and inhibits apoptosis FOXO6In oxidative
expression by
stress experiments in the jejunum of weaned heifers fed zearalenone
gene knockdown promotes sirtuin6 (SIRT6) expression, which ultimately enhances (ZEA), there was a Nrf2-
linear and quadratic decrease in the relative expression of total SOD and GSH-Px activities
mediated activation of antioxidant signaling and inhibits apoptosis [66]. In oxidative
and reduced levels of Keap1 mRNA and protein in the jejunum (p < 0.05) with increasing
stress
dietaryexperiments in the jejunum
ZEA concentrations, while the of weaned
levels heifers
of Nrf2, GPx1, fed
NQO1,zearalenone (ZEA), there was a
and glutamate-cysteine
linear and quadratic decrease in the relative expression of total SOD
ligase mRNA and relative expression of modifier subunits of protein increased linearly and GSH-Px andactivities
and reduced (p
quadratically levels of suggesting
< 0.05), Keap1 mRNA and protein jejunal
that ZEA-induced in the oxidative
jejunum stress
(p < 0.05) with the
promotes increasing
dietary
expressionZEA concentrations,
of downstream while target
antioxidant the levels
genesof Nrf2, GPx1,
expressing NQO1, NQO1,
HO1, and glutamate-cyste-
and glutamate-
cysteine
ine ligaseligase
mRNA against
andoxidative stress by upregulating
relative expression of modifierthe Keap1/Nrf2
subunits signaling
of protein [67]. linearly
increased
and quadratically (p < 0.05), suggesting that ZEA-induced jejunal oxidative stress pro-
motes the expression of downstream antioxidant target genes expressing NQO1, HO1,
and glutamate-cysteine ligase against oxidative stress by upregulating the Keap1/Nrf2
signaling [67].
 Animals 2021, 11, 1384 8 of 21

4.2. MAPK Signaling Pathway

The MAPK signaling pathway is an important oxidative stress-sensitive transduction
pathway that plays an important role in oxidative stress. In-depth studies on the MAPK
signaling pathway in skeletal muscle are an important aspect in resolving muscle damage
under stress conditions. It is a well-studied classical signaling pathway with multiple
important functions in regulating cell growth, metabolism, mutagenesis, transcription,
translation, and recombination [68]. The most studied MAPK-regulated cellular functions
Animals 2021, 11, x include extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase, and p38 [69] 9 of 2
(Figure 4).

Figure4.4.Signaling
Figure Signaling pathway
pathway of MAPK
of MAPK under
under oxidative
oxidative stress.stress.

The MAPK
4.3. AMPK familyPathway
Signaling is an important component of the oxidative stress-sensitive signal-
ing pathway that is involved in regulating cellular responses such as growth, development,
AMPK is and
differentiation, a highly conserved
apoptosis regulator
when cells of cellular
are exposed energystimuli
to external metabolism [83,84] that i
(e.g., growth
activated
factors, by multiple
cytokines, upstream signals,
neurotransmitters, such as cellular
and hormones) [70–73].AMP:ATP
Research on andtheADP:ATP
relation- ratios
CaMKKb,
ship between and LKB1.
stress and AMPK participates
MAPK signaling in theis regulation
pathway of cellular
a topic of interest. events,that
It is evident such as the
activation
assembly of of the
thep38MAPK signaling
tight junction, pathway is an and
cell proliferation, important manifestation
differentiation of organ-
[85–89]. Inhibition o
ismal oxidative
the AMPK stress. has
pathway Shinaet al. [74] found
suppressive that on
effect overexpression of p38MAPK
barrier function [90], butinhibited
activation of the
apoptosis induced by oxidative stress and played a protective
pathway can facilitate the assembly of tight junctions [91]. The study role for cells. of
Their
Yangstudy
et al. (2018
confirmed that the MAPK signaling pathway is activated in oxidative stress and is involved
a, b) indicated that heat stress induced the dephosphorylation of AMPK in Sertoli cells
in mediating oxidative stress-induced cellular damage [75–77].
but this was contrary
The MAPK signaling to pathway
its effectisinsignificant
other somatic
in thecells [92]. Furthermore,
regulation of skeletal muscle the finding
indicated thatWill
development. in cultured
et al. (2013)immature
found thatboar
leptinSertoli
could cells,
affect heat stress of
the growth inhibited the AMPK sig
porcine skeletal
naling pathway by suppressing the expression of CaMKKb, and
muscle myogenic cells by altering the expression of key genes in the MAPK signaling activation or overexpres
sion of AMPK
pathway [78]. Thiscouldwasreverse the heat-induced
also corroborated by recentdownregulation
studies that theofMAPK
tight junction
signaling protein
pathway
[93]. plays a key role in regulating skeletal muscle growth and development during
oxidative stress [79–81].
Numerous studiesMAPKshowed may be accumulation
that involved in regulating
of ROS genes
couldcontrolled
lead to the bydysfunction
the
of tight junction via various signaling pathways [94,95]. In the gill of fish, ROS induced
tight junction damage through Nrf2, mTOR, and NF-κB signaling molecules [96]. LPS
induced excessive generation of ROS led to disruption of gut epithelial barrier in vitro
[97]. Activation of AMPK also improved LPS-induced dysfunction of the blood–brain bar
Animals 2021, 11, 1384 9 of 21

expression of the NF-kB signaling pathway (such as several antioxidant enzyme-induced

NF-kB signaling pathways). ERK1/2 phosphorylates transcription factors associated with
growth and development [82]. Moreover, several important adaptations in skeletal muscle,
such as mitosis, organ hypertrophy, and myofiber conversion, are regulated by the MAPK
signaling pathway, and these adaptations play an important role in determining oxidative–
antioxidative homeostasis in the intracellular environment.

4.3. AMPK Signaling Pathway

AMPK is a highly conserved regulator of cellular energy metabolism [83,84] that is
activated by multiple upstream signals, such as cellular AMP:ATP and ADP:ATP ratios,
CaMKKb, and LKB1. AMPK participates in the regulation of cellular events, such as the
assembly of the tight junction, cell proliferation, and differentiation [85–89]. Inhibition
of the AMPK pathway has a suppressive effect on barrier function [90], but activation
of the pathway can facilitate the assembly of tight junctions [91]. The study of Yang
et al. (2018 a, b) indicated that heat stress induced the dephosphorylation of AMPK in
Sertoli cells, but this was contrary to its effect in other somatic cells [92]. Furthermore, the
findings indicated that in cultured immature boar Sertoli cells, heat stress inhibited the
AMPK signaling pathway by suppressing the expression of CaMKKb, and activation or
overexpression of AMPK could reverse the heat-induced downregulation of tight junction
proteins [93].
Numerous studies showed that accumulation of ROS could lead to the dysfunction
of tight junction via various signaling pathways [94,95]. In the gill of fish, ROS induced
tight junction damage through Nrf2, mTOR, and NF-κB signaling molecules [96]. LPS-
induced excessive generation of ROS led to disruption of gut epithelial barrier in vitro [97].
Activation of AMPK also improved LPS-induced dysfunction of the blood–brain barrier
via suppressing the generation of ROS in mice and human brain [98,99]. To investigate
whether heat stress-induced oxidative stress participates in AMPK-mediated changes in
the tight junction, Yang et al. (2020) used NAC to inhibit the overproduction of ROS [100].
Pre-treatment with NAC decreased the level of ROS and increased the expression of
CaMKKb and the phosphorylation level of AMPK, and this, in turn, reversed the heat-
induced downregulation of tight junction proteins in immature boar Sertoli cells. Thus,
these findings implied that heat stress-induced oxidative stress mediated changes in tight
junction proteins via the CaMKKb-AMPK axis.
Several studies have reported that AMPK played a central protective role in attenu-
ating oxidative injury and regulating mitochondrial function [101,102]. AMPK has been
implicated in being involved in the regulation of oxidative stress, through phosphorylating
some transcription factors, including the master transcriptional regulator of lysosomal
genes, TFEB. TFEB is tightly connected with stress, with non-stressed conditions reduc-
ing hyperphosphorylation and cytoplasmic reservation, and stress conditions facilitating
hypophosphorylation and nuclear translocation. It was demonstrated that addition with
curcumin in IPEC-J2 cells challenged with H2 O2 unregulated the AMPK phosphorylation
and TFEB level in the nucleus [103].

5. Nutritional Modulation Measures to Mitigate Oxidative Stress

Oxidative stress is common in the intensive production of pigs, and it poses a greater
risk to animal health and increases feeding costs. Therefore, it is important to develop
effective oxidative stress mitigation techniques.
Under oxidative stress, body nutrient metabolism direction changes, additional supple-
mentation of certain nutrients or non-nutritional additives help reduce stress. Commonly
used supplements belong to the following categories: 1. amino acid, such as cysteine,
arginine, and tryptophan; 2. Vitamins, such as vitamins E, A, and C; 3. mineral elements,
such as zinc, copper, manganese, selenium, etc.; 4. natural compounds, such as curcumin
and resveratrol.
Animals 2021, 11, 1384 10 of 21

5.1. Functional Amino Acids

Cysteine: In a piglet model, cysteine supplementation significantly increased intestinal
GSH content, activities of antioxidant enzymes SOD, GSH-Px, and catalase, and further
alleviated inflammatory response and intestinal damage induced by LPS [104]. The supple-
mentation of 1.2 g/kg cysteine precursor (acetylcysteine) in development-delayed piglets
upregulated the expression of GSH biosynthesis related genes in liver and increased the
GSH content, which significantly improved the growth and development of piglets [105].
In the lipopolysaccharide model, dietary acetylcysteine supplementation also showed
significant anti-inflammatory effects on lipopolysaccharide-induced piglet inflammation
oxidative stress [106,107].
Arginine: Arginine can indirectly regulate the oxidation system in the body through a
variety of ways. In the piglet model of oxidative stress, arginine significantly increased the
activities of GSH-Px and SOD, and alleviated the oxidative damage induced by diquat [108].
The experiment of finishing pigs showed that arginine improved the antioxidant capacity
of muscle and meat quality indexes of pork [109]. Recent study found that L-arginine
inhibited inflammatory response and oxidative stress induced by lipopolysaccharide via
arginase-1 signaling in IPEC-J2 cells [110].
Tryptophan: Tryptophan and its metabolites have also been reported to have an-
tioxidant properties [111]. Studies have shown that oxidative stress induced by diquat
significantly reduced blood tryptophan content in piglets [112], while feeding tryptophan
in suckling piglets inhibited the secretion of stress hormone, and improved production
performance [113]. In vitro studies showed that tryptophan could activate the mTOR
signaling pathway in intestinal epithelial cells of piglets, and upregulated the expression of
amino acid transporters and tight junction proteins, which had a positive effect on intesti-
nal function [114]. However, the addition of high dose tryptophan had a certain degree
of toxicity on the intestinal morphology of piglets [115]. Melatonin is one of the main
metabolites of tryptophan. The study of Ji et al. [116] suggested that melatonin treatment
decreased PM2.5-induced oxidative stress level in the brains and lungs and relieved airway
inflammation and chronic cough. In vitro experiments found that melatonin alleviated
oxidative stress injury induced by H2 O2 in pigs and promoted the development of pig
embryos [117].

5.2. Vitamin-Based Antioxidant Supplementation

Vitamin E: Vitamin E is the most important fat-soluble antioxidant [118] and benefits
the organism by reducing oxidative stress and affecting cytokine expression [119]. Vitamin E
was found to resist PVC-induced sperm damage and embryotoxicity, increase sperm count
and viability in animals, improve sperm DNA damage, increase in vitro fertilization rates,
and promote embryo development [120]. In another study, piglets fed with peroxidized
soybean oil exhibited oxidative stress and adversely affected growth, and supplementation
with vitamin E increased serum vitamin concentrations (p < 0.001) compared to control and
polyphenol treatment (1.98, 1.25, and 1.26 mg/kg) [121]. In that study, both vitamin E and
polyphenols improved antioxidant capacity in piglets, although there was no significant
change in growth performance or oxidative status compared to the control group.
Vitamin A and beta-carotene: Structurally, β-carotene consists of two vitamin A molecules
and is, thus, used as a source of vitamin A [122]. Based on the needs of the body, the nega-
tive feedback regulation mechanism causes the conversion of β-carotene to vitamin A, and
this mechanism effectively intercepts the problem of excessive accumulation of vitamin A in
the body [123]. Deficiency of vitamin A in cells results in ROS, mitochondrial dysfunction,
PARP-1-dependent energy deprivation, and programmed T-cell death, which decreases
the immunity of the organism [124]. Ahmed M. Elomda et al. [125] studied the breakdown
product of β-carotene in the in vitro cultured rabbit mulberry embryos, and found that
the activities of SOD and GPx antioxidant enzymes were significantly higher (p < 0.05)
in the group with the addition of 100 or 1000 nM retinol than in the control group. Their
results indicated an increased antioxidant capacity, in addition to a significant upregulation
Animals 2021, 11, 1384 11 of 21

of key genes for embryonic development (e.g., GJA1 and POU5F1 genes, gap junction
protein α1, and POU 5-like homology cassette 1), which cause significantly enhanced rabbit
embryo development (p < 0.001). Vitamin A supplementation (129 mg/kg) in lactating and
post-weaning rats attenuated oxidative stress and metabolic disturbances due to a high-fat
diet, significantly reducing the body weight and amount of the white adipose tissue in rat
pups, but increased the amount of brown adipose tissue. This provides one of the possible
reasons for obesity/overweight in early life.
Vitamin C: Vitamin C protects cells from damage by acting as an antioxidant to scav-
enge ROS and prevent lipid peroxidation and protein alkylation through the vitamin
E-dependent pathway [126]. Dietary supplementation with vitamin C at any dose (LVc and
HVc) significantly improved growth and feed utilization in fish and increased animal body
weight [127]. The role of vitamin C in metabolic syndrome was reviewed in 2020 [128], and
positive outcomes of vitamin C were found to be mediated in part through its antioxidant
and anti-inflammatory properties. Vitamin C supplementation significantly increased SOD
and GPx levels and reduced MDA levels compared to those in controls (p < 0.05). Reduced
oxidative stress induced by the insecticide mixture fipronil (Fip) + pirimiphos-methyl (Pyr),
reduced insecticide neurotoxicity, and improved motility in juvenile zebrafish, possibly by
mechanisms that alter the expression of hypothalamic–pituitary–gonadal axis genes [129]
and increase cortisol levels [130].

5.3. The Mineral Elements

Copper: One of the enzymes that neutralize oxidative stress is Cu/Zn SOD, which has
some ability to scavenge ROS; hence, adequate levels of copper in the body are important
to mitigate oxidative stress [131,132]. The addition of cholesterol to the animal diet can
lead to copper deficiency and, thus, promote oxidative damage [133]. Copper deficiency
can also alter the microbiome of animals [134]. Supplementation of weaned piglets’ diets
with copper nanoparticles enhanced their antioxidant capacity, clearly indicating that the
addition of 100 mg/kg body weight of copper nanoparticles to the diet may be a potential
alternative for weaned piglets [135].
Zinc: Zinc is one of the essential trace elements that are present in many metabolic
enzymes, transcription factors, and cellular signaling proteins and acts as a catalyst for
enzymes in DNA replication, gene transcription, and RNA and protein synthesis [136,137].
A possible mechanism for the antioxidant properties of zinc is Cu-Zn-SOD, which is an
important cellular resistance component to the first line of defense against ROS [138]. The
addition of ZnAA (zinc-amino acid complex) could alleviate oxidative stress by reducing
plasma MDA levels and decreasing GPx activity [139]. Increased intestinal villi length and
the ratio of villi length to crypt depth indicated improved intestinal morphology, increased
feed utilization efficiency, and improved body weight and FCR. In another study [140], the
addition of 200 mg/kg Zn could effectively protect weaned piglets from oxidative stress
by improving the antioxidant system, and different Zn sources (2-hydroxy-4 methyl-thio
butanoic acid (HMZn) vs. ZnSO4 ) did not affect growth performance during the first
two weeks. 2-hydroxy-4 methyl-thio butanoic acid HMZn increased serum SOD and GPx
activities and total antioxidant capacity (T-AOC) (p < 0.05). Compared to the diquat group,
different sources of zinc increased serum GPx and T-AOC activities and increased relative
liver and kidney Nrf2, SOD1, and GPx mRNA expression (p < 0.05). The addition of HMZn
increased the depth of jejunal villi (p > 0.05), and downregulated mRNA expression of
inflammatory factors in the small intestine, liver, and kidney, ultimately indicating that
HMZn is a more effective source of zinc.
Selenium: The antioxidant effect of selenium is mainly reflected in its role as a compo-
nent of GSH-Px, which is an important antioxidant enzyme in animals that protects the cell
membranes of the animal organism from oxidative damage. Selenium deficiency generates
oxidative stress through the regulation of selenoproteins, and subsequent activation of
inflammatory responses via NF-κB, HIF-1α, and NLRP3 pathways, ultimately leading to
organ damage [141–143]. Doan et al. (2020) studied the addition of different selenium
Animals 2021, 11, 1384 12 of 21

sources, such as sodium selenite, soy protein-chelated Se, and selenized yeast [144]. To
study the oxidative stress induced by diquat, they categorized the nursery pigs into five
groups, (1) the negative control (NC): fed with basal diet and injected with sterile saline
via the intraperitoneal cavity, (2) the positive control (PC): fed with basal diet and injected
with diquat solution, (3) fed with a basal diet supplemented with 0.3 mg/kg of Se from
sodium selenite (SS), (4) soy protein-chelated Se (SC), and (5) selenized yeast (SY). Organic
selenium-enhanced endogenous antioxidant activity in all aspects compared to the PC
group (p < 0.05), with SY being the most effective, ultimately indicating that the addition of
a selenium-enriched yeast source at a dose of 0.3 mg/kg selenium was the most effective.
In the mouse model of intestinal oxidative stress, a new form of selenium nanoparticle
(biogenic nanoselenium (BNS) particles) were found to protect the mouse intestinal bar-
rier function and preserve intestinal redox homeostasis more efficiently than Se-Met and
Nano-Se [145]. In vitro experiments with porcine jejunum epithelial (IPEC-J2) cells verified
the stronger epithelial barrier-protecting effect of BNS particles against oxidative stress,
with reduced cell apoptosis and an improved cell redox state. Furthermore, the study
of Sun et al. (2020) reported that selenium supplementation protects against oxidative
stress-induced cardiomyocyte cell cycle arrest through activation of PI3K/Akt [146].

5.4. The Natural Compounds

Curcumin: Curcumin is a compound from turmeric that has certain anti-inflammatory,
antioxidant, antiproliferative, and antiangiogenic activities [147,148]. Curcumin can scav-
enge free radicals and carry out antioxidant functions by inducing the Nrf2 signaling
pathway [149]. The addition of 400 mg/kg curcumin to the basal diet was effective in
alleviating intrauterine growth retardation (IUGR)-induced intestinal oxidative stress in
piglets and improved intestinal antioxidant function [150]. The work of Cao et al. (2020)
proposed that curcumin could effectively ameliorated oxidative stress, enhanced intesti-
nal barrier function and mitochondrial function through induction of Parkin-dependent
mitophagy via AMPK activation and subsequent TFEB nuclear translocation [103].
Resveratrol: Resveratrol is a compound derived from grapes and wine [151] that
reduces inflammation and regulates redox mechanism through Sir2-related enzymes,
the Sirtuins1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1α
(PGC-1α) axis, and signaling pathways such as PI3K/Akt/mTOR [152,153]. Dietary sup-
plementation of 300 mg/kg resveratrol fed to pregnant and lactating sows increased the
antioxidant capacity of the sow’s placenta and milk compared to the control group [154],
which also increased the antioxidant level of piglets as well as the litter weaning and piglet
weaning weights (p < 0.05). These data from Cao et al. (2019) indicated that resveratrol
was effective in protecting the intestinal barrier, improving the redox status, alleviating
mitochondrial damage and inducing mitophagy in piglets challenged with diquat [155].
Table 1 summarizes the antioxidant effects of some natural compounds.

Table 1. The antioxidant effects of some natural compounds.

Active Ingredients Experimental Model Doses Efficacy Ref

diquat-induced protecting the intestinal barrier
Resveratrol intestinal barrier function in 100 mg/kg, 14-day antioxidant capacity↑ [155]
piglets. alleviating mitochondrial damage
Growth performance↑
Intrauterine growth
Curcumin 400 mg/kg, 24-day hepatic antioxidant capacity↑ [156]
retardation piglets
Nrf2 and Hmox1 levels↑
alleviates intestinal injury during transport
transport-induced
Quercetin 25 mg/kg, 4-week by modulation of intestinal oxidative status [157]
intestinal injury pigs
and inflammation
Animals 2021, 11, 1384 13 of 21

Table 1. Cont.

Active Ingredients Experimental Model Doses Efficacy Ref

Resisting intestinal oxidative stress by
increasing diversity and improving the
Proanthocyanidin weaned piglet 250 mg/kg, 28-day balance of gut microbes. [158]
Piglets had better growth performance and
reduced diarrhea incidence.
antioxidant capacity↑
Garcinol finishing pigs 600 mg/kg growth performance ↑ [159]
pork quality↑
Protective effects on oxidative stress,
weaned piglet model
inflammation, and intestinal barrier
Protocatechuic acid challenged with 4000 mg/kg [160]
function through regulation of intestinal
lipopolysaccharide (LPS)
flora
antioxidant capacity↑
increased piglet weaning weight and the
Artemisia annua L. heat-stressed sows 1.0 g/kg [161]
activities of T-SOD and T-AOC in serum
and promote the intestinal barrier integrity.
enterotoxigenic Escherichia
coli-induced intestinal expression of p38 MAPK↑
Icariin 1 g/kg BW [162]
epithelial barrier disruption antioxidant capacity↑
in piglets
regulating oxidative stress and
Chinese miniature pigs
Dioscin 80 mg/kg inflammation via Sirt1/Nrf2 and p38 [92]
(male, 20–30 kg, 1–2 month)
MAPK pathways
diquat-induced oxidative antioxidant capacity↑
Chitosan (CS) 500 mg/kg [163]
stress in weaned piglets anti-inflammatory↑
antioxidant capacity↑
Grape pomace weaned piglets 9% GP growth performance↑ [164]
pork quality↑
intestinal morphology↑
Soybean isoflavone young piglets fed oxidized
20 mg/kg antioxidant capacity↑ [165]
(ISF) fish oil
immune function↑
intestinal morphology↑
Konjac flour (KF) Gestating sows 2.2% antioxidant capacity↑ [166]
insulin sensitivity
Polyphenolic
(byproduct from total antioxidant capacity in plasma and
olive mill piglets tissues↑ [167]
wastewater CARB and TBARS in plasma and tissues↓
processing)
Oregano essential antioxidant capacity↑
large white sows 15 mg/kg [168]
oil (OEO) Performance of future generations↑
(250 and
antioxidant capacity↑
Isoproterenol-Induced 500 mg/kg; gastric
Red ginseng significant cardioprotective potential,
myocardial infarction in gavages, [169]
(Panax ginseng) adjunct in the treatment and prophylaxis of
Porcine respectively) for 9
myocardial infarction.
days
antioxidant capacity↑
A porcine model of acute cardiomyocyte apoptosis↓
Shenyuan 400 mg/kg·d [170]
myocardial infarction (AMI) therapeutic role in improving the natural
process of AMI
Verbascoside piglets 5 mg/kg stress biomarkers in swine gut↓ [171]
Animals 2021, 11, 1384 14 of 21

6. Conclusions
Therefore, enhancing the antioxidant capacity of pigs by supplementing/adding
relevant nutrients is a good practice to enhance the amount of enzymatic/non-enzymatic
antioxidants or stimulate the expression of antioxidant genes, as well as to control the key
sites of the redox signaling pathway in animal production.
At present, there are still many topics that need to be studied urgently in the field of
pig oxidative stress and nutrition regulation. (1) Pig weaning is a comprehensive process,
and the specific mechanism of weaning oxidative stress and its accompanying or leading
role in the process of weaning stress still need to be further studied. (2) Oxidative stress is
closely related to a variety of human metabolic diseases, and pigs are the most ideal model
animal for human disease research [81]; however, there are still few studies on pig oxidative
stress and related human diseases. (3) There is a lack of mature and stable models of pig
oxidative stress at home and abroad, which directly restricts the study of pig oxidative
stress. Methionine overdose can induce oxidative stress. Thus, it is unknown whether
oxidative stress is induced by increasing dietary methionine content in a pig model. (4)
The research on oxidative stress of pigs at home and abroad is mainly focused on the
piglet stage. There is no systematic comparison of the oxidative stress response in different
growth stages of pigs, and different oxidative stress models have different targeting organs
for oxidative damage in pigs, which hinders the systematic study of the mechanism of
oxidative stress in pigs.

Author Contributions: Writing—original draft preparation, M.X.; writing—review and editing,

Y.H.; funding acquisition, X.G. All authors have read and agreed to the published version of the
manuscript.
Funding: This research was funded by the central Public-interest Scientific Institution Basal Re-
search Fund (2018-YWF-YTS-10), the National Key Research and Development Program of China
(2016YFD050050104), and the Agricultural Science and Technology Innovation Program (ASTIP-
IAS07).
Institutional Review Board Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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