The Interplay of Oxidative Stress and Inflammation: Mechanistic Insights and Therapeutic Potential of Antioxidants

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Editorial
The Interplay of Oxidative Stress and Inflammation: Mechanistic
Insights and Therapeutic Potential of Antioxidants
Ayman M. Mahmoud ,
1,2
Fiona L. Wilkinson,
3
Mansur A. Sandhu,
4
and Adam P. Lightfoot
3
1
Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Egypt
2
Biotechnology Department, Research Institute of Medicinal and Aromatic Plants (RIMAP), Beni-Suef University, Egypt
3
Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, UK
4
Department of Biomedical Sciences, Faculty of Veterinary & Animal Sciences, PMAS, Arid Agriculture University, Pakistan
Correspondence should be addressed to Ayman M. Mahmoud; ayman.mahmoud@science.bsu.edu.eg
Received 28 July 2021; Accepted 28 July 2021; Published 20 August 2021
Copyright © 2021 Ayman M. Mahmoud 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.
Oxidative stress is caused by the overproduction of Reactive
Oxygen Species (ROS) and diminished cellular antioxidant
defenses. Under physiological conditions, ROS are involved
in processes, including cellular homeostasis, modulation of
cellular metabolism, signaling and redox state, and being
used by the immune system to inactivate viruses and inhibit
bacterial growth. However, excess ROS production can dam-
age lipids, DNA, and proteins, which can lead to cell death.
ROS-induced damage underpins various oxidative stress-
related human diseases and aging. In addition, cellular anti-
oxidant defenses may decrease during aging, resulting in
age-related increase in ROS and oxidative stress. Excess
ROS can also activate proinflammatory signaling pathways
and the release of multiple inflammatory mediators, such as
cytokines, chemokines, eicosanoids, and others. Therefore,
oxidative stress is implicated in the pathogenesis, develop-
ment, and progression of a sustained inflammatory state.
Furthermore, excess ROS and inflammation work together
to trigger and orchestrate necrotic and apoptotic cell death,
where mitochondrial dysfunction, caspase activation, and
Bcl-2 family proteins are involved in ROS-mediated apopto-
sis. In addition, several protein kinases and signaling path-
ways (including mitogen-activated protein kinases, nuclear
factor-kappaB, protein kinase C, and others) modulate apo-
ptosis depending on the cellular context.
Oxidative stress and inflammation are increasingly rec-
ognized as having key roles in the pathogenesis of various
diseases, including diabetes, obesity, cancer, neurodegenera-
tion, metabolic syndrome, cardiovascular disease, liver dis-
ease, and others. Therefore, understanding the molecular
mechanisms underlying the mutual relationship between
oxidative stress and inflammation can lead to the discovery
of novel strategies to prevent and/or treat various diseases.
Although cells are equipped with numerous nonenzymatic
molecules and enzymatic scavengers of ROS, these defenses
are not always adequate to attenuate the excess ROS produc-
tion. Therefore, agents that can boost antioxidant defense
mechanisms and prevent increased ROS generation can rep-
resent an effective treatment for oxidative stress/inflamma-
tion-related diseases.
This special issue encompasses 25 research articles, one
clinical study, and 6 review articles focusing on the interplay
of oxidative stress and inflammation in different disease con-
ditions, including diabetes and its complications, liver injury,
pancreatitis, lung fibrosis, ocular diseases, cardiovascular dis-
eases, hemorrhagic shock, nonalcoholic fatty liver disease,
cardiac hypertrophy, myocardial infarction, depression,
celiac disease, and others.
The guest editors are pleased to present a compendium of
these cutting-edge original research and review articles as
follows:
Research article: “Hydrostatin-SN10 Ameliorates
Pancreatitis-Induced Lung Injury by Affecting IL-6-
Induced JAK2/STAT3-Associated Inflammation and
Hindawi
Oxidative Medicine and Cellular Longevity
Volume 2021, Article ID 9851914, 4 pages
https://doi.org/10.1155/2021/9851914

Oxidative Stress.”In this article, X. Piao et al. evaluated the
protective effect of the peptide hydrostatin-SN10 against lung
injury associated with pancreatitis induced by taurocholate
in mice. Hydrostatin-SN10 reduced malondialdehyde
(MDA), proinflammatory cytokines, and the number of apo-
ptotic cells and boosted antioxidants. These effects were asso-
ciated with the suppressed IL-6-stimulated JAK2/STAT3
pathway in the lung.
Research article: “Methane-Rich Saline: A Potential Resus-
citation Fluid for Hemorrhagic Shock.”Based on previous
studies showing the beneficial effects of methane-rich saline
(MRS), used as a resuscitation fluid in animal models, Y. Tong
et al. explored its protective effect in hemorrhagic shock
induced in rats by bloodletting via intubation of the right fem-
oral artery. MRS restored systemic blood pressure, ameliorated
serum levels of liver and heart function markers, MDA, proin-
flammatory cytokines, apoptosis markers in the heart, and
upregulated the PGC-1α/SIRT3/SOD2 signaling pathway.
Research article: “Plant Sterol Ester of α-Linolenic Acid
Attenuates Nonalcoholic Fatty Liver Disease by Rescuing
the Adaption to Endoplasmic Reticulum Stress and Enhanc-
ing Mitochondrial Biogenesis.”H. Han et al. showed that
nonalcoholic fatty liver disease (NAFLD) can be effectively
controlled by supplementing the diet with a plant sterol ester
of α-linolenic acid as it inhibited liver steatosis, improved
liver maladies, mitigated inflammatory responses, downregu-
lated stress markers in the endoplasmic reticulum, and
increased mitochondrial biogenesis.
Research article: “Flavonoids from Apios americana Med-
ikus Leaves Protect RAW264.7 Cells against Inflammation via
Inhibitionof MAPKs, Akt-mTORPathways, and Nfr2 Activa-
tion.”Q. Chu et al. investigated the anti-inflammatory activity
of a flavonoid-rich Apios americana leaf extract (ALE) in vitro.
Treatment with ALE reduced the release of proinflammatory
cytokines, nitric oxide (NO), and oxidative stress and inhib-
ited NF-κB and MAPK signaling and upregulation of
HMGB1-Beclin1, Sirt1-FoxO1, and Nrf2-Keap1 pathways in
lipopolysaccharide- (LPS-) induced RAW264.7 cells.
Research article: “Aronia melanocarpa Prevents Alcohol-
Induced Chronic Liver Injury via Regulation of Nrf2 Signaling
in C57BL/6 Mice.”In this study, Z. Wang et al. analyzed the
components of Aronia melanocarpa (AM) and explored its
effects on alcohol-induced chronic liver injury in mice. The
component analysis of AM revealed 17 types of amino acids,
17 types of fatty acids, 8 types of minerals, and 3 types of
nucleotides. In alcohol-induced mice, AM showed hepatopro-
tective effects, suppressed oxidative stress and inflammation
markers, activated Nrf2 signaling, and enhanced antioxidants.
Research article: “Tetrahydroxystilbene Glucoside Ame-
liorates Infrasound-Induced Central Nervous System (CNS)
Injury by Improving Antioxidant and Anti-Inflammatory
Capacity.”X. Zhou et al. studied the therapeutic effects of
2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glycoside (THSG) in
infrasound-caused injury in the CNS. THSG suppressed
inflammation, oxidative stress, and apoptotic cell death,
enhanced antioxidant defenses in the hippocampal tissues
of the mouse model, and ameliorated the learning and mem-
ory impairments caused by infrasound.
Research article: “Comparative Study on Pulmonary
Toxicity in Mice Induced by Exposure to Unflavoured and
Apple- and Strawberry-Flavoured Tobacco Waterpipe
Smoke.”A. Nemmar et al. investigated the pulmonary toxic-
ity induced by daily exposure to plain-, apple-flavored, and
strawberry-flavored waterpipe smoking (WPS) in mice.
Exposure to WPS altered lung function and morphology
and induced oxidative stress and inflammation by activating
NF-κB. The toxic effect of flavored tobacco WPS was found
to be greater than that of unflavored WPS.
Research article: “Hydrogen Sulfide Protects against
Paraquat-Induced Acute Liver Injury in Rats by Regulating
Oxidative Stress, Mitochondrial Function, and Inflamma-
tion.”In this study, Z. Liu et al. reported that exogenous
hydrogen sulfide enhanced antioxidative capability, upregu-
lated Nrf2 and SIRT3/IDH2 signaling, improved mitochon-
drial function, and suppressed ROS-induced NLRP3
inflammasome activation, resulting in amelioration of para-
quat hepatotoxicity.
Research article: “Musa balbisiana Fruit Rich in Polyphe-
nols Attenuates Isoproterenol-Induced Cardiac Hypertrophy
in Rats via Inhibition of Inflammation and Oxidative Stress.”
S. Kumari et al. evaluated the protective effect of Musa bal-
bisiana (MB) fruit pulp powder against cardiac hypertro-
phy induced by isoproterenol in rats and in vitro in
H9c2 cells. The fruit powder ameliorated cardiac hypertro-
phy markers and attenuated ISO-induced inflammation
and oxidative stress.
Research article: “Mesenchymal Stem Cells Attenuate
Diabetic Lung Fibrosis via Adjusting Sirt3-Mediated Stress
Responses in Rats.”In this study, Y. Chen et al. reported
the beneficial effect of mesenchymal stem cells (MSCs) in
diabetes-induced lung injury. Bone marrow MSCs effectively
attenuated lung fibrosis via modulating Sirt3-mediated
responses, including inflammation, oxidative stress, apopto-
sis, autophagy, and endoplasmic reticulum stress in
streptozotocin-induced diabetic rats.
Research article: “Fucoidan Ameliorates Oxidative Stress,
Inflammation, DNA Damage, and Hepatorenal Injuries in
Diabetic Rats Intoxicated with Aflatoxin B
1
.”M. S. Alessia
et al. indicated that the sulfated polysaccharide fucoidan
can effectively normalize serum markers of liver and kidney
function and attenuate inflammation, oxidative stress, and
DNA damage in STZ-diabetic rats.
Research article: “Lactobacillus delbrueckii Ameliorates
Intestinal Integrity and Antioxidant Ability in Weaned Pig-
lets after a Lipopolysaccharide Challenge.”In this study, F.
Chen et al. reported that dietary supplementation of Lactoba-
cillus delbrueckii improved intestinal integrity and immune
response and attenuated intestinal oxidative damage in
LPS-challenged piglets.
Research article: “Water-Soluble Pristine C
60
Fullerenes
Inhibit Liver Fibrotic Alteration and Prevent Liver Cirrhosis
in Rats.”H. Kuznietsova et al. evaluated the impact of the
effective free radical scavenger, pristine C
60
fullerenes
(C
60
FAS), on liver fibrosis and cirrhosis and their ability to
modulate the main growth factor receptors involved in liver
fibrogenesis. C
60
FAS attenuated hepatocyte injury, oxidative
stress, and connective tissue deposition in N-
2 Oxidative Medicine and Cellular Longevity

diethylnitrosamine/carbon tetrachloride-intoxicated rats.
The computational modeling revealed that C
60
FAS can block
the hinge prohibiting ATP binding to EGFR and FGFR.
Research article: “Vagus Nerve Stimulation Ameliorates
Renal Ischemia-Reperfusion Injury through Inhibiting NF-
κB Activation and iNOS Protein Expression.”M. Wang
et al. found that vagus nerve stimulation treatment attenu-
ated renal ischemia/reperfusion injury in rats by inhibiting
iNOS expression, oxidative stress, and inflammation via
NF-κB inactivation.
Research article: (E)-N′-(1-(7-Hydroxy-2-Oxo-2H-
Chromen-3-Yl) Ethylidene) Benzohydrazide, a Novel Syn-
thesized Coumarin, Ameliorates Isoproterenol-Induced
Myocardial Infarction in Rats through Attenuating Oxidative
Stress, Inflammation, and Apoptosis.”A. Feriani et al. inves-
tigated the ameliorative effect of a novel synthesized couma-
rin, 7-hyd.HC, on isoproterenol-induced myocardial
infarction in rats. 7-hyd.HC ameliorated serum cardiac func-
tion markers, normalized cardiac function and ECG pattern,
and mitigated oxidative stress, apoptosis, and fibrinogen pro-
duction in ISO-induced rats.
Research article: “Nauclea latifolia Sm. Leaf Extracts
Extenuates Free Radicals, Inflammation, and Diabetes-
Linked Enzymes.”F. N. Iheagwam et al. evaluated the
in vitro anti-inflammatory, antioxidant, α-amylase, and α-
glucosidase inhibitory activities of ethanolic and aqueous
extracts of Nauclea latifolia leaves. Both extracts showed pos-
itive effects and could serve as antioxidant and anti-
inflammatory candidates.
Research article: “β-Phenethyl Isothiocyanate Induces
Cell Death in Human Osteosarcoma through Altering Iron
Metabolism, Disturbing the Redox Balance, and Activating
the MAPK Signaling Pathway.”H. Lv et al. reported that β-
phenethyl isothiocyanate (PEITC) reduced cell viability,
inhibited proliferation, and caused G
2
/M cell cycle arrest in
MNNG/HOS, U-2 OS, MG-63, and 143B cell lines and
delayed tumor growth in a xenograft osteosarcoma mouse
model. The chemopreventive effect of PEITC was associated
with the induction of oxidative stress and triggering ferropto-
sis, apoptosis, and autophagy.
Research article: “Tanshinone IIA Protects against Acute
Pancreatitis in Mice by Inhibiting Oxidative Stress via the
Nrf2/ROS Pathway.”In this investigation, W. Chen et al.
reported that tanshinone IIA, the active constituent of Salvia
miltiorrhiza Bunge, conferred protection against acute pan-
creatitis in mice by suppressing oxidative stress via activation
of the Nrf2/ROS pathway.
Research article: “Oxidant/Antioxidant Profile in the
Thoracic Aneurysm of Patients with the Loeys-Dietz Syn-
drome.”M. E. Soto et al. reported that redox homeostasis is
altered in thoracic aortic aneurysms (TAA) in Loeys-Dietz
syndrome patients, favoring ROS overproduction that con-
tributes to the decline of antioxidant defenses.
Research article: “Chitoheptaose Promotes Heart Reha-
bilitation in a Rat Myocarditis Model by Improving Antioxi-
dant, Anti-Inflammatory, and Antiapoptotic Properties.”Q.
Zhao et al. emphasized the cardioprotective role of chitosan
oligosaccharides (COS) in LPS-stimulated RAW264.7 cells
and a rat model of myocarditis. Seven COS were evaluated
for their reactive scavenging, inflammatory and apoptotic
factors, and myocardial protective effects. Chitoheptaose
was the most effective among the tested COS where it showed
a myriad of cardioprotective roles in the myocarditis model
via its antioxidant, anti-inflammatory, and antiapoptotic
activities.
Research article: “Mulberry Fruit Prevents Diabetes and
Diabetic Dementia by Regulation of Blood Glucose through
Upregulation of Antioxidative Activities and CREB/BDNF
Pathway in Alloxan-Induced Diabetic Mice.”A. Y. Min
et al. investigated the effect of the ethyl acetate fraction of
the ethanolic extract of mulberry fruit (MFE) on biochemical
and behavioral deficits in alloxan-induced diabetic mice. The
results showed that MFE exerts antidiabetic and neuropro-
tective effects by upregulating antioxidative activities and
the p-CREB/BDNF pathway.
Research article: “FNDC5 Attenuates Oxidative Stress
and NLRP3 Inflammasome Activation in Vascular Smooth
Muscle Cells via Activating the AMPK-SIRT1 Signal Path-
way.”In this study, B. Zhou et al. evaluated the protective role
of fibronectin type III domain-containing 5 (FNDC5) in
angiotensin II- (Ang II-) induced vascular oxidative stress
and inflammation. The results revealed that FNDC5 defi-
ciency aggravates while exogenous FNDC5 alleviates the
Ang II-induced vascular oxidative stress and NLRP3 inflam-
masome activation via the AMPK-SIRT1 signal pathway in
vascular smooth muscle cells.
Research article: “Inhibition of P2X7 Purinergic Receptor
Ameliorates Cardiac Fibrosis by Suppressing NLRP3/IL-1β
Pathway.”J. Zhou et al. examined the involvement of P2X7
purinergic receptor (P2X7R) in the development of cardiac
fibrosis using a transverse aortic constriction (TAC) mouse
model and cardiac fibroblasts (CFs) hyperstimulated by
TGF-β1 for 48 h. P2X7R activation promoted cardiac fibro-
sis, and its inhibition protected against CF activation and car-
diac fibrosis by modulating the NLRP3/IL-1βpathway.
Research article:“Inhibition of JNK Alleviates Chronic
Hypoperfusion-Related Ischemia Induces Oxidative Stress
and Brain Degeneration via Nrf2/HO-1 and NF-κB Signal-
ing.”M. S. Khan et al. aimed to determine redox imbalance
and c-Jun N-terminal kinase-associated detrimental effects
in chronic ischemia and the inhibitory effect of a specific
JNK inhibitor (SP600125) on JNK-mediated brain degenera-
tion in adult mice. The results indicated that the inhibition of
JNK reduced neurodegeneration and regulated cognitive dys-
function in the chronic ischemic mouse model.
Research article: “PARK7 Diminishes Oxidative Stress-
Induced Mucosal Damage in Celiac Disease.”A. Veres-
Székely et al. investigated the role of increased Parkinson’s
disease 7 (PARK7) levels on the epithelial cell and mucosal
integrity of the small intestine. PARK7 induced the expres-
sion of stress-response elements, and PARK7-binding
Comp23 reduced the oxidative damage of duodenal epithelial
cells by upregulating Nrf2- and P53-regulated genes.
Clinical study: “The Beneficial Effects of Alpha Lipoic
Acid Supplementation on Lp-PLA2 Mass and Its Distribu-
tion between HDL and apoB-Containing Lipoproteins in
Type 2 Diabetic Patients: A Randomized, Double-Blind,
3Oxidative Medicine and Cellular Longevity

Placebo-Controlled Trial.”N. Baziar et al. aimed to investi-
gate the effect of alpha-lipoic acid (ALA) on the
lipoprotein-associated phospholipase A2 (Lp-PLA2) mass
and its distribution in diabetic patients. They concluded
that ALA may decrease the cardiovascular risk in type 2
diabetic patients by reducing the oxidized low-density lipo-
protein (ox-LDL) and Lp-PLA2 mass and improving the
Lp-PLA2 distribution among lipoproteins in type 2 dia-
betic patients.
Review article: “Unveiling the Role of Inflammation and
Oxidative Stress on Age-Related Cardiovascular Diseases.”
In this review, A. J. P. Oliveira de Almeida et al. discussed
the basics of inflammation and oxidative stress, including
the crosstalk between them, and the implications on age-
related cardiovascular diseases. The authors recommended
therapies counteracting oxidative stress and inflammation
without inhibiting their physiological functions as promising
targets in the search for healthy aging.
Review article: “PGC-1α,Inflammation, and Oxidative
Stress: an Integrative View in Metabolism.”S. Rius-Pérez
et al. highlighted the role and pathways of peroxisome
proliferator-activated receptor-γcoactivator- (PGC-) 1αas
a transcriptional coactivator. The review introduced a sum-
mary of the role of PGC-1αacting as an interesting therapeu-
tic target and an essential node connecting metabolic
regulation, redox control, and inflammatory pathways.
Review article: “Targeting Inflammatory-Mitochondrial
Response in Major Depression: Current Evidence and Fur-
ther Challenges.”A. P. V. Visentin et al. provided a review
of major depressive disorder and its association with inflam-
mation, mitochondrial dysfunction, and oxidative stress and
discussed the putative links between these events. They
highlighted the need of new investigations focusing on the
antidepressant effects of antioxidants.
Review article: “Coumarins as Modulators of the
Keap1/Nrf2/ARE Signaling Pathway.”E. H. M. Hassanein
et al. provided a review compiling the research findings of
seventeen coumarin derivatives of plant origin as antioxidant
and anti-inflammatory agents, emphasizing the role of Nrf2
activation in their pharmacological activities. They utilized
molecular docking simulations to investigate the potential
binding mode of these coumarins with Keap1 as a strategy
to disrupt Keap1/Nrf2 protein-protein interaction and acti-
vate Nrf2 signaling.
Review article: “Adjuvant Therapies in Diabetic Retinop-
athy as an Early Approach to Delay Its Progression: The
Importance of Oxidative Stress and Inflammation.”In this
review, R. R. Robles-Rivera et al. focused on the promising
values of nutraceuticals and different compounds as an adju-
vant approach in the treatment of diabetic retinopathy to
diminish its progression.
Review article: “Potential Protective and Therapeutic
Roles of the Nrf2 Pathway in Ocular Diseases: An Update.”
Here, M. Wang et al. focused on the possible involvement
of Nrf2, a redox-sensitive transcription factor, in the occur-
rence and development of ocular diseases. They have also
discussed the role of noncoding RNAs and exogenous com-
pounds, which control the expression of Nrf2 through differ-
ent pathways, in ocular diseases.
The editors anticipate this special issue to be of inter-
est to the readers and expect researchers to benefit from
making further progress in understanding the mechanisms
of oxidative stress and inflammation crosstalk in different
diseases and the therapeutic potential of antioxidants.
Conflicts of Interest
The editors declare that they have no conflicts of interest
regarding the publication of this special issue.
Acknowledgments
We would like to thank the authors for submitting their
insightful and interesting research for publication and the
reviewers for sharing their expertise, constructive critiques,
and their contributions to improve the manuscripts.
Ayman M. Mahmoud
Fiona L. Wilkinson
Mansur A. Sandhu
Adam P. Lightfoot
4 Oxidative Medicine and Cellular Longevity