1 s2.0 S1568163720302737 Main PDF
1 s2.0 S1568163720302737 Main PDF
1 s2.0 S1568163720302737 Main PDF
PII: S1568-1637(20)30273-7
DOI: https://doi.org/10.1016/j.arr.2020.101138
Reference: ARR 101138
Please cite this article as: Scassellati C, Galoforo AC, Bonvicini C, Esposito C, Ricevuti G,
Ozone: a natural bioactive molecule with antioxidant property as potential new strategy in
aging and in neurodegenerative disorders, Ageing Research Reviews (2020),
doi: https://doi.org/10.1016/j.arr.2020.101138
This is a PDF file of an article that has undergone enhancements after acceptance, such as
the addition of a cover page and metadata, and formatting for readability, but it is not yet the
definitive version of record. This version will undergo additional copyediting, typesetting and
review before it is published in its final form, but we are providing this version to give early
visibility of the article. Please note that, during the production process, errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal
pertain.
Catia Scassellatia,*,§ , Antonio Carlo Galoforob*, Cristian Bonvicinic, Ciro Espositod, and Giovanni
Ricevutie
a
Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia,
Italy
b
Oxygen-Ozone Therapy Scientific Society (SIOOT), Gorle, Italy; University of Pavia, Pavia, Italy
c
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli,
of
Brescia, Italy
d
Department of Internal Medicine and Therapeutics, University of Pavia, Italy; Nephrology and
ro
dialysis unit, ICS S. Maugeri SPA SB Hospital, Pavia, Italy; High School in Geriatrics, University
of Pavia, Italy
e
-p
Department of Drug Sciences, University of Pavia, Italy; P.D. High School in Geriatrics,
re
University of Pavia, Italy, St.Camillus Medical University, Rome, Italy
lP
§ Corresponding author:
IRCCS Centro S. Giovanni di Dio Fatebenefratelli, Via Pilastroni 4, Brescia 25123, Italy.
na
E-mail: c.scassellati@fatebenefratelli.eu
Highlights
Jo
persist.
1
• A plethora of scientific evidence supports other crucial properties of O3 in
physiopathological processes.
neurodegenerative disorders.
of
Abstract
ro
-p
Systems medicine is founded on a mechanism-based approach and identifies in this way
specific therapeutic targets. This approach has been applied for the transcription factor nuclear
re
factor (erythroid-derived 2)–like 2 (Nrf2). Nrf2 plays a central role in different pathologies
lP
features. We here present wide scientific background indicating how a natural bioactive molecule
with antioxidant/anti-apoptotic and pro-autophagy properties such as the ozone (O3) can represent a
na
potential new strategy to delay neurodegeneration. Our hypothesis is based on different evidence
demonstrating the interaction between O3 and Nrf2 system. Through a meta-analytic approach, we
ur
improves blood circulation, and has antimicrobial activity, with potential effects on gut microbiota.
Thus, we provides a consistent rationale to implement future clinical studies to apply the oxygen-
ozone (O2-O3) therapy in an early phase of aging decline, when it is still possible to intervene before
to potentially develop a more severe neurodegenerative pathology. We suggest that O3 along with
2
other antioxidants (polyphenols, mushrooms) implicated in the same Nrf2-mechanisms, can showed
neurogenic potential, providing evidence as new preventive strategies in aging and in NDs.
Ozone (O3); Oxygen-Ozone (O2-O3) therapy; antioxidant system; stress oxidative biomarkers.
1. Introduction
Life span has almost doubled in the last century (WHO, 2011, Wyss-Coray, 2016), and
consequently aging-specific diseases are becoming prevalent (Moskalev et al., 2017). However, the
pathophysiologic mechanisms underlying most of them are still poorly understood and challenges
of
regarding treatments efficacy and costs persist.
ro
amyotrophic lateral sclerosis, ALS, Huntington Disease, HD) are the most prevalent cognitive and
-p
motor disorders of the elderly. These aging-specific diseases are characterized by the loss of
homeostasis during aging, leading to low-grade stress by pathologic formation of Reactive Oxygen
re
Species (ROS), chronic inflammation, mitochondrial dysfunction and metabolic unbalance (Dugger,
lP
specific proteins (Yanar et al., 2020), given the connection between excessive ROS accumulation
Despite their distinct causative factors and clinical symptoms, these diseases as well as
aging have common pathogenetic features (Aso et al., 2012). This implicates potentiality in the
ur
identification of therapeutic targets on a set of disease phenotypes and physiological conditions that
Jo
are mechanistically linked. Thus, contrary to a hitherto linear approach that considered one disease,
one medicine, to date there is a need for a new concept of therapy condensed as “several diseases,
one medicine”. In this way, diseases are diagnosed not only by clinical symptoms, but mainly by
the underlying molecular signatures (Goh et al., 2007). Based on this network medicine approach,
(Cuadrado et al., 2018, Cuadrado et al., 2019) reported extensive evidence about the central role
playing by nuclear factor (erythroid-derived 2)–like 2 (Nrf2). Nrf2 is widely known and
3
investigated as a master regulator of multiple cytoprotective responses and as a key molecular node
within a cluster of a wide spectrum of diseases, including NDs. Moreover, Nrf2 activation is
impaired in aging by the involvement of microRNA (Zhang, H. et al., 2015, Schmidlin et al., 2019,
Silva-Palacios et al., 2018). This suggests that Nrf2 could represent a common therapeutic and
systems medicine target, for aging and for its related disorders. Nrf2 can transcriptionally modulate
the cytoprotective genes belonging to the vitagene network. This network regulates endogenous
cellular defense mechanisms, and involves redox sensitive genes such as members of the Heat
Shock Proteins (HSP) family (heme-oxigenase HO-1, Hsp70), but also sirtuins and the thioredoxin
of
(Trx)/thioredoxin reductase (TrxR1) system (Calabrese, V. et al., 2010).
Based on this rationale, in this review we present wide scientific background indicating how
ro
a natural bioactive molecule with antioxidant property such as the ozone (O3) can be indicated as a
-p
potential new strategy to delay neurodegeneration. This hypothesis is based on the widely
demonstrated evidence regarding the interaction between O3 and Nrf2 (Galie et al., 2018, Siniscalco
re
et al., 2018, Re et al., 2014, Vaillant et al., 2013). We first describe the relevant, well known and
lP
targeted by the O3 administration via Nrf2 biological pathway. Secondarily, we report a list of the
main stress oxidative biomarkers modulated by the O3 treatment via Nrf2 and that, in turn are
na
have been performed to demonstrate the effect in terms of Odd Ratio (OR) of O3 on endogenous
ur
We thus provide scientific evidence to build a consistent rationale for apply for the first time
the Oxygen-Ozone (O2-O3) therapy in an early phase of aging decline, when it is still possible to
O3 is a triatomic gaseous molecule which has been using as a powerful oxidant in medicine
for more than 150 years (Elvis, Ekta, 2011). In nature, O3 is generated during storms due to the
4
electrical discharges of the rays that react with atmospheric O2 to produce O3. In humans, a
revolutionary discovery leaded to demonstrate that neutrophils isolated from human peripheral
blood and coated with antibodies can catalyse the generation of O3 by a water oxidation pathway,
leading to efficient killing of bacteria (Wentworth et al., 2002, Babior et al., 2003, Lerner,
Eschenmoser, 2003).
In 1785, Van Mauren was the first identifying the distinctive odor of O3. The actual gas was
later discovered by the German chemist, Christian Friedrich Schonbein at the University of Basel in
Switzerland on March 13th, 1839 when working with a voltaic pile in the presence of O2 (Altman,
of
2007). Friederich noticed the emergence of a gas with an electric and pungent smell, and named it
ozone, which is derived from the Greek word for smell (Bocci, V., 2011). In 1860, Jacques-Louis
ro
Soret, a Swiss chemist demonstrated that the O3 was made up of three atoms of oxygen (Altman,
-p
2007). O3 was used as first antiseptic for operating rooms and to disinfect surgical instruments in
1856, and in 1860 the first O3 water treatment plant was built in Monaco to disinfect water (Altman,
re
2007). Nikola Tesla patented the first portable O3 generator in 1896 in the United States. The
lP
physicist, Joachim Hansler invented the first reliable O3 generator, and this was the breakthrough in
the use of O3 for medical applications. This invention is considered the prelude to the ozonated
autohemotherapy procedure and served as the basis for O3 therapy expansion over the last 40 years.
na
The use of O3 in the clinical practice was introduced in the past century (Wolff, 1915).
During the World War I, from 1914 to 1918, doctors used O3 to successfully treat post traumatic
ur
gangrene in German soldiers, bone fractures, inflammations, and abscesses (Bocci, 2011). Due to its
Jo
prophylactic proprieties, O3 was also used to prevent infections in local medical procedures and to
procedure applied in medicine for the treatment of more than 50 pathological processes, whose
dDifferent clinical trials evidenced the effectiveness of this therapy in the treatment of degenerative
5
disorders such as multiple sclerosis (Smith et al., 2017, Delgado-Roche et al., 2017, Ameli et al.,
2019), but also cardiovascular, peripheral vascular, neurological, orthopaedic, gastrointestinal and
genitourinary pathologies (Bocci, V., 2011, Elvis, Ekta, 2011, Re et al., 2008, Bocci, V., 2012,
Smith et al., 2017, Braidy et al., 2018); fibromyalgia (Moreno-Fernandez et al., 2019, Tirelli et al.,
2019); skin diseases/wound healing (Fitzpatrick et al., 2018, Wang, X., 2018); diabetes/ulcers
(Martinez-Sanchez et al., 2005, Guclu et al., 2016, Rosul, Patskan, 2016, Izadi et al., 2019,
Ramirez-Acuna et al., 2019); infectious diseases (Smith et al., 2017, Mandhare et al., 2012, Song et
al., 2018), including the recent global pandemic disease of coronavirus disease 2019 (COVID-19)
of
(Zheng et al., 2020); dentistry (Isler et al., 2018, Khatri et al., 2015, Srikanth et al., 2013,
Azarpazhooh et al., 2009); lung diseases (Hernandez Rosales et al., 2005); osteomyelitis (Bilge et
ro
al., 2018). The potential role of O2-O3 as an adjuvant therapy for cancer treatment has been also
-p
suggested in in vitro and animal studies as well as in isolated clinical reports (Clavo et al., 2018).
At present, we have commenced a randomized double-blind clinical trial with the aim to test
re
the efficacy of this therapy in a cognitive frailty cohort, a grant approved by the Italian Minister of
lP
Health (RF-2016-02363298). This pilot study will permit to validate the O2-O3 therapy in an early
phase of cognitive decline, when it is still possible to intervene, before to develop a potential
neurodegenerative pathology.
na
To date, the O2-O3 therapy acquires a further prestigious significance, after the medicine
Nobel prize for “discovery of how cells sense oxygen” in 2019. Indeed, O2 is the most vital element
ur
required for human life and it is the key to good health; O3 is O2 with an extra molecule added. The
Jo
O2 availability affects genes expression of different factors (HIFs, Hypoxia Inducible Factors),
leading to the activation of trophic proteins (VEGF, Vascular Endothelial Growth Factor; PDGF,
erythropoiesis, angiogenesis and anaerobic glucose metabolism (Zhou et al., 2019). O3 plays a role
of cellular adapter to hypoxia, because it is well known its effects in increasing the levels of VEGF,
6
PDGF, HIF (Curro et al., 2018, Zhang, J. et al., 2014, Re et al., 2010), exactly as the cell does when
there is no O2 available.
Oxidative stress is a condition where ROS and Nitrogen Species (RNS) production exceeds
the cellular antioxidant defence system, leading to the imbalance between the two systems and this
may contribute to the neuronal damage and the abnormal neurotransmission. It is widely known its
implication in the pathogenesis and progression of NDs (Singh et al., 2019). Brain and
mitochondria are the most involved systems due to their high sensitivity to oxidative damage caused
of
by free radicals. Oxidative damage may impair the cells in their structure and function, being cause
and effect of a mitochondrial reduced activity. The damage is not confined to the brain but also
ro
evident in peripheral cells and tissues.
-p
ROS and RNS are also major factors in cellular senescence that leads to increase number of
senescent cells in tissues on a large scale (Liguori et al., 2018). Cellular senescence is a
re
physiological mechanism that stops cellular proliferation in response to damages that occur during
lP
(SASP), involving secretion of soluble factors (interleukins, chemokines, and growth factors),
factors. Under basal condition, Nrf2 binds to its repressor Keap1 (Kelch-like ECH-associated
Jo
protein 1), an adapter between Nrf2 and Cullin 3 protein, which leads to ubiquitination followed by
proteasome degradation. This Keap1-mediated degradation activity requires two reactive cysteine
PUFA (polyunsaturated fatty acids), leading to the formation of the two fundamental messengers:
hydrogen peroxide (H2O2) as a ROS and 4-hydroxynonenal (4HNE) as a lipid oxidation product
7
(LOP) (Bocci, V. et al., 1998) (Figure 1). ROS are the early and short-acting messengers, while
LOPs are late and long-lasting messengers. LOPs diffuse into all cells and inform them of a
minimal oxidative stress. After the oxidative/electrophilic stress challenge (4HNE, (Ishii et al.,
2004), other aldehydes (Levonen et al., 2004), induced by O3 (Galie et al., 2018, Siniscalco et al.,
2018, Re et al., 2014, Vaillant et al., 2013), modification of the cysteine residues of Keap1 (S-HNE
or―S―S) inhibits ubiquitin conjugation to Nrf2 by the Keap1 complex (Brigelius-Flohe, Flohe,
2011), provoking the nuclear accumulation of Nrf2. Once in the nucleus, Nrf2 dimerizes and binds
to cis-acting DNA AREs (Antioxidant Response Elements) in genes such as Heme Oxygenase 1
of
(HO-1), a gene encoding enzyme that catalyses the degradation of heme in carbon monoxide (CO)
and free iron, and biliverdin to bilirubin. CO acts as an inhibitor of another important pathway NF-
ro
κB (Nuclear Factor Kappa B Subunit 1) signalling, which leads to the decreased expression of pro-
-p
inflammatory cytokines, while bilirubin also acts as an important lipophilic antioxidant.
Furthermore, HO-1 directly inhibits the pro-inflammatory cytokines and activating the anti-
re
inflammatory cytokines, thus leads to balancing of the inflammatory process (Ahmed, S. M. et al.,
lP
2017). Our research group confirmed that mild ozonisation, tested on in vitro systems, induced
In addition, Nrf2 regulates also the constitutive and inducible expression of antioxidants
including, but not limited to, Superoxide Dismutases (SOD), Glutathione Peroxidase (GSH-Px),
ur
phase II enzymes of drug metabolism and HSPs (Galie et al., 2018, Bocci, V., Valacchi, 2015,
Jo
A further mechanism involves casein kinase 2 (CK2), another regulator of the Nrf2 activity
through its phosphorylation. It has been demonstrated that O3 influenced the CK2 levels together
with Nrf2 phosphorylation, reducing oxidative stress and pro-inflammatory cytokines in multiple
sclerosis patients (Delgado-Roche et al., 2017). Similarly, O3 inhibits oxidative stress through
8
inhibition of the mitogen-activated protein kinase phosphatase (MAPK) 1 signalling pathway
Oxidative stress is one of the major drivers of protein misfolding that, accumulating and
aggregating as insoluble inclusions can determine neurodegeneration (Hohn et al., 2020, Knowles et
al., 2014). It is known that Nfr2 promotes the clearance of oxidized or otherwise damaged proteins
through the autophagy mechanism (Tang et al., 2019). Interestingly, also O3 can modulate the
degradation protein systems, not only via Nrf2 pathway, but also via activation of the AMP-
of
demonstrated in (Zhao, X. et al., 2018) (Figure 1B).
O3 can protect against overproduction of nitric oxide (NO), when NO is a toxic oxidant. NO
ro
can rapidly react with other free radicals such as O2−• to generate highly reactive oxidant
-p
peroxinitrite (ONOO−) and other RNS, which in turn damages the biomolecules (e.g., lipids,
protein, DNA/RNA), playing thus a key role in chronic inflammation and neurodegeneration
re
(Massaad, 2011, Toda et al., 2009). It has been demonstrated that O3 downregulates inducible nitric
lP
oxide synthase (iNOS), which generates NO (Manoto et al., 2018, Smith et al., 2017) via NF-κB
property
Mitochondrial dysfunction is one of the main features of the aging process, particularly in
ur
organs requiring a high-energy source such as the heart, muscles, brain, or liver. Neurons rely
Jo
almost exclusively on the mitochondria, which produce the energy required for most of the cellular
cause increase in ROS for lowered oxidative capacity and antioxidant defence, with consequent
increased oxidative damage to protein and lipids, decreased ATP production and accumulation of
DNA damage (Garcia-Escudero et al., 2013, Reutzel et al., 2020). Moreover, mitochondrial
9
bioenergetic dysfunction and release of pro-apoptotic mitochondrial proteins into the cytosol initiate
Nrf2 transcribes several genes not only those implicated in antioxidant expression and
energy regulation, but also those involved in mitochondria biogenesis: increases the mitophagy,
permeability transition pore opening (Holmstrom et al., 2016). Multiple lines of evidence have
shown that Nfr2 activation is part of the retrograde response aimed at restoring mitochondrial
functions after stress insults, and that the impairment of Nrf2 functions is a hallmark of many
of
mitochondrial-related disorders (Shan et al., 2013).
It has been demonstrated that O3 administration can act on specific mechanisms to promote
ro
cell survival and proliferation, blocking the apoptotic processes. In particular, O3 decreases the
-p
expression of caspases 1-3-9, HIFα, Tumor Necrosis Factor-a (TNF-α), Bcl-2-associated X protein
(Bax), poly (ADP-ribose) polymerase 1 (PARP-1) and p53 genes (Figure 2) (Yong et al., 2017,
re
Guclu et al., 2016, Wang, L. et al., 2018). Bax is located in the mitochondrial membranes and exerts
lP
pro-apoptosis effect through the mitochondrial pathway, promoting cytochrome C activation (Mac
Nair et al., 2016); p53 and Caspase-3 are executive molecules of apoptosis by blocking cell cycle
(Wang, J. et al., 2016). Enzymes such as SOD, CAT, and GSH-Px, can regulate p53, Bax and Bcl-2
na
Moreover, O3 stimulates the Kreb’s cycle in the mitochondria by enhancing the oxidative
ur
carboxylation of pyruvate and stimulating the production of adenosine triphosphate (ATP) (Guven
Jo
et al., 2008). It also causes a significant reduction of nicotinamide adenine dinucleotide (NADH), an
increase of the coenzyme A levels to fuel the Kreb’s cycle and oxidizes cytochrome C (Brigelius-
O3 treatment was proven to reduce mitochondrial damage in a rat heart following ischemia-
reperfusion (Meng et al., 2017), as well as in a rat brain and cochlea following noise-induced
10
hearing loss (Nasezadeh et al., 2017). Moreover, in vitro, O3 increased the length of the
mitochondrial cristae and the content of mitochondrial Hsp70 (Costanzo et al., 2018).
and vitagene systems are showed in Table 1. These biomarkers have been studied and found
modulated after the O2-O3 therapy in more of 150 studies performed in different in vivo (human and
of
animal models) and in vitro samples and conditions. In Table 1, we also reported the relative
ro
From these 29 biomarkers, we focused, in this section, on those implicated in endogenous
-p
antioxidant-Nrf2 pathway (GSH; GSH-Px; glutathione reductase, GR; SOD; CAT; 4HNE;
Advanced Oxidation Protein Products, AOPP in bold in Table 1). Where it was possible (available
re
studies), we performed meta-analyses for these biomarkers on human (see supplementary material).
lP
after Bonferroni correction 0.05/6=0.0083). Similar results were obtained even considering single
na
markers, except for GR (Z=1.04; p=0.30) and GSH (Z = 0.80, p=0.42). GR has been investigated
only in two studies, coming from the same authors (Hernandez Rosales et al., 2005). Thus, there are
ur
not enough evidence on its single real involvement. Concerning GSH, Diaz-Luis et al., (Díaz-Luis
Jo
et al., 2018) is the only study showing a negative effect of O3. As we followed the criteria for which
the data were extracted before and after O3 treatment (see supplementary material), this study found
an increased GSH levels after O3 administration, only when the authors performed the comparisons
with control group of healthy subjects (in a sort of postconditioning). Thus, if we eliminated this
study, the results of the single meta-analysis of GSH highlighted its positive increase determined by
these meta-analyses. This is essentially explained by the presence of different factors: the type of
Although there are contrasting results, most of the studies agree on the decrease in tissue
oxidation protein products; AOPP), and increase in the tissue levels of antioxidants (antioxidant
of
defense markers —for instance GSH; SOD; CAT; GSH-Px; TH; glutathione disulfide, GSSG;
Ferric Reducing the Ability of Plasma (FRAP), after O3 administration, maintaining in this way
ro
antioxidant–prooxidant balance by the O2-O3 therapy.
-p
Interestingly, different studies have been performed on aging-specific conditions. A recent
work (El-Mehi, Faried, 2020) demonstrated that antioxidant properties of O3 can ameliorate age-
re
associated structural alterations of the rat cerebral cortex, improving age- related oxidative stress
lP
reflected in the histopathological and immunohistochemical alterations. The authors detected severe
structural and cellular neurodegenerative changes in the frontal cortex of the aged rats. O3
oxidative stress, and upregulation of GSH, SOD and CAT. Similarly, O3 influenced iNOS, caspase-
3, glial fibrillary acidic protein (GFAP), Ki67 and acetylcholinesterase (AChE). These findings
ur
indicate reduction not only in oxidative stress, but also in apoptosis (down-regulation caspase-3)
Jo
67 expression) and in cholinergic plasticity (decrease AChE activity). The authors suggest that O3
might be useful for improving the age – related cognitive and memory deterioration, by increasing
cholinergic communication.
Safwat et al. (Safwat et al., 2014) demonstrated that O3 showed a beneficial effect on the
aging reducing liver and kidney damage through its antioxidant property. O3 was efficient in
12
elevating the reduced hepatic and renal GSH contents as well as in normalizing hepatic GSH-Px
activity of aged rats. Moreover, O3 succeeded in attenuating the elevated hepatic and renal MDA
Another work (El-Sawalhi et al., 2013) reported that O3 alleviated age-associated redox state
imbalance, as evidenced by reduction of lipid and protein oxidation markers and lessening of
lipofuscin deposition. Moreover, O3 restored GSH levels in brain and heart tissues, and normalized
GSH-Px activity in the heart tissue of the aged-rats. O3 also mitigated age-associated energy failure
in the heart and the hippocampus, improved cardiac cytosolic Ca(2+) homeostasis and restored the
of
attenuated Na(+) , K(+) -ATPase activity in the hippocampus of these rats.
ro
adenosine triphosphate/adenosine diphosphate ratio, mitochondrial SOD and complex IV
-p
(cytochrome-c oxidase) activities. O3 improved glutathione redox index (GSHRI), complex I
(NADH-ubiquinone oxidoreductase) and mitochondrial mtNOS activities, and attenuated the rise
re
MDA and mitochondrial PC levels (Shehata et al., 2012).
lP
administration in the mechanisms of aging (Table 1). We prevalently focused on those implicated in
na
It has been reported that the levels of lipid peroxidation products, reactive carbonyl
ur
compounds, such as 4HNE, are increased in aging tissues (Csala et al., 2015), and this increase is
Jo
positively correlated with age. Impaired protein function, manifested as an increase in PC, plays a
crucial role in aging processes (Cabiscol et al., 2014). With increase of PC, the spontaneous
carbonyl-amino crosslinking and accumulation were mostly irreparable changes associated with
2012, Rusanova et al., 2018, Qing et al., 2012, Silva et al., 2015, Muller et al., 2015). A recent work
13
investigated the antioxidant enzymes (GSH-Px, CAT, SOD), nonenzymatic antioxidants (GR),
redox status (total antioxidant capacity, TAC, total oxidant status, TOS, oxidative stress index,
OSI), and oxidative damage products (AOPP, MDA) in a healthy sample divided according to age:
2-14 (children and adolescents), 25-45 (adults), and 65-85 (elderly people). They demonstrated that
salivary and blood antioxidant defense is most effective in adults. Contrarily, a progressive decrease
in the efficiency of central antioxidant systems (↓GSH-Px, ↓SOD, ↓GSH, ↓TAC in erythrocytes and
plasma vs. adults) was observed in the elderly. Both local and systemic antioxidant systems were
less efficient in children and adolescents than in the group of middle-aged people, which indicates
of
age-related immaturity of antioxidant mechanisms. Oxidative damage to proteins (↑AOPP) and
lipids (↑MDA) was significantly higher in saliva and plasma of elderly people in comparison with
ro
adults and children/adolescents (Maciejczyk et al., 2019). Similarly, Cakatay et al. (Cakatay et al.,
-p
2008) found, in a young, middle-aged and elderly individuals, PCO and AOPP levels of the elderly
and middle aged individuals higher compared with those of the young.
re
Although not involved in Nrf2 signaling but influenced by O3 treatment, the increased
lP
formation, represents the most common hallmark of the aging brain, marker of oxidative DNA
damage. The simultaneous increased oxidation of mtDNA and deficiency of DNA repair could
na
enhance the lesion to mitochondrial genome, potentially causing neuronal damages (Mecocci et al.,
2018).
ur
Several evidence support the implication of the pro-oxidation and antioxidant defence
for NDs, we prevalently focused on those implicated in the Nrf2 signalling (in bold in Table 1).
leads to the impairment of daily and routine activities. It is one of the most prevalent NDs
14
manifesting 45 million people worldwide. AD is characterized by the deposition of protein
aggregates, extracellular amyloid plaques (A), intracellular tau () or neurofibrillary tangles, and
loss of synaptic connections in specific regions of brain (Schipper, 2010, Mattson, 2004, Selkoe,
oligomer peptides, which, along with protein, mediates neurodegeneration, thus causing
Different studies indicate the relationship between A-induced oxidative imbalance and
of
elevated levels of by-products of lipid peroxidation (e.g., 4HNE, MDA), protein oxidation (e.g.,
ro
carbonyl), and DNA/RNA oxidation (e.g., OH8dG) (Wang, X. et al., 2014, Zhao, Y., Zhao, 2013,
Pratico, 2008, Mecocci et al., 2018). These alterations were observed also in peripheral
-p
lymphocytes and lymphocyte mitochondria (for review (Mecocci et al., 2018). Higher levels of PC,
measured in mitochondria extracted from lymphocytes, have been observed in AD (for review
re
(Mecocci et al., 2018).
lP
Decreased levels of antioxidant enzymes like SOD, CAT, GSH and GSSG, decreased ratio
observed in blood or brain of AD patients (Singh et al., 2019, Liu et al., 2004, Kim et al., 2006,
The RNS such as NO are also found to have a deleterious effect on neurons. Indeed, RNS
elevation has been observed both in astrocytes as well as in neurons in an AD brain (for review
Jo
(Singh et al., 2019). An increase in the expression of neuronal nNOS or NOS-1, cytokine-inducible
iNOS or NOS-2, and endothelial eNOS or NOS-3 isozymes has been observed in AD astrocytes.
The direct association of iNOS and eNOS with A aggregates indicating towards beta amyloid
assisted in the induction of NOS to produce NO, which in turn leads to the formation of 3-
15
Other findings reported increased levels of CK2 in the hippocampus and temporal cortex of
AD patients (Rosenberger et al., 2016) and increased levels in AOPP (Can et al., 2013, Altunoglu et
al., 2015), compared to non-demented controls. It has been observed that AD patients show an
increased oxidation of red blood cells GSH, which indicates oxidative stress in peripheral cells, and
an increased level of plasma thiobarbituric acid reactive substances (TBARS), which indicates a
higher free radical oxidation of plasma unsaturated phospholipids (Vina et al., 2005).
Moreover, HO-1 has been proposed as systemic marker in early sporadic AD (Schipper et
al., 2000). Indeed, plasma HO-1 protein levels are significantly decreased in patients with probable
of
sporadic AD (Schipper, 2007). The up-regulation of HO-1 in AD brain can be explained because of
local oxidative stress. Instead, the mechanism responsible for the downregulation of HO-1 in the
ro
blood of AD patients remains unclear, even though the existence of a HO-1 suppressor that inhibits
-p
HO-1 mRNA levels in the lymphocytes in AD plasma has been proposed (Maes et al., 2006).
However, the results about HO-1 plasma levels in patients with AD are controversial. A study
re
founds no changes in the serum level of HO-1 in a big cohort of AD patients, as compared with
lP
elderly control subjects, whereas increased level were observed in PD patients, highlighting
different mechanisms involved in the peripheral response to oxidative stress in the two diseases
(Mateo et al., 2010). Moreover, another study reports that in plasma of probable AD patients, both
na
HO-1 and biliverdin reductase (BVR) levels are increased because of the enhanced oxidative stress.
The authors suggested that plasma BVR status, more than HO-1, can represent a potential
ur
biochemical marker for the prediction of AD at the earliest stages of disease (Di Domenico et al.,
Jo
characterized by the progressive degeneration of the dopaminergic neurons located in the substantia
nigra (SN) pars compacta (Spillantini et al., 1998) which affects movement. The main
forms of the presynaptic protein α-synuclein (αSyn; a small protein with 140 amino acids abundant
in presynaptic nerve terminals) (Spillantini et al., 1998). αSyn plays a role in synaptic transmission
and dopamine levels adjustment. αSyn primarily affect tyrosine hydroxylase phosphorylation and
activity and the expression level of dopamine transporter on the cell membrane.
Different evidence supported the involvement of the pro-oxidation and antioxidant defence
biomarkers influenced by O3 listed in Table 1 also with PD (focus on Nrf2). Altered levels of GSH
and GSSG, decreased ratio of GSH/GSSG, and/or impaired expressions or activities of GSH-related
of
enzymes have been detected in PD (Liu et al., 2004). TOS and OSI levels were found higher in the
ro
RNS also plays major role in nitrosative stress in PD. NO, produced by nNOS or iNOS was
-p
found in large quantities in cells, as well as in the extracellular space around dopaminergic neurons
(Tieu et al., 2003). It has been observed that in PD brains, NO obstructs various enzymes including
re
complex I and IV of the mitochondrial electron transport chain, hinders the function of proteins by
lP
forming S-nitrosothiols, mediates lipid peroxidation, resulting in elevated levels of ROS and brain
deteriorating effect. In situ hybridization and immunohistochemical studies also established the role
of NO in PD via postmortem brain tissue analysis, which indicates an elevated level of iNOS and
na
nNOS in basal ganglia structures (Eve et al., 1998, Hunot et al., 1996). ONOO- has been shown to
inhibit the presynaptic dopamine transporter, which mediates the uptake of dopamine from the
ur
synaptic cleft to stop dopamine signalling, and to refill the dopamine vesicles. Its inactivation will
Jo
Oxidative damage in nucleic acids is likely to be a major risk factor for PD (Bosco et al.,
2006, Puspita et al., 2017). Oxidative DNA lesions, such as 8-oxoguanine (8-oxoG), accumulate in
nuclear and mitochondrial genomes during aging, and such accumulation can increase dramatically
neuron disease; it is sometimes called Lou Gehrig’s disease, after the famous baseball player who
had this condition. ALS is characterized by the progressive degeneration of upper and lower motor
neurons in the spinal cord, cortex, and brainstem (Kikuchi et al., 2002). Although for most of the
last 2 decades mutation of Cu–Zn SOD1 was the only genetic aberration associated with the onset
of familial ALS, recent studies have discovered additional abnormalities associated with the onset
of sporadic and non-SOD1 familial ALS. These include a host of RNA/DNA-binding proteins such
as the 43-kDa transactive response (TAR) DNA-binding protein (TDP-43) and the fused in
of
sarcoma/translocated in liposarcoma (FUS/TLS). The most common genetic mutation is identified
as expanded GGGGCC hexanucleotide repeat in the non-coding region of the C9Orf72 gene located
ro
on chromosome 9p21 (Mendez, Sattler, 2015).
-p
Wang et al., (Wang, Z. et al., 2019) reported increased blood levels of 8-OHdG, MDA, and
AOPP and decreased GSH and uric acid levels in the peripheral blood of ALS patients. These
re
biomarkers have been found in sporadic ALS patient’s urine, cerebrospinal fluid (CSF), blood, and
lP
individual tissues.
HD named after George Huntington in 1872, is a fatal and autosomal dominant inherited
na
by deterioration of the cerebral cortex and thalamus. HD is caused by a mutation in the huntingtin
ur
repeat in this gene, which in turn translates into an abnormally long repeat of polyglutathione in the
mutant huntingtin protein. HD is mainly characterized by impaired motor and cognitive traits,
Lipid peroxidation, DNA damage, and specifically protein carbonylation were found to be
more pronounced in HD (Tunez et al., 2011). Dysregulation in cysteine metabolism was observed
in HD (Paul et al., 2018). Cysteine plays vital roles in redox homeostasis, being a component of the
18
major antioxidant GSH and a potent antioxidant by itself. In HD patients, decreased GSH levels and
increased lipid peroxidation was observed as compared with controls (Oliveira, Laurindo, 2018). In
postmortem brain specimens of HD, a twofold increase of OH8dG in mtDNA was found in the
parietal and slightly less in the frontal cortex compared to controls (Polidori et al., 1999).
6. Molecular mechanisms involving ozone (O3), Nrf2 and vitagene network and their
At the core of adaptive responses at the cell and origin of biological organization is the
concept of hormesis (Calabrese, V. et al., 2010). Hormesis describes a process that results in
of
ameliorating and improve cellular stress resistance, survival, and longevity in response to sub-lethal
levels of stress (Mattson, 2008). Generally, a favorable biological response to low exposure to any
ro
stressor is found within the hormetic zone, whereas cell damage occurs at higher doses. The
-p
hormetic dose response results from either a direct stimulation or through an overcompensation
stimulatory response following disruption in homeostasis (Calabrese, E. J., Baldwin, 2000). This
re
theory is, to date a frontier area of neurobiological research, focal to understanding and developing
lP
It has widely been reported that the activation of Nrf2 by several different mechanisms
na
(calorie restriction, physical exercise, polyphenols, mushrooms) can be a way to improve life
health, due to its transcriptionally modulation on the vitagene network. Calabrese et al. (Calabrese,
ur
V. et al., 2010), performed an exhaustive review on this topic, and they described in detail each
Jo
single element of the vitagene pathway. Members of the Hsp70s are, in their function as molecular
misfolded proteins, as well as in assembly and disassembly of protein complexes. Trx, is a major
redox control system, consisting of a 12 kDa redox active protein Trx, and a homodimeric seleno-
protein called TrxR1. TrxR1 is a flavoprotein that catalyzes the NADPH-dependent reduction of
oxidized thioredoxin protein. It is usually located in the cytosol, but it translocates into the nucleus
19
in response to various stimuli associated with oxidative stress, thereby playing a central role in
protecting against oxidative stress. Sirtuins are histone deacetylases which, in the presence of NAD+
as a cofactor, catalyze the deacetylation reaction of histone substrates and transcriptional regulators.
Sirtuins regulate different biological processes, such as apoptosis, cell differentiation, energy
contrast aging and combat many associated pathologies, including NDs (Leri et al., 2020,
Calabrese, E. J., 2020). Natural polyphenols (i.e. curcumin, resveratrol, flavonols present in Ginkgo
of
biloba extracts, polyphenols present abundantly in the leaves and in the ripening fruits of the olive
tree, Olea europaea), as well as mushrooms (Hericium Erinaceus, Coriolus versicolor) can
ro
significantly modulated Nrf2 and Nrf2-dependent vitagenes expression, showing neuroprotective
-p
action. This can potentially resolves pathologies such as AD, PD and also Meniere’s Disease,
another degenerative pathology (Amara et al., 2020, Trovato, Siracusa, Di Paola, Scuto, Fronte et
re
al., 2016, Trovato, Siracusa, Di Paola, Scuto, Ontario et al., 2016, Trovato Salinaro et al., 2018,
lP
In line with these findings, several studies demonstrated that also O3 can modulate the
2011, Calabrese et al., 2013), according an inverted V shape curve. We researched studies for meta-
analyses regarding Nrf2, HO-1, Hsp70, TrxR1 and sirtuins. Whereas no studies were performed
ur
between sirtuins, TrxR1 and O3, the results indicated that O3 can statistically increase the
Jo
expression/protein levels of Nrf2, HO-1 and Hsp70 molecules (Figure 4, Random model, Z=4.72
our work has been excluded because we performed transcriptomic analyses (Scassellati et al.,
2017), we confirmed the increase of the gene enconding HO-1 (HMOX-1), after difference
concentrations of O3. The high heterogeneity in effect size among the studies (p<0.0001 I2=66%) is
essentially determined by two factors: different sources of samples (human, cell and animal models)
20
and different methodology (biochemical and western blot analyses, ultrastructural and
performed the analysis as homogeneously as possible: in this case, O3 concentration (20g/ml) and
et al., 2004). Moreover, as reported for polyphenols and mushrooms (Hsiao et al., 2016, Ferreiro et
al., 2018, Oh et al., 2014, Pan et al., 2018, Hasanzadeh et al., 2020, Wang, Y. et al., 2019), O3 has
been found to be involved in β-catenin system (Emon et al., 2017) as well as in NLRP3 (nitrogen
of
permease regulator-like 3) inflammasome (Yu et al., 2017, Wang, Z., Zhang et al., 2018).
ro
All these evidence support that, as polyphenols and mushrooms, O3 acts in the same
adaptive mechanisms that enhance resilience against subsequent and acute stressor agents within a
time-sensitive window of ∼ 10–14 days. (Calabrese, E. J., 2016). Different studies demonstrated
that the supplementation with Coriolus versicolor (Ferreiro et al., 2018, Scuto et al., 2019, Trovato
na
Salinaro et al., 2018, Trovato, Siracusa, Di Paola, Scuto, Fronte et al., 2016), and Hericium
Herinaceus (Trovato Salinaro et al., 2018, Trovato, Siracusa, Di Paola, Scuto, Ontario et al., 2016),
ur
biomass and polyphenols (Mao et al., 2019) can maintain the response to neutralize intracellular
Jo
Same behaviour was also widely reported for O3. The term “ozone oxidative
facilitate adaptation to oxidative stress. This occurs through mild immune system activation,
enhanced release of growth factors and/or activation of metabolic pathways that help maintain
and Leon OS et al., 1998 (Leon et al., 1998). From 1998-1999, a plethora of investigations on this
topic was conducted. In Table 2, we reported 65 findings, of which 55 on OzoneOP, whereas 10 are
rat models of cochlear, hepatic, intestinal, renal, cardiac, lung and skeletal ischemia through an
oxidative preconditioning mechanism that prevents the increase of the endogenous pro-oxidant and
stimulates antioxidant mechanisms (Table 2). Some authors also developed an in vitro
of
Hypoxia/Reoxygenation (H/R) model to simulate OzoneOP, using normal rat kidney epithelial
(NRK-52E) cells. This to eliminate confounding variables linked to animal models (Wang, L.,
ro
Chen, Liu, Chen, Weng, Qiu & Liu, 2014, Wang, L. et al., 2018). Interestingly, the results
-p
confirmed those obtained in in vivo animal model (Table 2).
OzoneOP prevents also other different kind of injury: lipopolysaccharide (LPS) injection,
re
carbon tetrachloride, partial hepatectomy, total body irradiation, methotrexate, intraperitoneal
lP
injection of rat fecal material, sepsis, kidney and cardiac transplantation, contrast-induced
agent, H2O2, doxorubicin, ototoxicity, noise exposure, hypothermia, lipofundin (Table 2).
na
Different methodological systems have been implemented in these studies. The several
authors analysed differences in mRNA gene expression levels as well as protein levels in Western
ur
molecular investigations. Interestingly, in some cases, the effects observed were strongly dose and
In some cases (10 in total), the studies have been performed in postconditioning, obtaining
the same outcomes. León Fernández et al. (Leon Fernandez et al., 2012) investigated the systemic
redox status of patients with low back pain and neck pain, and if O3 oxidative postconditioning
22
modified the pathological oxidative stress and protected against oxidative protein damage. In 33
patients with diagnosis of disc hernia (DH), 100% showed a severe oxidative stress. Major changes
in SOD, total hydroperoxides, AOPP, fructolysine, and MAD were observed. After O3
decrease in pain in both DH. This demonstrated that O2-O3 therapy protected against oxidation of
8. Conclusions
According to (Cuadrado et al., 2018, Cuadrado et al., 2019), systems medicine identifies a
of
cluster of chronic disease pathophenotypes including NDs in which Nrf2 plays a fundamental role.
Similarly, Nfr2 is strongly implicated in aging processes (Zhang, H. et al., 2015, Schmidlin et al.,
ro
2019, Silva-Palacios et al., 2018). These condition/diseases share common mechanisms and results
-p
represent a first attempt to structure Nrf2 as a common therapeutic and systems medicine approach.
We here have presented extensively research and strength on the antioxidant activities of O3
re
correlated with the interaction with Nrf2 (Galie et al., 2018, Siniscalco et al., 2018, Re et al., 2014,
lP
Vaillant et al., 2013), along with anti-apoptotic functions by acting on mitochondrial Bax, caspases,
p53 and HIFα molecules (Yong et al., 2017, Guclu et al., 2016), pro-autophagy and bioenergetic
activities on Kreb’s cycle. This paper provides a road map for mechanism-based systems medicine
na
where O3-Nfr2-vitagene network play a crucial role in the modulation of the cellular redox balance,
in the reduction of the formation of ROS/RNS, in the change of apoptotic and autophagy
ur
mechanisms (Vikram et al., 2017). This underlines the evidence to become potential new
Jo
therapeutic targets for NDs, and at the sample time to reduce the aging physiological mechanisms
and cognitive decline, potential risk factors to develop more severe neurodegeneration damage.
Challenges regarding treatments efficacy and costs still persist for NDs. Thus, we suggest
that O2-O3 therapy could represent a useful, safe, no-invasive, no-pharmacological, economical,
effective treatment for these neurodegenerative conditions. In the medical setting, this therapy
employs a gas mixture of O2/O3, obtained from the modification of medical-grade O2 using
23
certificated O3 generator device (Bocci, V., 2011). Based on the basic mechanisms of action of O3
in blood, the therapeutic range of O3 has been precisely calculated and found to be 10–80 μg/ml of
O3 in blood (Schwartz-Tapia et al., 2015). O3 medical preparations are classified into three types:
ozonized water, ozonized oil and ozonized gas, whereas different and main routes of application
with relative concentrations of O3 are widely described in Schwart-Tapia et al., 2015 (Schwartz-
The side effects are minimal; the World Federation of Ozone therapy (WFOT) estimates the
incidence of complications at 0.0007%. Moreover, the treatment is not only perfectly tolerated but
of
most of patients have reported a feeling of wellness and euphoria throughout the cycle. This fact
explains why the compliance of the patients remains excellent throughout the years.
ro
The mechanisms of the positive effects of O3 are attributed not only to up-regulation of
-p
cellular antioxidant enzyme activity, but also to the activation of the immune and anti-inflammatory
tissues, and enhancement of general metabolism, along with being a potent bactericide, fungicide
and virucidal with potential effect on gut microbiota (for review (Scassellati et al., 2020).
domains, directly or indirectly through the mediation of gut microbiota (Cattaneo et al., 2017).
Nrf2-ARE and vitagene network, but also NF-κB (Nuclear Factor Kappa B Subunit 1), NFAT
ur
(nuclear factor activated T-cells), AP-1 (Activated Protein-1), HIFα are the principal signalling
Jo
pathways on which O3 exercises its effects (for review (Scassellati et al., 2020). These effects could
be sharable with those involved in NDs, where high inflammation and oxidant state, mitochondria
dysfunctions, metabolic alterations, and slowdown in regenerative processes and immune system
As reported in (Smith et al., 2017), to date systems are available and proposed to have a
more precise measurement of the redox state of a patient. One system proposes simultaneously
24
measuring different biological markers in the blood such as GSH, GSH-Px, GST, SOD, CAT,
conjugated dienes, total hydroperoxides, and TBARS. Using an algorithm, information can be
gathered about the total antioxidant activity, total pro-oxidant activity, redox index, and grade of
oxidative stress. Thus, systems like this can provide insights to the correct dosage and response to
With the awareness that further studies are needed, this review reports substantial scientific
evidence for building a rationale of using the O2-O3 therapy for delay aging processes and
neurodegeneration, exploiting well documented omni various functions of O3. This therapy could
of
represent a convenient, inexpensive monodomain intervention, working in absence of side effects
that will permit to modulate the oxidant, but also immune, inflammatory, metabolic, microbiota and
ro
regenerative processes impaired in NDs.
-p
There is a recent consistent upsurge of interest in complementary medicine, especially
dietary supplements and foods functional in delaying the onset of age-associated NDs. O3 along
re
with other antioxidants (polyphenols, mushrooms) can open new neuroprotective strategies, and
lP
could represent therapeutic targets to minimize the deleterious consequences associated to oxidative
Authors’ Contributions
na
Catia Scassellati and Antonio Carlo Galoforo contributed equally to this work.
Conflicts of Interest
Jo
Acknowledgments
This research was supported by grants from the Italian Ministry of Health as Ricerca
Corrente
25
References
Ademowo, O.S., Dias, H.K.I., Milic, I., Devitt, A., Moran, R., Mulcahy, R., Howard, A.N., Nolan,
J.M. Griffiths, H.R. 2017. Phospholipid oxidation and carotenoid supplementation in
Alzheimer's disease patients. Free Radic.Biol.Med., 108, 77-85.
Ahmed, L.A., N,Salem HA FAU - Mawsouf, Mohamed, S,Mawsouf MN FAU - Attia, Amina,
M,Attia AS FAU - Agha, Azza Agha, A.M. 2012. Cardioprotective effects of ozone oxidative
preconditioning in an in vivo model of ischemia/reperfusion injury in rats. Scandinavian
journal of clinical and laboratory investigation JID - 0404375, 72, 345-354.
Ahmed, S.M., Luo, L., Namani, A., Wang, X.J. Tang, X. 2017. Nrf2 signaling pathway: Pivotal
roles in inflammation. Biochim.Biophys.Acta Mol.Basis Dis., 1863, 585-597.
of
Ajamieh, H., Merino, N., Candelario-Jalil, E., Menendez, S., Martinez-Sanchez, G., Re, L.,
Giuliani, A. Leon, O.S. 2002. Similar protective effect of ischaemic and ozone oxidative
preconditionings in liver ischaemia/reperfusion injury. Pharmacol.Res., 45, 333-339.
ro
Ajamieh, H.H., Berlanga, J., Merino, N., Sanchez, G.M., Carmona, A.M., Cepero, S.M., Giuliani,
A., Re, L. Leon, O.S. 2005. Role of protein synthesis in the protection conferred by ozone-
oxidative-preconditioning in hepatic ischaemia/reperfusion. Transpl.Int., 18, 604-612.
-p
Ajamieh, H.H., Menéndez S FAU - Martínez-Sánchez, G, Martínez-Sánchez G FAU - Candelario-
Jalil, E, Candelario-Jalil E FAU - Re, L, Re L FAU - Giuliani, A, Giuliani A FAU - Fernández,
re
Olga Sonia León Fernández, O.S. 2004. Effects of ozone oxidative preconditioning on nitric
oxide generation and cellular redox balance in a rat model of hepatic ischaemia-reperfusion.
Liver international : official journal of the International Association for the Study of the Liver
lP
Altman, N. 2007, The oxygen prescription : the miracle of oxidative therapies, Healing Arts Press,
Rochester, Vt.
na
Altunoglu, E., Guntas, G., Erdenen, F., Akkaya, E., Topac, I., Irmak, H., Derici, H., Yavuzer, H.,
Gelisgen, R. Uzun, H. 2015. Ischemia-modified albumin and advanced oxidation protein
products as potential biomarkers of protein oxidation in Alzheimer's disease.
Geriatr.Gerontol.Int., 15, 872-880.
ur
Amara, I., Scuto, M., Zappala, A., Ontario, M.L., Petralia, A., Abid-Essefi, S., Maiolino, L.,
Signorile, A., Trovato Salinaro, A. Calabrese, V. 2020. Hericium Erinaceus Prevents DEHP-
Jo
Ameli, J., Banki, A., Khorvash, F., Simonetti, V., Jafari, N.J. Izadi, M. 2019. Mechanisms of
pathophysiology of blood vessels in patients with multiple sclerosis treated with ozone therapy:
a systematic review. Acta Biomed., 90, 213-217.
Aslaner, A., Cakir, T., Celik, B., Dogan, U., Mayir, B., Akyuz, C., Polat, C., Basturk, A., Soyer, V.,
Koc, S. Sehirli, A.O. 2015. Does intraperitoneal medical ozone preconditioning and treatment
ameliorate the methotrexate induced nephrotoxicity in rats? Int.J.Clin.Exp.Med., 8, 13811-
13817.
26
Aso, E., Lomoio, S., Lopez-Gonzalez, I., Joda, L., Carmona, M., Fernandez-Yague, N., Moreno, J.,
Juves, S., Pujol, A., Pamplona, R., Portero-Otin, M., Martin, V., Diaz, M. Ferrer, I. 2012.
Amyloid generation and dysfunctional immunoproteasome activation with disease progression
in animal model of familial Alzheimer's disease. Brain Pathol., 22, 636-653.
Ayala, A., Munoz, M.F. Arguelles, S. 2014. Lipid peroxidation: production, metabolism, and
signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med.Cell.Longev,
2014, 360438.
Azarpazhooh, A., Limeback, H., Lawrence, H.P. Fillery, E.D. 2009. Evaluating the effect of an
ozone delivery system on the reversal of dentin hypersensitivity: a randomized, double-blinded
clinical trial. J.Endod., 35, 1-9.
Babior, B.M., Takeuchi, C., Ruedi, J., Gutierrez, A. Wentworth, P.,Jr 2003. Investigating antibody-
catalyzed ozone generation by human neutrophils. Proc.Natl.Acad.Sci.U.S.A., 100, 3031-3034.
of
Baker, M.A., Weinberg, A., Hetherington, L., Villaverde, A.I., Velkov, T., Baell, J. Gordon, C.P.
2015. Defining the mechanisms by which the reactive oxygen species by-product, 4-
hydroxynonenal, affects human sperm cell function. Biol.Reprod., 92, 108.
ro
Bakkal, B.H., Gultekin, F.A., Guven, B., Turkcu, U.O., Bektas, S. Can, M. 2013. Effect of ozone
oxidative preconditioning in preventing early radiation-induced lung injury in rats.
Braz.J.Med.Biol.Res., 46, 789-796.
-p
Barber, E., Menendez, S., Leon, O.S., Barber, M.O., Merino, N., Calunga, J.L., Cruz, E. Bocci, V.
re
1999. Prevention of renal injury after induction of ozone tolerance in rats submitted to warm
ischaemia. Mediators Inflamm., 8, 37-41.
lP
Benedetti, E., D'Angelo, B., Cristiano, L., Di Giacomo, E., Fanelli, F., Moreno, S., Cecconi, F.,
Fidoamore, A., Antonosante, A., Falcone, R., Ippoliti, R., Giordano, A. Cimini, A. 2014.
Involvement of peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) in
BDNF signaling during aging and in Alzheimer disease: possible role of 4-hydroxynonenal (4-
HNE). Cell.Cycle, 13, 1335-1344.
na
Bilge, A., Ozturk, O., Adali, Y. Ustebay, S. 2018. Could Ozone Treatment be a Promising
Alternative for Osteomyelitis? an Experimental Study. Acta Ortop.Bras., 26, 67-71.
ur
Bocci, V. 2012. How a calculated oxidative stress can yield multiple therapeutic effects. Free
Radic.Res., 46, 1068-1075.
Jo
Bocci, V., Valacchi, G. 2015. Nrf2 activation as target to implement therapeutic treatments.
Front.Chem., 3, 4.
Bocci, V., Valacchi, G., Corradeschi, F. Fanetti, G. 1998. Studies on the biological effects of ozone:
8. Effects on the total antioxidant status and on interleukin-8 production. Mediators Inflamm.,
7, 313-317.
Bocci, V.A., Zanardi, I. Travagli, V. 2011. Ozone acting on human blood yields a hormetic dose-
response relationship. J.Transl.Med., 9, 66-5876-9-66.
27
Borrego, A., Zamora, Z.B., Gonzalez, R., Romay, C., Menendez, S., Hernandez, F., Montero, T.
Rojas, E. 2004. Protection by ozone preconditioning is mediated by the antioxidant system in
cisplatin-induced nephrotoxicity in rats. Mediators Inflamm., 13, 13-19.
Bosco, D.A., Fowler, D.M., Zhang, Q., Nieva, J., Powers, E.T., Wentworth, P.,Jr, Lerner, R.A.
Kelly, J.W. 2006. Elevated levels of oxidized cholesterol metabolites in Lewy body disease
brains accelerate alpha-synuclein fibrilization. Nat.Chem.Biol., 2, 249-253.
Braidy, N., Izadi, M., Sureda, A., Jonaidi-Jafari, N., Banki, A., Nabavi, S.F. Nabavi, S.M. 2018.
Therapeutic relevance of ozone therapy in degenerative diseases: Focus on diabetes and spinal
pain. J.Cell.Physiol., 233, 2705-2714.
Braithwaite, S.P., Stock, J.B., Lombroso, P.J. Nairn, A.C. 2012. Protein phosphatases and
Alzheimer's disease. Prog.Mol.Biol.Transl.Sci., 106, 343-379.
of
Brigelius-Flohe, R., Flohe, L. 2011. Basic principles and emerging concepts in the redox control of
transcription factors. Antioxid.Redox Signal., 15, 2335-2381.
ro
Cabiscol, E., Tamarit, J. Ros, J. 2014. Protein carbonylation: proteomics, specificity and relevance
to aging. Mass Spectrom.Rev., 33, 21-48.
Cakatay, U., Kayali, R. Uzun, H. 2008. Relation of plasma protein oxidation parameters and
-p
paraoxonase activity in the ageing population. Clin.Exp.Med., 8, 51-57.
Calabrese, E.J. 2020. Hormesis and Ginseng: Ginseng Mixtures and Individual Constituents
re
Commonly Display Hormesis Dose Responses, Especially for Neuroprotective Effects.
Molecules, 25, 10.3390/molecules25112719.
lP
Calabrese, E.J. 2016. Preconditioning is hormesis part II: How the conditioning dose mediates
protection: Dose optimization within temporal and mechanistic frameworks. Pharmacol.Res.,
110, 265-275.
Calabrese, E.J., Baldwin, L.A. 2000. Chemical hormesis: its historical foundations as a biological
na
Calabrese, V., Cornelius, C., Dinkova-Kostova, A.T., Calabrese, E.J. Mattson, M.P. 2010. Cellular
stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic
ur
Calunga, J.L., Trujillo, Y., Menendez, S., Zamora, Z., Alonso, Y., Merino, N. Montero, T. 2009.
Ozone oxidative post-conditioning in acute renal failure. J.Pharm.Pharmacol., 61, 221-227.
Can, M., Varlibas, F., Guven, B., Akhan, O. Yuksel, G.A. 2013. Ischemia modified albumin and
plasma oxidative stress markers in Alzheimer's disease. Eur.Neurol., 69, 377-380.
Candelario-Jalil, E., Mohammed-Al-Dalain, S., Fernandez, O.S., Menendez, S., Perez-Davison, G.,
Merino, N., Sam, S. Ajamieh, H.H. 2001. Oxidative preconditioning affords protection against
carbon tetrachloride-induced glycogen depletion and oxidative stress in rats. J.Appl.Toxicol.,
21, 297-301.
28
Cattaneo, A., Cattane, N., Galluzzi, S., Provasi, S., Lopizzo, N., Festari, C., Ferrari, C., Guerra,
U.P., Paghera, B., Muscio, C., Bianchetti, A., Volta, G.D., Turla, M., Cotelli, M.S., Gennuso,
M., Prelle, A., Zanetti, O., Lussignoli, G., Mirabile, D., Bellandi, D., Gentile, S., Belotti, G.,
Villani, D., Harach, T., Bolmont, T., Padovani, A., Boccardi, M., Frisoni, G.B. INDIA-FBP
Group 2017. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and
peripheral inflammation markers in cognitively impaired elderly. Neurobiol.Aging, 49, 60-68.
Chen, H., Xing B FAU - Liu, Xiuheng, Liu X FAU - Zhan, Bingyan, Zhan B FAU - Zhou,
Jiangqiao, Zhou J FAU - Zhu, Hengcheng, Zhu H FAU - Chen, Zhiyuan Chen, Z. 2008. Ozone
oxidative preconditioning inhibits inflammation and apoptosis in a rat model of renal
ischemia/reperfusion injury. European journal of pharmacology JID - 1254354, 581, 306-314.
Chen, H., Xing, B., Liu, X., Zhan, B., Zhou, J., Zhu, H. Chen, Z. 2008a. Ozone oxidative
preconditioning protects the rat kidney from reperfusion injury: the role of nitric oxide.
J.Surg.Res., 149, 287-295.
of
Chen, H., Xing, B., Liu, X., Zhan, B., Zhou, J., Zhu, H. Chen, Z. 2008b. Similarities between ozone
oxidative preconditioning and ischemic preconditioning in renal ischemia/reperfusion injury.
Arch.Med.Res., 39, 169-178.
ro
Chevion, M., Berenshtein, E. Stadtman, E.R. 2000. Human studies related to protein oxidation:
protein carbonyl content as a marker of damage. Free Radic.Res., 33 Suppl, S99-108.
-p
Clark, A.R., Ohlmeyer, M. 2019. Protein phosphatase 2A as a therapeutic target in inflammation
and neurodegeneration. Pharmacol.Ther., 201, 181-201.
re
Clavo, B., Santana-Rodriguez, N., Llontop, P., Gutierrez, D., Suarez, G., Lopez, L., Rovira, G.,
Martinez-Sanchez, G., Gonzalez, E., Jorge, I.J., Perera, C., Blanco, J. Rodriguez-Esparragon,
lP
F. 2018. Ozone Therapy as Adjuvant for Cancer Treatment: Is Further Research Warranted?
Evid Based.Complement.Alternat Med., 2018, 7931849.
Costanzo, M., Boschi, F., Carton, F., Conti, G., Covi, V., Tabaracci, G., Sbarbati, A. Malatesta, M.
2018. Low ozone concentrations promote adipogenesis in human adipose-derived adult stem
na
Cristani, M., Speciale, A., Saija, A., Gangemi, S., Minciullo, P.L. Cimino, F. 2016. Circulating
Advanced Oxidation Protein Products as Oxidative Stress Biomarkers and Progression
ur
Csala, M., Kardon, T., Legeza, B., Lizak, B., Mandl, J., Margittai, E., Puskas, F., Szaraz, P.,
Szelenyi, P. Banhegyi, G. 2015. On the role of 4-hydroxynonenal in health and disease.
Biochim.Biophys.Acta, 1852, 826-838.
Cuadrado, A., Manda, G., Hassan, A., Alcaraz, M.J., Barbas, C., Daiber, A., Ghezzi, P., Leon, R.,
Lopez, M.G., Oliva, B., Pajares, M., Rojo, A.I., Robledinos-Anton, N., Valverde, A.M.,
Guney, E. Schmidt, H.H.H.W. 2018. Transcription Factor NRF2 as a Therapeutic Target for
Chronic Diseases: A Systems Medicine Approach. Pharmacol.Rev., 70, 348-383.
29
Cuadrado, A., Rojo, A.I., Wells, G., Hayes, J.D., Cousin, S.P., Rumsey, W.L., Attucks, O.C.,
Franklin, S., Levonen, A.L., Kensler, T.W. Dinkova-Kostova, A.T. 2019. Therapeutic targeting
of the NRF2 and KEAP1 partnership in chronic diseases. Nat.Rev.Drug Discov., 18, 295-317.
Curro, M., Russo, T., Ferlazzo, N., Caccamo, D., Antonuccio, P., Arena, S., Parisi, S., Perrone, P.,
Ientile, R., Romeo, C. Impellizzeri, P. 2018. Anti-Inflammatory and Tissue Regenerative
Effects of Topical Treatment with Ozonated Olive Oil/Vitamin E Acetate in Balanitis Xerotica
Obliterans. Molecules, 23, 10.3390/molecules23030645.
Delgado-Roche, L., Hernandez-Matos, Y., Medina, E.A., Morejon, D.A., Gonzalez, M.R. Martinez-
Sanchez, G. 2014. Ozone-Oxidative Preconditioning Prevents Doxorubicin-induced
Cardiotoxicity in Sprague-Dawley Rats. Sultan Qaboos Univ.Med.J., 14, e342-8.
of
165.
Delgado-Roche, L., Riera-Romo, M., Mesta, F., Hernandez-Matos, Y., Barrios, J.M., Martinez-
Sanchez, G. Al-Dalaien, S.M. 2017. Medical ozone promotes Nrf2 phosphorylation reducing
ro
oxidative stress and pro-inflammatory cytokines in multiple sclerosis patients.
Eur.J.Pharmacol., 811, 148-154.
-p
Di Domenico, F., Barone, E., Mancuso, C., Perluigi, M., Cocciolo, A., Mecocci, P., Butterfield,
D.A. Coccia, R. 2012. HO-1/BVR-a system analysis in plasma from probable Alzheimer's
disease and mild cognitive impairment subjects: a potential biochemical marker for the
re
prediction of the disease. J.Alzheimers Dis., 32, 277-289.
Dugger, B.N., Dickson, D.W. 2017. Pathology of Neurodegenerative Diseases. Cold Spring Harb
Perspect.Biol., 9, 10.1101/cshperspect.a028035.
na
El-Mehi, A.E., Faried, M.A. 2020. Controlled ozone therapy modulates the neurodegenerative
changes in the frontal cortex of the aged albino rat. Ann.Anat., 227, 151428.
ur
El-Sawalhi, M.M., Darwish, H.A., Mausouf, M.N. Shaheen, A.A. 2013. Modulation of age-related
changes in oxidative stress markers and energy status in the rat heart and hippocampus: a
significant role for ozone therapy. Cell Biochem.Funct., 31, 518-525.
Jo
Emon, S.T., Uslu, S., Aydinlar, E.I., Irban, A., Ince, U., Orakdogen, M. Suyen, G.G. 2017. Effects
of Ozone on Spinal Cord Recovery via the Wnt/ Β-Catenin Pathway Following Spinal
Cord Injury in Rats. Turk.Neurosurg., 27, 946-951.
Eve, D.J., Nisbet, A.P., Kingsbury, A.E., Hewson, E.L., Daniel, S.E., Lees, A.J., Marsden, C.D.
Foster, O.J. 1998. Basal ganglia neuronal nitric oxide synthase mRNA expression in
Parkinson's disease. Brain Res.Mol.Brain Res., 63, 62-71.
30
Facchinetti, M.M. 2020. Heme Oxygenase-1. Antioxidants & Redox Signaling, .
Fedorova, M., Bollineni, R.C. Hoffmann, R. 2014. Protein carbonylation as a major hallmark of
oxidative damage: update of analytical strategies. Mass Spectrom.Rev., 33, 79-97.
Feitosa, C.M., da Silva Oliveira, G.L., do Nascimento Cavalcante, A., Morais Chaves, S.K. Rai, M.
2018. Determination of Parameters of Oxidative Stress in vitro Models of Neurodegenerative
Diseases-A Review. Curr.Clin.Pharmacol., 13, 100-109.
Fernandez Iglesias, A., Gonzalez Nunez, L., Calunga Fernandez, J.L., Rodriguez Salgueiro, S.
Santos Febles, E. 2011. Ozone postconditioning in renal ischaemia-reperfusion model.
Functional and morphological evidences. Nefrologia, 31, 464-470.
Ferreiro, E., Pita, I.R., Mota, S.I., Valero, J., Ferreira, N.R., Fernandes, T., Calabrese, V., Fontes-
Ribeiro, C.A., Pereira, F.C. Rego, A.C. 2018. Coriolus versicolor biomass increases dendritic
of
arborization of newly-generated neurons in mouse hippocampal dentate gyrus. Oncotarget, 9,
32929-32942.
ro
Fitzpatrick, E., Holland, O.J. Vanderlelie, J.J. 2018. Ozone therapy for the treatment of chronic
wounds: A systematic review. Int.Wound.J., 15, 633-644.
Goh, K.I., Cusick, M.E., Valle, D., Childs, B., Vidal, M. Barabasi, A.L. 2007. The human disease
network. Proc.Natl.Acad.Sci.U.S.A., 104, 8685-8690.
na
Gu, F., Chauhan, V. Chauhan, A. 2015. Glutathione redox imbalance in brain disorders.
Curr.Opin.Clin.Nutr.Metab.Care, 18, 89-95.
Guanche, D., Hernandez, F., Zamora, Z. Alonso, Y. 2010. Effect of ozone pre-conditioning on
ur
Guclu, A., Erken, H.A., Erken, G., Dodurga, Y., Yay, A., Ozcoban, O., Simsek, H., Akcilar, A.
Kocak, F.E. 2016. The effects of ozone therapy on caspase pathways, TNF-alpha, and HIF-
1alpha in diabetic nephropathy. Int.Urol.Nephrol., 48, 441-450.
Gultekin, F.A., Bakkal, B.H., Guven, B., Tasdoven, I., Bektas, S., Can, M. Comert, M. 2013.
Effects of ozone oxidative preconditioning on radiation-induced organ damage in rats.
J.Radiat.Res., 54, 36-44.
Gultekin, F.A., Cakmak, G.K., Turkcu, U.O., Yurdakan, G., Demir, F.E. Comert, M. 2013. Effects
of ozone oxidative preconditioning on liver regeneration after partial hepatectomy in rats.
J.Invest.Surg., 26, 242-252.
31
Guven, A., Gundogdu, G., Sadir, S., Topal, T., Erdogan, E., Korkmaz, A., Surer, I. Ozturk, H. 2008.
The efficacy of ozone therapy in experimental caustic esophageal burn. J.Pediatr.Surg., 43,
1679-1684.
Haj, B., Sukhotnik, I., Shaoul, R., Pollak, Y., Coran, A.G., Bitterman, A. Matter, I. 2014. Effect of
ozone on intestinal recovery following intestinal ischemia-reperfusion injury in a rat.
Pediatr.Surg.Int., 30, 181-188.
Hasanzadeh, S., Read, M.I., Bland, A.R., Majeed, M., Jamialahmadi, T. Sahebkar, A. 2020.
Curcumin: an inflammasome silencer. Pharmacol.Res., 159, 104921.
Hernandez Rosales, F.A., Calunga Fernandez, J.L., Turrent Figueras, J., Menendez Cepero, S.
of
Montenegro Perdomo, A. 2005. Ozone therapy effects on biomarkers and lung function in
asthma. Arch.Med.Res., 36, 549-554.
ro
Hohn, A., Tramutola, A. Cascella, R. 2020. Proteostasis Failure in Neurodegenerative Diseases:
Focus on Oxidative Stress. Oxid Med.Cell.Longev, 2020, 5497046.
Holmstrom, K.M., Kostov, R.V. Dinkova-Kostova, A.T. 2016. The multifaceted role of Nrf2 in
mitochondrial function. Curr.Opin.Toxicol., 1, 80-91.
-p
Hsiao, C.M., Wu, Y.S., Nan, F.H., Huang, S.L., Chen, L. Chen, S.N. 2016. Immunomodulator
re
'mushroom beta glucan' induces Wnt/beta catenin signalling and improves wound recovery in
tilapia and rat skin: a histopathological study. Int.Wound.J., 13, 1116-1128.
lP
Hunot, S., Boissiere, F., Faucheux, B., Brugg, B., Mouatt-Prigent, A., Agid, Y. Hirsch, E.C. 1996.
Nitric oxide synthase and neuronal vulnerability in Parkinson's disease. Neuroscience, 72, 355-
363.
Ishii, T., Itoh, K., Ruiz, E., Leake, D.S., Unoki, H., Yamamoto, M. Mann, G.E. 2004. Role of Nrf2
na
in the regulation of CD36 and stress protein expression in murine macrophages: activation by
oxidatively modified LDL and 4-hydroxynonenal. Circ.Res., 94, 609-616.
Isler, S.C., Unsal, B., Soysal, F., Ozcan, G., Peker, E. Karaca, I.R. 2018. The effects of ozone
ur
Izadi, M., Kheirjou, R., Mohammadpour, R., Aliyoldashi, M.H., Moghadam, S.J., Khorvash, F.,
Jafari, N.J., Shirvani, S. Khalili, N. 2019. Efficacy of comprehensive ozone therapy in diabetic
foot ulcer healing. Diabetes Metab.Syndr., 13, 822-825.
Jiang, B., Su, Y., Chen, Q., Dong, L., Zhou, W., Li, H. Wang, Y. 2020. Protective Effects of Ozone
Oxidative Postconditioning on Long-term Injury After Renal Ischemia/Reperfusion in Rat.
Transplant.Proc., 52, 365-372.
Jung, J., Na, C. Huh, Y. 2012. Alterations in nitric oxide synthase in the aged CNS. Oxid
Med.Cell.Longev, 2012, 718976.
32
Kesik, V., Uysal, B., Kurt, B., Kismet, E. Koseoglu, V. 2009. Ozone ameliorates methotrexate-
induced intestinal injury in rats. Cancer.Biol.Ther., 8, 1623-1628.
Khatri, I., Moger, G. Kumar, N.A. 2015. Evaluation of effect of topical ozone therapy on salivary
Candidal carriage in oral candidiasis. Indian J.Dent.Res., 26, 158-162.
Kikuchi, S., Shinpo, K., Ogata, A., Tsuji, S., Takeuchi, M., Makita, Z. Tashiro, K. 2002. Detection
of N epsilon-(carboxymethyl)lysine (CML) and non-CML advanced glycation end-products in
the anterior horn of amyotrophic lateral sclerosis spinal cord. Amyotroph Lateral Scler.Other
Motor Neuron.Disord., 3, 63-68.
Kim, T.S., Pae, C.U., Yoon, S.J., Jang, W.Y., Lee, N.J., Kim, J.J., Lee, S.J., Lee, C., Paik, I.H. Lee,
C.U. 2006. Decreased plasma antioxidants in patients with Alzheimer's disease.
Int.J.Geriatr.Psychiatry, 21, 344-348.
of
Knowles, T.P., Vendruscolo, M. Dobson, C.M. 2014. The amyloid state and its association with
protein misfolding diseases. Nat.Rev.Mol.Cell Biol., 15, 384-396.
ro
Koca, K., Yurttas, Y., Yildiz, C., Cayci, T., Uysal, B. Korkmaz, A. 2010. Effect of hyperbaric
oxygen and ozone preconditioning on oxidative/nitrosative stress induced by tourniquet
ischemia/reperfusion in rat skeletal muscle. Acta Orthop.Traumatol.Turc., 44, 476-483.
-p
Koçak, H.E., Taşkın Ü, Aydın, S., Oktay, M.F., Altınay, S., Çelik, D.S., Yücebaş, K. & Altaş, B.
2016. Effects of ozone (O(3)) therapy on cisplatin-induced ototoxicity in rats.
Eur.Arch.Otorhinolaryngol., 273, 4153-4159.
re
Komosinska-Vassev, K., Olczyk, P., Winsz-Szczotka, K., Kuznik-Trocha, K., Klimek, K. Olczyk,
K. 2012. Age- and gender-related alteration in plasma advanced oxidation protein products
lP
Kucukgul, A., Erdogan, S., Gonenci, R. & Ozan, G. 2016, "Beneficial effects of nontoxic ozone on
H(2)O(2)-induced stress and inflammation", Biochemistry and cell biology = Biochimie et
na
biologie cellulaire JID - 8606068, [Online], vol. 94, no. 6, pp. 577-583.
Kurtoglu, T., Durmaz, S., Akgullu, C., Gungor, H., Eryilmaz, U., Meteoglu, I., Karul, A. Boga, M.
2015. Ozone preconditioning attenuates contrast-induced nephropathy in rats. J.Surg.Res., 195,
ur
604-611.
Lackie, R.E., Maciejewski, A., Ostapchenko, V.G., Marques-Lopes, J., Choy, W.Y., Duennwald,
Jo
M.L., Prado, V.F. Prado, M.A.M. 2017. The Hsp70/Hsp90 Chaperone Machinery in
Neurodegenerative Diseases. Front.Neurosci., 11, 254.
León Fernández, O.S., Jorge,Ajamieh HH FAU - Berlanga, Berlanga J FAU - Menéndez, Silvia,
Menéndez S FAU - Viebahn-Hánsler, Renate, Viebahn-Hánsler R FAU - Re, Lamberto, Re L
FAU - Carmona, Anna,M. Carmona, A.M. 2008. Ozone oxidative preconditioning is mediated
by A1 adenosine receptors in a rat model of liver ischemia/ reperfusion. Transplant
international : official journal of the European Society for Organ Transplantation JID -
8908516, .
33
Leon Fernandez, O.S., Pantoja, M., Diaz Soto, M.T., Dranguet, J., Garcia Insua, M., Viebhan-
Hansler, R., Menendez Cepero, S. Calunga Fernandez, J.L. 2012. Ozone oxidative post-
conditioning reduces oxidative protein damage in patients with disc hernia. Neurol.Res., 34,
59-67.
Leon, O.S., Menendez, S., Merino, N., Castillo, R., Sam, S., Perez, L., Cruz, E. Bocci, V. 1998.
Ozone oxidative preconditioning: a protection against cellular damage by free radicals.
Mediators Inflamm., 7, 289-294.
Leri, M., Scuto, M., Ontario, M.L., Calabrese, V., Calabrese, E.J., Bucciantini, M. Stefani, M. 2020.
Healthy Effects of Plant Polyphenols: Molecular Mechanisms. Int.J.Mol.Sci., 21,
10.3390/ijms21041250.
of
Levonen, A.L., Landar, A., Ramachandran, A., Ceaser, E.K., Dickinson, D.A., Zanoni, G., Morrow,
J.D. Darley-Usmar, V.M. 2004. Cellular mechanisms of redox cell signalling: role of cysteine
modification in controlling antioxidant defences in response to electrophilic lipid oxidation
ro
products. Biochem.J., 378, 373-382.
Liguori, I., Russo, G., Curcio, F., Bulli, G., Aran, L., Della-Morte, D., Gargiulo, G., Testa, G.,
-p
Cacciatore, F., Bonaduce, D. Abete, P. 2018. Oxidative stress, aging, and diseases.
Clin.Interv.Aging, 13, 757-772.
re
Liu, H., Wang, H., Shenvi, S., Hagen, T.M. Liu, R.M. 2004. Glutathione metabolism during aging
and in Alzheimer disease. Ann.N.Y.Acad.Sci., 1019, 346-349.
lP
Luth, H.J., Holzer, M., Gartner, U., Staufenbiel, M. Arendt, T. 2001. Expression of endothelial and
inducible NOS-isoforms is increased in Alzheimer's disease, in APP23 transgenic mice and
after experimental brain lesion in rat: evidence for an induction by amyloid pathology. Brain
Res., 913, 57-67.
na
Luth, H.J., Munch, G. Arendt, T. 2002. Aberrant expression of NOS isoforms in Alzheimer's
disease is structurally related to nitrotyrosine formation. Brain Res., 953, 135-143.
Mac Nair, C.E., Schlamp, C.L., Montgomery, A.D., Shestopalov, V.I. Nickells, R.W. 2016. Retinal
ur
glial responses to optic nerve crush are attenuated in Bax-deficient mice and modulated by
purinergic signaling pathways. J.Neuroinflammation, 13, 93-016-0558-y.
Jo
Maciejczyk, M., Zalewska, A. Ladny, J.R. 2019. Salivary Antioxidant Barrier, Redox Status, and
Oxidative Damage to Proteins and Lipids in Healthy Children, Adults, and the Elderly. Oxid
Med.Cell.Longev, 2019, 4393460.
Madej, P., Plewka, A., Madej, J.A., Plewka, D., Mroczka, W., Wilk, K. Dobrosz, Z. 2007. Ozone
therapy in induced endotoxemic shock. II. The effect of ozone therapy upon selected
histochemical reactions in organs of rats in endotoxemic shock. Inflammation, 30, 69-86.
Maes, O.C., Kravitz, S., Mawal, Y., Su, H., Liberman, A., Mehindate, K., Berlin, D., Sahlas, D.J.,
Chertkow, H.M., Bergman, H., Melmed, C. Schipper, H.M. 2006. Characterization of alpha1-
34
antitrypsin as a heme oxygenase-1 suppressor in Alzheimer plasma. Neurobiol.Dis., 24, 89-
100.
Maki, R.A., Holzer, M., Motamedchaboki, K., Malle, E., Masliah, E., Marsche, G. Reynolds, W.F.
2019. Human myeloperoxidase (hMPO) is expressed in neurons in the substantia nigra in
Parkinson's disease and in the hMPO-alpha-synuclein-A53T mouse model, correlating with
increased nitration and aggregation of alpha-synuclein and exacerbation of motor impairment.
Free Radic.Biol.Med., 141, 115-140.
Manoto, S.L., Maepa, M.J. Motaung, S.K. 2018. Medical ozone therapy as a potential treatment
modality for regeneration of damaged articular cartilage in osteoarthritis. Saudi J.Biol.Sci., 25,
672-679.
Mao, Z.J., Lin, H., Hou, J.W., Zhou, Q., Wang, Q. Chen, Y.H. 2019. A Meta-Analysis of
Resveratrol Protects against Myocardial Ischemia/Reperfusion Injury: Evidence from Small
of
Animal Studies and Insight into Molecular Mechanisms. Oxid Med.Cell.Longev, 2019,
5793867.
Martinez de Toda, I., De la Fuente, M. 2015. The role of Hsp70 in oxi-inflamm-aging and its use as
ro
a potential biomarker of lifespan. Biogerontology, 16, 709-721.
Martinez-Sanchez, G., Al-Dalain, S.M., Menendez, S., Re, L., Giuliani, A., Candelario-Jalil, E.,
-p
Alvarez, H., Fernandez-Montequin, J.I. Leon, O.S. 2005. Therapeutic efficacy of ozone in
patients with diabetic foot. Eur.J.Pharmacol., 523, 151-161.
re
Massaad, C.A. 2011. Neuronal and vascular oxidative stress in Alzheimer's disease.
Curr.Neuropharmacol., 9, 662-673.
lP
Mateo, I., Infante, J., Sanchez-Juan, P., Garcia-Gorostiaga, I., Rodriguez-Rodriguez, E., Vazquez-
Higuera, J.L., Berciano, J. Combarros, O. 2010. Serum heme oxygenase-1 levels are increased
in Parkinson's disease but not in Alzheimer's disease. Acta Neurol.Scand., 121, 136-138.
Mattson, M.P. 2004. Pathways towards and away from Alzheimer's disease. Nature, 430, 631-639.
Mazzetti, A.P., Fiorile, M.C., Primavera, A. Lo Bello, M. 2015. Glutathione transferases and
ur
Mecocci, P., Boccardi, V., Cecchetti, R., Bastiani, P., Scamosci, M., Ruggiero, C. Baroni, M. 2018.
Jo
A Long Journey into Aging, Brain Aging, and Alzheimer's Disease Following the Oxidative
Stress Tracks. J.Alzheimers Dis., 62, 1319-1335.
Mendez, E.F., Sattler, R. 2015. Biomarker development for C9orf72 repeat expansion in ALS.
Brain Res., 1607, 26-35.
Meng, W., Xu, Y., Li, D., Zhu, E., Deng, L., Liu, Z., Zhang, G. Liu, H. 2017. Ozone protects rat
heart against ischemia-reperfusion injury: A role for oxidative preconditioning in attenuating
mitochondrial injury. Biomed.Pharmacother., 88, 1090-1097.
35
Merelli, A., Rodriguez, J.C.G., Folch, J., Regueiro, M.R., Camins, A. Lazarowski, A. 2018.
Understanding the Role of Hypoxia Inducible Factor During Neurodegeneration for New
Therapeutics Opportunities. Curr.Neuropharmacol., 16, 1484-1498.
Moldogazieva, N.T., Mokhosoev, I.M., Mel'nikova, T.I., Porozov, Y.B. Terentiev, A.A. 2019.
Oxidative Stress and Advanced Lipoxidation and Glycation End Products (ALEs and AGEs) in
Aging and Age-Related Diseases. Oxid Med.Cell.Longev, 2019, 3085756.
Morsy, M.D., Hassan, W.N. Zalat, S.I. 2010. Improvement of renal oxidative stress markers after
ozone administration in diabetic nephropathy in rats. Diabetol.Metab.Syndr., 2, 29-5996-2-29.
of
Moskalev, A., Proshkina, E., Belyi, A. Solovev, I. 2017. Genetics of aging and longevity. Russian
Journal of Genetics: Applied Research, 7, 369-384.
ro
Mota, A., Hemati-Dinarvand, M., Akbar Taheraghdam, A., Reza Nejabati, H., Ahmadi, R.,
Ghasemnejad, T., Hasanpour, M. Valilo, M. 2019. Association of Paraoxonse1 (PON1)
Genotypes with the Activity of PON1 in Patients with Parkinson's Disease. Acta
Neurol.Taiwan., 28(3), 66-74.
-p
Muller, G.C., Gottlieb, M.G., Luz Correa, B., Gomes Filho, I., Moresco, R.N. Bauer, M.E. 2015.
The inverted CD4:CD8 ratio is associated with gender-related changes in oxidative stress
re
during aging. Cell.Immunol., 296, 149-154.
Nakabeppu, Y., Tsuchimoto, D., Yamaguchi, H. Sakumi, K. 2007. Oxidative damage in nucleic
lP
Nakamura, T., Lipton, S.A. 2020. Nitric Oxide-Dependent Protein Post-Translational Modifications
Impair Mitochondrial Function and Metabolism to Contribute to Neurodegenerative Diseases.
Antioxid.Redox Signal., 32, 817-833.
na
Nasezadeh, P., Shahi, F., Fridoni, M., Seydi, E., Izadi, M. Salimi, A. 2017. Moderate O3/O2
therapy enhances enzymatic and non-enzymatic antioxidant in brain and cochlear that protects
noise-induced hearing loss. Free Radic.Res., 51, 828-837.
ur
Negre-Salvayre, A., Auge, N., Ayala, V., Basaga, H., Boada, J., Brenke, R., Chapple, S., Cohen, G.,
Feher, J., Grune, T., Lengyel, G., Mann, G.E., Pamplona, R., Poli, G., Portero-Otin, M., Riahi,
Jo
Y., Salvayre, R., Sasson, S., Serrano, J., Shamni, O., Siems, W., Siow, R.C., Wiswedel, I.,
Zarkovic, K. Zarkovic, N. 2010. Pathological aspects of lipid peroxidation. Free Radic.Res.,
44, 1125-1171.
Nitti, M., Piras, S., Brondolo, L., Marinari, U.M., Pronzato, M.A. Furfaro, A.L. 2018. Heme
Oxygenase 1 in the Nervous System: Does It Favor Neuronal Cell Survival or Induce
Neurodegeneration? Int.J.Mol.Sci., 19, 10.3390/ijms19082260.
Nowotny, K., Jung, T., Grune, T. Hohn, A. 2014. Reprint of "accumulation of modified proteins
and aggregate formation in aging". Exp.Gerontol., 59, 3-12.
36
Oh, S., Gwak, J., Park, S. Yang, C.S. 2014. Green tea polyphenol EGCG suppresses Wnt/beta-
catenin signaling by promoting GSK-3beta- and PP2A-independent beta-catenin
phosphorylation/degradation. Biofactors, 40, 586-595.
Oliveira, P.V.S., Laurindo, F.R.M. 2018. Implications of plasma thiol redox in disease.
Clin.Sci.(Lond), 132, 1257-1280.
Onal, M., Elsurer, C., Selimoglu, N., Yilmaz, M., Erdogan, E., Bengi Celik, J., Kal, O. Onal, O.
2017. Ozone Prevents Cochlear Damage From Ischemia-Reperfusion Injury in Guinea Pigs.
Artificial organs JID - 7802778, 41, 744-752.
Ozkan, H., Ekinci, S., Uysal, B., Akyildiz, F., Turkkan, S., Ersen, O., Koca, K. Seven, M.M. 2015.
Evaluation and comparison of the effect of hypothermia and ozone on ischemia-reperfusion
injury of skeletal muscle in rats. J.Surg.Res., 196, 313-319.
of
Ozturk, O., Eroglu, H.A., Ustebay, S., Kuzucu, M. Adali, Y. 2018. An experimental study on the
preventive effects of N-acetyl cysteine and ozone treatment against contrast-induced
nephropathy. Acta cirurgica brasileira JID - 9103983, 33, 508-517.
ro
Pan, H., Kim, E., Rankin, G.O., Rojanasakul, Y., Tu, Y. Chen, Y.C. 2018. Theaflavin-3, 3'-digallate
inhibits ovarian cancer stem cells via suppressing Wnt/beta-Catenin signaling pathway.
J.Funct.Foods, 50, 1-7.
-p
Paul, B.D., Sbodio, J.I. Snyder, S.H. 2018. Cysteine Metabolism in Neuronal Redox Homeostasis.
Trends Pharmacol.Sci., 39, 513-524.
re
Pawlak-Osinska, K., Kazmierczak, H., Kazmierczak, W. Szpoper, M. 2004. Ozone therapy and
pressure-pulse therapy in Meniere's disease. Int.Tinnitus J., 10, 54-57.
lP
Pedruzzi, L.M., Stockler-Pinto, M.B., Leite, M.,Jr Mafra, D. 2012. Nrf2-keap1 system versus NF-
kappaB: the good and the evil in chronic kidney disease? Biochimie, 94, 2461-2466.
Perez, D.I., Gil, C. Martinez, A. 2011. Protein kinases CK1 and CK2 as new targets for
na
Picon-Pages, P., Garcia-Buendia, J. Munoz, F.J. 2019. Functions and dysfunctions of nitric oxide in
brain. Biochim.Biophys.Acta Mol.Basis Dis., 1865, 1949-1967.
ur
Polidori, M.C., Mecocci, P., Browne, S.E., Senin, U. Beal, M.F. 1999. Oxidative damage to
mitochondrial DNA in Huntington's disease parietal cortex. Neurosci.Lett., 272, 53-56.
Jo
Poulsen, H.E., Nadal, L.L., Broedbaek, K., Nielsen, P.E. Weimann, A. 2014. Detection and
interpretation of 8-oxodG and 8-oxoGua in urine, plasma and cerebrospinal fluid.
Biochim.Biophys.Acta, 1840, 801-808.
Puspita, L., Chung, S.Y. Shim, J.W. 2017. Oxidative stress and cellular pathologies in Parkinson's
disease. Mol.Brain, 10, 53-017-0340-9.
37
Qing, Z., Ling-Ling, E., Dong-Sheng, W. Hong-Chen, L. 2012. Relationship of advanced oxidative
protein products in human saliva and plasma: age- and gender-related changes and stability
during storage. Free Radic.Res., 46, 1201-1206.
Qiu, T., Wang, Z., Liu, X., Chen, H., Zhou, J., Chen, Z., Wang, M., Jiang, G., Wang, L., Yu, G.,
Zhang, L., Shen, Y., Zhang, L., He, L., Wang, H. Zhang, W. 2017. Effect of ozone oxidative
preconditioning on oxidative stress injury in a rat model of kidney transplantation.
Experimental and therapeutic medicine, 13, 1948-1955.
Radi, R. 2018. Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular
medicine. Proc.Natl.Acad.Sci.U.S.A., 115, 5839-5848.
of
8, 10.3390/antibiotics8040193.
ro
Re, L., Martinez-Sanchez, G., Bordicchia, M., Malcangi, G., Pocognoli, A., Morales-Segura, M.A.,
Rothchild, J. Rojas, A. 2014. Is ozone pre-conditioning effect linked to Nrf2/EpRE activation
-p
pathway in vivo? A preliminary result. Eur.J.Pharmacol., 742, 158-162.
Re, L., Mawsouf, M.N., Menendez, S., Leon, O.S., Sanchez, G.M. Hernandez, F. 2008. Ozone
therapy: clinical and basic evidence of its therapeutic potential. Arch.Med.Res., 39, 17-26.
Reutzel, M., Grewal, R., Dilberger, B., Silaidos, C., Joppe, A. Eckert, G.P. 2020. Cerebral
Mitochondrial Function and Cognitive Performance during Aging: A Longitudinal Study in
na
Rizvi, S.I., Jha, R. Maurya, P.K. 2006. Erythrocyte plasma membrane redox system in human
aging. Rejuvenation Res., 9, 470-474.
ur
Rodriguez, Z.Z., Guanche, D., Alvarez, R.G., Martinez, Y., Alonso, Y. Schulz, S. 2011. Effects of
ozone oxidative preconditioning on different hepatic biomarkers of oxidative stress in
Jo
Rodriguez, Z.Z., Guanche, D., Alvarez, R.G., Rosales, F.H., Alonso, Y. Schulz, S. 2009.
Preconditioning with ozone/oxygen mixture induces reversion of some indicators of oxidative
stress and prevents organic damage in rats with fecal peritonitis. Inflamm.Res., 58, 371-375.
Rosenberger, A.F., Morrema, T.H., Gerritsen, W.H., van Haastert, E.S., Snkhchyan, H., Hilhorst,
R., Rozemuller, A.J., Scheltens, P., van der Vies, S.M. Hoozemans, J.J. 2016. Increased
occurrence of protein kinase CK2 in astrocytes in Alzheimer's disease pathology.
J.Neuroinflammation, 13, 4-015-0470-x.
38
Rosul, M.V., Patskan, B.M. 2016. Ozone therapy effectiveness in patients with ulcerous lesions due
to diabetes mellitus. Wiad.Lek., 69, 7-9.
Rougemont, M., Do, K.Q. Castagne, V. 2002. New model of glutathione deficit during
development: Effect on lipid peroxidation in the rat brain. J.Neurosci.Res., 70, 774-783.
Rusanova, I., Diaz-Casado, M.E., Fernandez-Ortiz, M., Aranda-Martinez, P., Guerra-Librero, A.,
Garcia-Garcia, F.J., Escames, G., Manas, L. Acuna-Castroviejo, D. 2018. Analysis of Plasma
MicroRNAs as Predictors and Biomarkers of Aging and Frailty in Humans. Oxid
Med.Cell.Longev, 2018, 7671850.
Safwat, M.H., El-Sawalhi, M.M., Mausouf, M.N. Shaheen, A.A. 2014. Ozone ameliorates age-
related oxidative stress changes in rat liver and kidney: effects of pre- and post-ageing
administration. Biochemistry (Mosc), 79, 450-458.
of
Salminen, A., Kaarniranta, K. Kauppinen, A. 2016. Age-related changes in AMPK activation: Role
for AMPK phosphatases and inhibitory phosphorylation by upstream signaling pathways.
Ageing Res.Rev., 28, 15-26.
ro
Sancak, E.B., Turkon, H., Cukur, S., Erimsah, S., Akbas, A., Gulpinar, M.T., Toman, H., Sahin, H.
Uzun, M. 2016. Major Ozonated Autohemotherapy Preconditioning Ameliorates Kidney
Ischemia-Reperfusion Injury. Inflammation, 39, 209-217.
-p
Scassellati, C., Ciani, M., Galoforo, A.C., Zanardini, R., Bonvicini, C. Geroldi, C. 2020. Molecular
mechanisms in cognitive frailty: potential therapeutic targets for oxygen-ozone treatment.
re
Mech.Ageing Dev., 186, 111210.
Scassellati, C., Costanzo, M., Cisterna, B., Nodari, A., Galie, M., Cattaneo, A., Covi, V., Tabaracci,
lP
G., Bonvicini, C. Malatesta, M. 2017. Effects of mild ozonisation on gene expression and
nuclear domains organization in vitro. Toxicol.In.Vitro., 44, 100-110.
10.3390/brainsci10040232.
Schipper, H.M. 2010. Biological markers and Alzheimer disease: a canadian perspective.
Int.J.Alzheimers Dis., 2010, 10.4061/2010/978182.
ur
Schipper, H.M. 2007. Biomarker potential of heme oxygenase-1 in Alzheimer's disease and mild
cognitive impairment. Biomark Med., 1, 375-385.
Jo
Schipper, H.M., Chertkow, H., Mehindate, K., Frankel, D., Melmed, C. Bergman, H. 2000.
Evaluation of heme oxygenase-1 as a systemic biological marker of sporadic AD. Neurology,
54, 1297-1304.
Schipper, H.M., Song, W., Tavitian, A. Cressatti, M. 2019. The sinister face of heme oxygenase-1
in brain aging and disease. Prog.Neurobiol., 172, 40-70.
Schmidlin, C.J., Dodson, M.B., Madhavan, L. Zhang, D.D. 2019. Redox regulation by NRF2 in
aging and disease. Free Radic.Biol.Med., 134, 702-707.
39
Schwartz-Tapia, A., Martínez-Sánchez, G., Sabah, F., Alvarado-Guémez, F., Bazzano-Mastrelli, N.,
Bikina, O., Borroto-Rodrígez, V., Cakir, R., Clavo, B., González-Sánchez, E., Grechkanev, G.,
Najm Dawood, A.H., Izzo, A., Konrad, H., Masini, M., Peretiagyn, S., Pereyra, V.R., Ruiz
Reyes, D., Shallenberger, F., Vongay, V., Xirezhati, A. Quintero-Marino, R. 2015, Madrid
Declaration on Ozone Therapy
, 2nd Madrid ed. ISCO3.
Scuto, M., Di Mauro, P., Ontario, M.L., Amato, C., Modafferi, S., Ciavardelli, D., Trovato Salinaro,
A., Maiolino, L. Calabrese, V. 2019. Nutritional Mushroom Treatment in Meniere's Disease
with Coriolus versicolor: A Rationale for Therapeutic Intervention in Neuroinflammation and
Antineurodegeneration. Int.J.Mol.Sci., 21, 10.3390/ijms21010284.
Selkoe, D.J. 2001. Alzheimer's disease results from the cerebral accumulation and cytotoxicity of
amyloid beta-protein. J.Alzheimers Dis., 3, 75-80.
of
Shan, Y., Schoenfeld, R.A., Hayashi, G., Napoli, E., Akiyama, T., Iodi Carstens, M., Carstens, E.E.,
Pook, M.A. Cortopassi, G.A. 2013. Frataxin deficiency leads to defects in expression of
antioxidants and Nrf2 expression in dorsal root ganglia of the Friedreich's ataxia YG8R mouse
model. Antioxid.Redox Signal., 19, 1481-1493.
ro
Shehata, N.I., Abd-Elgawad, H.M., Mawsouf, M.N. Shaheen, A.A. 2012. The potential role of
ozone in ameliorating the age-related biochemical changes in male rat cerebral cortex.
Biogerontology, 13, 565-581.
-p
Silva, T.O., Jung, I.E., Moresco, R.N., Barbisan, F., Ribeiro, E.E., Ribeiro, E.A., Motta, K., Britto,
re
E., Tasch, E., Bochi, G., Duarte, M.M., Oliveira, A.R., Marcon, M., Bello, C., dos Santos
Montagner, G.F. da Cruz, I.B. 2015. Association between advanced oxidation protein products
and 5-year mortality risk among amazon riparian elderly population. Free Radic.Res., 49, 204-
lP
209.
Silva-Palacios, A., Ostolga-Chavarria, M., Zazueta, C. Konigsberg, M. 2018. Nrf2: Molecular and
epigenetic regulation during aging. Ageing Res.Rev., 47, 31-40.
na
Singh, A., Kukreti, R., Saso, L. Kukreti, S. 2019. Oxidative Stress: A Key Modulator in
Neurodegenerative Diseases. Molecules, 24, 10.3390/molecules24081583.
Siniscalco, D., Trotta, M.C., Brigida, A.L., Maisto, R., Luongo, M., Ferraraccio, F., D'Amico, M.
ur
Sivandzade, F., Prasad, S., Bhalerao, A. Cucullo, L. 2019. NRF2 and NF-B interplay in
cerebrovascular and neurodegenerative disorders: Molecular mechanisms and possible
therapeutic approaches. Redox Biol., 21, 101059.
Smith, N.L., Wilson, A.L., Gandhi, J., Vatsia, S. Khan, S.A. 2017. Ozone therapy: an overview of
pharmacodynamics, current research, and clinical utility. Med.Gas Res., 7, 212-219.
Son, T.G., Zou, Y., Yu, B.P., Lee, J. Chung, H.Y. 2005. Aging effect on myeloperoxidase in rat
kidney and its modulation by calorie restriction. Free Radic.Res., 39, 283-289.
40
Spillantini, M.G., Crowther, R.A., Jakes, R., Hasegawa, M. Goedert, M. 1998. alpha-Synuclein in
filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy
bodies. Proc.Natl.Acad.Sci.U.S.A., 95, 6469-6473.
Srikanth, A., Sathish, M. Sri Harsha, A.V. 2013. Application of ozone in the treatment of
periodontal disease. J.Pharm.Bioallied Sci., 5, S89-94.
Stadlbauer, T.H., Eisele, A., Heidt, M.C., Tillmanns, H.H. Schulz, S. 2008. Preconditioning with
ozone abrogates acute rejection and prolongs cardiac allograft survival in rats.
Transplant.Proc., 40, 974-977.
Sun, W., Pei, L. 2012. Ozone preconditioning and exposure to ketamine attenuates hepatic
inflammation in septic rats. Arch.Med.Sci., 8, 918-923.
Tang, Z., Hu, B., Zang, F., Wang, J., Zhang, X. Chen, H. 2019. Nrf2 drives oxidative stress-induced
of
autophagy in nucleus pulposus cells via a Keap1/Nrf2/p62 feedback loop to protect
intervertebral disc from degeneration. Cell.Death Dis., 10, 510-019-1701-3.
ro
Tarafdar, A., Pula, G. 2018. The Role of NADPH Oxidases and Oxidative Stress in
Neurodegenerative Disorders. Int.J.Mol.Sci., 19, 10.3390/ijms19123824.
Tasdoven, I., Emre, A.U., Gultekin, F.A., Oner, M.O., Bakkal, B.H., Turkcu, U.O., Gun, B.D.
-p
Tasdoven, G.E. 2019. Effects of ozone preconditioning on recovery of rat colon anastomosis
after preoperative radiotherapy. Adv.Clin.Exp.Med., 28, 1683-1689.
re
Teskey, G., Abrahem, R., Cao, R., Gyurjian, K., Islamoglu, H., Lucero, M., Martinez, A., Paredes,
E., Salaiz, O., Robinson, B. Venketaraman, V. 2018. Glutathione as a Marker for Human
Disease. Adv.Clin.Chem., 87, 141-159.
lP
Tieu, K., Ischiropoulos, H. Przedborski, S. 2003. Nitric oxide and reactive oxygen species in
Parkinson's disease. IUBMB Life, 55, 329-335.
Tirelli, U., Cirrito, C., Pavanello, M., Piasentin, C., Lleshi, A. Taibi, R. 2019. Ozone therapy in 65
na
Toda, N., Ayajiki, K. Okamura, T. 2009. Cerebral blood flow regulation by nitric oxide in
neurological disorders. Can.J.Physiol.Pharmacol., 87, 581-594.
ur
Trovato Salinaro, A., Pennisi, M., Di Paola, R., Scuto, M., Crupi, R., Cambria, M.T., Ontario, M.L.,
Tomasello, M., Uva, M., Maiolino, L., Calabrese, E.J., Cuzzocrea, S. Calabrese, V. 2018.
Jo
Trovato, A., Siracusa, R., Di Paola, R., Scuto, M., Fronte, V., Koverech, G., Luca, M., Serra, A.,
Toscano, M.A., Petralia, A., Cuzzocrea, S. Calabrese, V. 2016. Redox modulation of cellular
stress response and lipoxin A4 expression by Coriolus versicolor in rat brain: Relevance to
Alzheimer's disease pathogenesis. Neurotoxicology, 53, 350-358.
Trovato, A., Siracusa, R., Di Paola, R., Scuto, M., Ontario, M.L., Bua, O., Di Mauro, P., Toscano,
M.A., Petralia, C.C.T., Maiolino, L., Serra, A., Cuzzocrea, S. Calabrese, V. 2016. Redox
41
modulation of cellular stress response and lipoxin A4 expression by Hericium Erinaceus in rat
brain: relevance to Alzheimer's disease pathogenesis. Immun.Ageing, 13, 23-016-0078-8.
eCollection 2016.
Tunez, I., Sanchez-Lopez, F., Aguera, E., Fernandez-Bolanos, R., Sanchez, F.M. Tasset-Cuevas, I.
2011. Important role of oxidative stress biomarkers in Huntington's disease. J.Med.Chem., 54,
5602-5606.
Tusat, M., Mentese, A., Demir, S., Alver, A., Imamoglu, M. 2017. Medical ozone therapy reduces
oxidative stress and testicular damage in an experimental model of testicular torsion in rats.
Int.Braz.J.Urol., 43, 1160–1166.
Uysal, B., Yasar, M., Ersoz, N., Coskun, O., Kilic, A., Cayc, T., Kurt, B., Oter, S., Korkmaz, A.
Guven, A. 2010. Efficacy of hyperbaric oxygen therapy and medical ozone therapy in
experimental acute necrotizing pancreatitis. Pancreas, 39, 9-15.
of
Vaillant, J.D., Fraga, A., Diaz, M.T., Mallok, A., Viebahn-Hansler, R., Fahmy, Z., Barbera, A.,
Delgado, L., Menendez, S. Fernandez, O.S. 2013. Ozone oxidative postconditioning
ameliorates joint damage and decreases pro-inflammatory cytokine levels and oxidative stress
ro
in PG/PS-induced arthritis in rats. Eur.J.Pharmacol., 714, 318-324.
Vina, E.R., Fang, A.J., Wallace, D.J. Weisman, M.H. 2005. Chronic inflammatory demyelinating
lP
Wang, J., Zhang, Y., Zhu, Q., Liu, Y., Cheng, H., Zhang, Y. Li, T. 2016. Emodin protects mice
against radiation-induced mortality and intestinal injury via inhibition of apoptosis and
modulation of p53. Environ.Toxicol.Pharmacol., 46, 311-318.
ur
Wang, L., Chen, H., Liu, X.H., Chen, Z.Y., Weng, X.D., Qiu, T. Liu, L. 2014. The protective effect
of ozone oxidative preconditioning against hypoxia/reoxygenation injury in rat kidney cells.
Ren.Fail., 36, 1449-1454.
Jo
Wang, L., Chen, H., Liu, X.H., Chen, Z.Y., Weng, X.D., Qiu, T., Liu, L. Zhu, H.C. 2014. Ozone
oxidative preconditioning inhibits renal fibrosis induced by ischemia and reperfusion injury in
rats. Exp.Ther.Med., 8, 1764-1768.
Wang, L., Chen, Z., Liu, Y., Du, Y. Liu, X. 2018. Ozone oxidative postconditioning inhibits
oxidative stress and apoptosis in renal ischemia and reperfusion injury through inhibition of
MAPK signaling pathway. Drug Des.Devel.Ther., 12, 1293-1301.
42
Wang, L., Chen, Z., Weng, X., Wang, M., Du, Y. Liu, X. 2019. Combined Ischemic
Postconditioning and Ozone Postconditioning Provides Synergistic Protection Against Renal
Ischemia and Reperfusion Injury Through Inhibiting Pyroptosis. Urology, 123, 296.e1-296.e8.
Wang, X. 2018. Emerging roles of ozone in skin diseases. Zhong Nan Da Xue Xue Bao Yi Xue
Ban, 43, 114-123.
Wang, X., Wang, W., Li, L., Perry, G., Lee, H.G. Zhu, X. 2014. Oxidative stress and mitochondrial
dysfunction in Alzheimer's disease. Biochim.Biophys.Acta, 1842, 1240-1247.
Wang, Y., Li, H., Li, Y., Zhao, Y., Xiong, F., Liu, Y., Xue, H., Yang, Z., Ni, S., Sahil, A., Che, H.
Wang, L. 2019. Coriolus versicolor alleviates diabetic cardiomyopathy by inhibiting cardiac
fibrosis and NLRP3 inflammasome activation. Phytother.Res., 33, 2737-2748.
Wang, Z., Bai, Z., Qin, X. Cheng, Y. 2019. Aberrations in Oxidative Stress Markers in
of
Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis. Oxid
Med.Cell.Longev, 2019, 1712323.
ro
Wang, Z., Han, Q., Guo, Y.L., Liu, X.H. Qiu, T. 2018. Effect of ozone oxidative preconditioning on
inflammation and oxidative stress injury in rat model of renal transplantation. Acta Cir.Bras.,
33, 238-249.
-p
Wang, Z., Zhang, A., Meng, W., Wang, T., Li, D., Liu, Z. Liu, H. 2018. Ozone protects the rat lung
from ischemia-reperfusion injury by attenuating NLRP3-mediated inflammation, enhancing
Nrf2 antioxidant activity and inhibiting apoptosis. Eur.J.Pharmacol., 835, 82-93.
re
Wentworth, P.,Jr, McDunn, J.E., Wentworth, A.D., Takeuchi, C., Nieva, J., Jones, T., Bautista, C.,
Ruedi, J.M., Gutierrez, A., Janda, K.D., Babior, B.M., Eschenmoser, A. Lerner, R.A. 2002.
lP
Wyss-Coray, T. 2016. Ageing, neurodegeneration and brain rejuvenation. Nature, 539, 180-186.
Xing, B., Chen, H., Wang, L., Weng, X., Chen, Z. Li, X. 2015. Ozone oxidative preconditioning
ur
protects the rat kidney from reperfusion injury via modulation of the TLR4-NF-kappaB
pathway. Acta Cir.Bras., 30, 60-66.
Jo
Yanar, K., Atayik, M.C., Simsek, B. Cakatay, U. 2020. Novel biomarkers for the evaluation of
aging-induced proteinopathies. Biogerontology, .
Yong, L., Lyu, X., Huang, C. & Xu, Y. 2017, "Effect of local ozone treatment on inflammatory
cytokine , growth cytokine and apoptosis molecule expression in anal fistula wound", .
Yu, G., Bai, Z., Chen, Z., Chen, H., Wang, G., Wang, G. Liu, Z. 2017. The NLRP3 inflammasome
is a potential target of ozone therapy aiming to ease chronic renal inflammation in chronic
kidney disease. Int.Immunopharmacol., 43, 203-209.
43
Zamora, Z.B., Borrego, A., Lopez, O.Y., Delgado, R., Gonzalez, R., Menendez, S., Hernandez, F.
Schulz, S. 2005. Effects of ozone oxidative preconditioning on TNF-alpha release and
antioxidant-prooxidant intracellular balance in mice during endotoxic shock. Mediators
Inflamm., 2005, 16-22.
Zamora, Z.B., Borrego, A., Lopez, O.Y., Delgado, R., Menendez, S., Schulz, S. Hernandez, F.
2004. Inhibition of tumor necrosis factor-alpha release during endotoxic shock by ozone
oxidative preconditioning in mice. Arzneimittelforschung, 54, 906-909.
Zhang, H., Davies, K.J.A. Forman, H.J. 2015. Oxidative stress response and Nrf2 signaling in
aging. Free Radic.Biol.Med., 88, 314-336.
Zhang, J., Guan, M., Xie, C., Luo, X., Zhang, Q. Xue, Y. 2014. Increased growth factors play a role
in wound healing promoted by noninvasive oxygen-ozone therapy in diabetic patients with foot
ulcers. Oxid Med.Cell.Longev, 2014, 273475.
of
Zhao, X., Li, Y., Lin, X., Wang, J., Zhao, X., Xie, J., Sun, T. Fu, Z. 2018. Ozone induces autophagy
in rat chondrocytes stimulated with IL-1beta through the AMPK/mTOR signaling pathway.
J.Pain Res., 11, 3003-3017.
ro
Zhao, Y., Zhao, B. 2013. Oxidative stress and the pathogenesis of Alzheimer's disease. Oxid
Med.Cell.Longev, 2013, 316523.
-p
Zheng, Z., Dong, M. Hu, K. 2020. A preliminary evaluation on the efficacy of ozone therapy in the
treatment of COVID-19. J.Med.Virol., .
re
Zhou, M., Hou, J., Li, Y., Mou, S., Wang, Z., Horch, R.E., Sun, J. Yuan, Q. 2019. The pro-
angiogenic role of hypoxia inducible factor stabilizer FG-4592 and its application in an in vivo
lP
44
Figure 1. Molecular mechanisms linked to antioxidant/pro-authophagy activities of ozone (O3) via
Nfr2 signalling.
of
ro
In the absence of stimuli, Nrf2 (nuclear factor erythroid 2–related factor 2) binds to its repressor
-p
Keap1 (kelch-like ECH-associated protein), an adapter between Nrf2 and Cullin 3 protein, which
two fundamental messengers: hydrogen peroxide (H2O2), 4-hydroxynonenal (4HNE) and lipid
oxidation products (LOPs). These messengers can influence the modifications of cysteine residues
present in Keap1 (S-HNE or―S―S) inhibiting ubiquitin conjugation to Nrf2 by the Keap1
na
complex and provoking the nuclear accumulation of Nrf2. Once in the nucleus, Nrf2 dimerizes and
binds to cis-acting DNA AREs (Antioxidant Response Elements) in different genes: Heme
ur
45
A) O3 involves casein kinase 2 (CK2), a regulator of the Nrf2 activity through its
B) O3 modulates the degradation protein systems (autophagy), via activation of the AMP-
C) O3 downregulates inducible nitric oxide synthase (iNOS), which generates nitric oxide (NO) via
Figure 2. Molecular mechanisms linked to anti-apoptotic property of ozone (O3) via pro-apoptotic
of
molecules inactivation.
ro
-p
re
lP
na
ur
Jo
Various apoptotic stimuli (ischemia, reactive oxidant species, ROS, ipoxia) can activate directly
p53 that in turn can play a role as transcription factor and activate the expression of pro-apoptotic
genes. Among these, Bak (Bcl-2 homologous antagonist/killer) and Bax (Bcl-2-associated X
protein) can stimulate in mitochondrial membrane the activation of Cytochrome C that in turn
46
activates Apaf1 (Apoptotic protease activating factor-1) and caspase 9 to close the circle to
stimulate the activity of caspase 3. Enzymes such as SOD (Superoxide dismutase), CAT (catalase),
and GSH-Px (glutathione peroxidase), can regulate p53, Bax and Bcl-2. O3 administration decreases
the expression of caspases 1-3-9, Hypoxia-inducible factor (HIFα), Tumor Necrosis Factor-α
(TNF-α), Bax and p53 genes. (BID an acronym for BH3-interacting domain death agonist).
Figure 3 Forest plot for odds ratio from meta-analysis of the endogenous Nrf2- antioxidant pathway
of
ro
-p
re
lP
na
ur
Jo
47
Jo
ur
na
lP
re
-p
ro
of
48
CI, confidence interval; Chi2, χ2 test of goodness of fit; Tau2, estimate of the between-study
Figure 4 Forest plot for odds ratio from meta-analysis of the endogenous Nrf2- vitagene pathway
of
ro
-p
re
lP
na
CI, confidence interval; Chi2, χ2 test of goodness of fit; Tau2, estimate of the between-study variance
ur
in a random-effects meta-analysis. Nuclear factor Nrf2, heme-oxigenase (HO-1), heat shock protein
(HSP)
Jo
49
Table 1. List of the pro-oxidation and antioxidant defence biomarkers influenced by ozone (O3) and implicated in neurodegenerative disorders
(NDs) as well as in aging processes.
f
oo
Ozone Name and Function Involvement in NDs Involvement in Aging
biomarkers processes
4-HNE 4-Hydroxynonenal: a common aldehyde byproduct of lipid peroxidation (Moldogazieva et al., (Benedetti et al., 2014,
during oxidative stress. 4-HNE is highly reactive and primarily produced 2019, Ayala et al., Csala et al., 2015)
pr
in the brain via lipid peroxidation of arachidonic acid, a highly abundant 2014, Baker et al.,
omega-6 polyunsaturated fatty acids (PUFA) component of neuronal 2015)
membranes. HNE may modify the ATP synthase, the final step in the
production of ATP from electron transport chain (ETC) inside
e-
mitochondria. 4-HNE activates Nrf2 by alkylating thiol groups of cysteine
residue in Keap1.
8-OHdG 8-hydroxydeoxyguanosine (8-Oxo-2'-deoxyguanosine (8-oxo-dG): (Wang, Z. et al., 2019, (Mecocci et al., 2018)
Pr
oxidized derivative of deoxyguanosine. Its concentrations within a cell are Nakabeppu et al.,
a measurement of oxidative stress (DNA oxidation). Reactive oxygen 2007, Poulsen et al.,
species (ROS) attack guanine bases in DNA easily and form 8- 2014, Polidori et al.,
hydroxydeoxyguanosine, which can bind to thymidine rather than 1999)
cytosine; thus, the level of 8-OHdG is generally regarded as a biomarker
l
na
of mutagenesis consequent to oxidative stress.
AOPP Advanced Oxidation Protein Products: are group of oxidatively modified (Wang, Z. et al., 2019, (Maciejczyk et al.,
protein products containing dityrosine, pentosidine, and carbonyl- Cristani et al., 2016) 2019, Cakatay et al.,
containing products generated by reactive oxygen species (ROS) or 2008, Komosinska-
formed via myeloperoxidase reaction during oxidative/chlorine stress. Vassev et al., 2012,
ur
al., 2015)
CAT Catalase: it catalyzes the decomposition of hydrogen peroxide to water (Feitosa et al., 2018) (Veal et al., 2018)
and oxygen. It is a scavenger enzyme of reactive oxygen species (ROS),
protecting the cell from oxidative damage by ROS.
FRAP Ferric Reducing the Ability of Plasma: total antioxidant capacity of (Ademowo et al., (Muller et al., 2015,
plasma. 2017) Rizvi et al., 2006)
Fructolysine It is an Amadori adduct of glucose to lysine. It is a precursor of the - -
50
advanced oxidation protein products, which are induced by oxidative
stress, and induces oxidative stress.
f
GR Glutathione reductase (or glutathione-disulfide reductase, GSR): it (Feitosa et al., 2018, (Veal et al., 2018)
oo
catalyses the reduction of glutathione disulfide (GSSG) to the sulfhydryl Liu et al., 2004,
form glutathione (GSH), which is a critical molecule in resisting oxidative Rougemont et al.,
stress and maintaining the reducing environment of the cell. 2002)
GSH Glutathione: it is antioxidant, capable of preventing damage to important (Mazzetti et al., 2015, (Maciejczyk et al.,
pr
cellular components caused by reactive oxygen species (ROS). It Liu et al., 2004, Gu et 2019, Teskey et al.,
maintains cellular thiol status. al., 2015, Rougemont 2018, Oliveira,
et al., 2002, Oliveira, Laurindo, 2018)
Laurindo, 2018)
e-
GSH- Glutathione peroxidase: it has peroxidase activity whose main biological (Mazzetti et al., 2015, (Maciejczyk et al.,
Px/GPx role is to protect the organism from oxidative damage. The biochemical Gu et al., 2015, 2019, Veal et al., 2018)
function is to reduce lipid hydroperoxides to their corresponding alcohols Rougemont et al.,
Pr
and to reduce free hydrogen peroxide to water. 2002)
GST Glutathione S-transferase: it is phase II metabolic isozyme, known for the (Mazzetti et al., 2015, (Veal et al., 2018)
ability to catalyze the conjugation of the reduced form of glutathione Gu et al., 2015,
(GSH) to xenobiotic substrates for the purpose of detoxification. Rougemont et al.,
l 2002)
na
HIF-1α Hypoxia-inducible factor (HIF)-1alpha: is a subunit of a heterodimeric (Merelli et al., 2018) (Yeo, 2019)
transcription factor hypoxia-inducible factor 1 (HIF-1). It is a basic helix-
loop-helix PAS domain containing protein and is considered as the master
transcriptional regulator of cellular and developmental response to
ur
hypoxia.
HO-1 heme-oxygenase-1: it catalyzes the conversion of heme into free iron, (Facchinetti, 2020) (Schipper et al., 2019)
carbon monoxide and biliverdin. It possesses two well-characterized
isoforms: HO-1 and HO-2. Under brain physiological conditions, the
Jo
f
or elimination of misfolded proteins. These mechanisms serve to promote
oo
cell survival conditions that would otherwise result in apoptosis.
IMA Ischemia-modified albumin: it measures ischemia in the blood vessels (Altunoglu et al., -
2015, Can et al.,
2013)
pr
LPO Lipid peroxide: is the oxidative degradation of lipids. (Feitosa et al., 2018, (Negre-Salvayre et al.,
Negre-Salvayre et al., 2010)
2010)
e-
MDA Malondialdehyde: is a marker for oxidative stress. It is a reactive aldehyde (Feitosa et al., 2018, (Csala et al., 2015,
produced by lipid peroxidation of polyunsaturated fatty acids. Wang, Z. et al., 2019, Maciejczyk et al., 2019)
Ayala et al., 2014)
MPO Myeloperoxidase: is a peroxidase enzyme. It requires heme as a cofactor. (Ray, Katyal, 2016, (Son et al., 2005)
Pr
It is expressed in neutrophil and monocyte, and is implicated in various Maki et al., 2019)
stages of inflammatory conditions with the production of a variety of
potent oxidants.
Nfr2/CK2 Nuclear factor erythroid 2-related factor 2: is a basic leucine zipper (bZIP) (Perez et al., 2011, (Sivandzade et al.,
l
protein that regulates the expression of antioxidant proteins that protect Sivandzade et al., 2019)
na
against oxidative damage triggered by injury and inflammation. 2019)
Casein kinase 2: a serine/threonine-selective protein kinase implicated in
cell cycle control, DNA repair, regulation of the circadian rhythm, and
other cellular processes. Regulator of the Nrf2 activity through its
ur
phosphorylation.
NO Nitric Oxide: is an important cellular signaling molecule which is derived (Hannibal, 2016, (Picon-Pages et al.,
from L-arginine by nitric oxide synthase (NOS). It works as a retrograde Nakamura, Lipton, 2019)
neurotransmitter in synapses, allows the brain blood flow, and has 2020, Radi, 2018)
Jo
f
production of nitric oxide (NO) from L-arginine. Nakamura, Lipton,
oo
2020)
PCC/PCO Protein carbonyl content: catalyses the carboxylation reaction of propionyl (Chevion et al., 2000, (Cabiscol et al., 2014,
CoA in the mitochondrial matrix. Fedorova et al., 2014) Cakatay et al., 2008)
PP Protein phosphatase: it is a serine/threonine phosphatase. It has been found (Braithwaite et al., (Salminen et al., 2016)
pr
to be important in the control of glycogen metabolism, muscle contraction, 2012, Clark,
cell progression, neuronal activities, splicing of RNA, mitosis, cell Ohlmeyer, 2019)
division, apoptosis, protein synthesis, and regulation of membrane
e-
receptors and channels.
SOD superoxide dismutase: are the first and most important line of scavenger (Feitosa et al., 2018, (Maciejczyk et al.,
antioxidant enzyme defence systems against ROS and particularly Schaffert, Carter, 2019, Veal et al., 2018)
superoxide anion radicals. There are two isoforms of SOD (cytoplasmatic 2020)
Pr
CuZn‐ SOD or SOD1 and mitchondrial Mn‐ SOD or SOD2).
TAC Total antioxidant capacity (Mota et al., 2019) (Maciejczyk et al.,
2019)
TAS Total antioxidant status (Mota et al., 2019)
TBARS l
Thiobarbituric acid reactive substances: byproducts of lipid peroxidation (Vina et al., 2005) (Muller et al., 2015)
na
(i.e. as degradation products of fats)
TH Total Hydroperoxides: indicator of oxidative stress. (Tarafdar, Pula, 2018)
TOS Total oxidant score (Mota et al., 2019)
Note: In bold the genes involved in Nrf2 signalling
ur
Jo
53
Table 2. Preconditioning/postconditioning studies of O3 on endogenous pro-antioxidant mechanisms in vivo on animal models and in vitro on cells.
f
Tissues Dosages Results References
oo
Preconditioning: 0.7 mg/kg, Reduction: malondialdehyde (MDA). Increase: superoxide dismutase (SOD), glutathione (Kesik et al., 2009)
intraperitoneally, 15 applications peroxidase GSH-Px.
(once daily), before methotrexate Histologically: ILEUM: less inflammatory cell infiltration and edema, reduction in
(Mtx) (6 mg/kg). vacuolated cells in the epithelium; LIVER/KIDNEY: no significant change, due
pr
probably to the cumulative prolonged effect of Mtx on these tissues.
Postconditioning : IN VIVO: Reduction dose-dependent manner: blood urea nitrogen (BUN), creatinine (Wang, L. et al.,
Sprague Dawley rats: 1, 2 (Cr), malondialdehyde (MDA), bcl-2-associated X (BAX) and poly (ADP-ribose) 2018)
mg/kg, rectal insufflations, 15 polymerase 1 (PARP-1) expression, MAPK signaling pathway. Increase dose-dependent
e-
applications, once a day, manner: superoxide dismutase (SOD).
ischemia/reperfusion. Histologically: ozone protected the tubular epithelium from swelling and from loss of the
Renal tubular epithelial cell brush border.
line, NRK-52E: 20, 30, 40 μg/mL IN VITRO: Reduction dose-dependent manner: MAPK pathways, CREB, c-fos, bcl-2-
Pr
in complete medium, hypoxia– associated X (BAX) and poly (ADP-ribose) polymerase 1 (PARP-1) expression,
reoxygenation. apoptosis, malondialdehyde (MDA), phosphorylation of p38, ERK1/2, and JNK.
Increase dose-dependent manner: superoxide dismutase (SOD).
Postconditioning: IN VIVO: Reduction: blood urea nitrogen (BUN), creatinine (Cr), malondialdehyde (Wang, L. et al.,
KIDNEY Sprague Dawley rats: 2 mg/kg, (MDA), caspase 1, caspase 11, interleukin 1 (Il-1), Interleukin-18 (IL18) 2019)
rectal l
insufflations, 15
na
expression/protein. Increase: superoxide dismutase (SOD).
applications, once a day, after IN VITRO: Reduction: malondialdehyde (MDA), caspase 1, caspase 11, interleukin 1
ischemia/reperfusion. (Il-1), Interleukin-18 (IL-18) expression/protein. Increase: superoxide dismutase
Renal tubular epithelial cell (SOD), cell viability.
line, NRK-52E: 20, 30, 40 μg/mL Histologic Examinations, Immunofluorescence Staining: prevented renal damage,
ur
in complete medium, after reduction in Jablonski grading scale scores, decreased caspase 1.
hypoxia–reoxygenation.
Postconditioning: 0.5 mg/kg, Reduction: serum creatinine (Cr), blood urea nitrogen (BUN), myeloperoxidase (MPO), (Jiang et al., 2020)
rectal insufflation, after
Jo
54
once a day, before Morphological/immunohistochemistry: increase in collagen staining, reduction in α- Qiu, Liu & Zhu,
ischemia/reperfusion. SMA expression. 2014)
f
Postconditioning: 0.5 mg/kg, Reduction: serum creatinine (Cr), blood urea nitrogen (BUN), thiobarbituric acid (Calunga et al.,
oo
daily for the 10 days' reperfusion, reactive substances (TBARS). Increase: fructosamine, phospholipase A2, superoxide 2009)
after ischaemia–reperfusion. A dismutase (SOD).
control was performed with Morphology: minimal alterations.
Oxygen.
Preconditioning: 1 mg/kg, rectal Reduction: serum blood urea nitrogen (BUN), creatinine (Cr), malondialdehyde (MDA), (Qiu et al., 2017)
pr
insufflations, 15 applications, renal allograft cell apoptosis index. Increase: superoxide dismutase (SOD), glutathione
once a day, before the kidney (GSH), catalase (CAT), nuclear factor erythroid 2-related factor 2 (Nrf-2), heme
transplantation. oxygenase 1 (HO-1).
e-
Morphological/immunohistochemistry: lower levels of damage, less severe renal
allograft.
Preconditioning: 0.7 mg/kg/d, Reduction: serum blood urea nitrogen (BUN), creatinine (Cr), serum/renal (Kurtoglu et al.,
intraperitoneally, 5 days, before malondialdehyde (MDA), total oxidant status (TOS). Increase: serum/renal nitric acid 2015)
Pr
the induction of contrast-induced (NO), total antioxidant status (TAS).
nephropathy. A control group was Histopathologic evaluation: reduction in degeneration of tubular epithelium, dilatation of
with Oxygen. Bowman capsule, necrosis in tubular epithelium, vascular congestion.
Preconditioning: 1 mg/kg, rectal Reduction: malondialdehyde (MDA), urea nitrogen (BUN), creatinine (Cr), Jablonski (Chen, Xing, Liu,
insufflations, 15 applications, grading scale scores. Increase: serum nitric acid (NO), NO synthase (endothelial, eNOS Zhan, Zhou, Zhu &
once a l day, before and inducible, iNOS) expression/protein, glutathione (GSH), superoxide dismutase Chen, 2008b)
na
ischemia/reperfusion and/or (SOD), glutathione peroxidase (GSH-Px).
ischemic preconditioning. Histological Examination/Immunohistochemistry: improved renal dysfunction,
histological damage, renal oxidative stress, increase presence of endothelial, eNOS and
inducible, iNOS.
Reduction dose-dependent manner: 40 μg/mL apoptosis rate, malondialdehyde (MDA),
ur
f
ischemia/reperfusion.
oo
/immunoistochemical, caspase-3, bcl-2-associated X (BAX), Bcl2.
Morphological/Immunoistochemical features: relieved tubular necrosis, medullary
haemorrhage, congestion and development of proteinaceous casts, reduction in Jablonski
scores.
Preconditioning: 1 mg/kg, rectal Reduction: serum blood urea nitrogen (BUN), creatinine (Cr), Jablonski grading scale (Chen, Xing, Liu,
pr
insufflations, 15 treatments, once scores, endothelin-1. Increase: serum nitric oxide (NO), NO synthase (endothelial, Zhan, Zhou, Zhu &
a day, before eNOS, inducible, iNOS) expression/protein, superoxide dismutase (SOD), glutathione Chen, 2008a)
ischemia/reperfusion. As control (GSH), glutathione peroxidase (GSH-Px).
e-
was used also Oxygen. Morphology: preservation of tissue histology.
Postconditioning: 0.5 mg/kg, Histopathological/Morphology: no significant differences for filtration fraction and (Fernandez Iglesias
rectal insufflations, 10 proteinuria, improvement in glomerular filtrate rate, renal plasma flow, creatinine, less et al., 2011)
applications, once a day, after overall histological damage.
Pr
ischemia/reperfusion. As control
was used also Oxygen.
Preconditioning: 1.1 mg/kg, Reduction: Systolic blood pressure (SBP), Diastolic blood pressure (DBP), Glycosylated (Morsy et al., 2010)
intraperitoneal, 5 days, before hemoglobin (HbA1c), serum blood urea nitrogen (BUN), creatinine (Cr), aldose
induction of diabetes. Other reductase (AR), malondialdehyde (MDA). Increase: superoxide dismutase (SOD),
l
groups were diabetic rats/insulin. glutathione peroxidase (GSH-Px), catalase (CAT).
na
Preconditioning: 25 mcg/ml, Reduction: malondialdehyde (MAD), Myeloperoxidase (MPO), Tumor necrosis factor-α (Aslaner et al.,
intraperitoneal, 15 days, before (TNF-α), interleukin-1β (IL-1β). Increase: glutathione (GSH). 2015)
methotrexate (20 mg/kg). Histolopatologically: reduction in degeneration of glomerular structures, glomerular
congestion, dilatation of Bowman’s space, degeneration of proximal tubuli, degeneration
ur
insufflations, 15 applications, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) (0.72, 1.1 mg/kg),
before cisplatin-induced catalase (CAT).
nephrotoxicity (6 mg/kg). Histopathological changes: at doses of 1.8 and 2.5 mg/kg, histopathological significant
improved changes in renal tissue
Preconditioning: 1 mg/kg, Increase: total antioxidant capacity (TAC), lipocalin (NGAL). No alteration in (Ozturk et al.,
intraperitoneal, 6 hours before and creatinine. 2018)
6 hours after contrast-induced Histopathological alterations: improving in Renal tubular injury, hemorrhage, cast
nephropathy agent (10 ml/kg), 5 formation.
56
days.
Preconditioning: Major Ozonated Reduction: interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), white blood cells, (Sancak et al.,
f
Autohemotherapy in 5m blood neutrophil to lymphocyte ratio (NLR), ischemia-modified albumin (IMA), total oxidant 2016)
oo
rabbit, before status (TOS), oxidative stress index (OSI). Increase: total antioxidant status (TAS).
ischemia/reperfusion. Histopathological changes: reduced the tubular brush border loss (TBBL), tubular cast
(TC), tubular necrosis (TN), intertubular hemorrhage congestion (IHC), dilatation of
bowman space (DBS).
Preconditioning: 0.5 mg/kg, rectal Reduction: Phospholipase A, Fructosamine. Increase: p-amino-hippurate (PAH), inulin, (Barber et al.,
pr
insufflations, 15 treatments, superoxide dismutase (SOD). 1999)
before ischaemia/reperfusion. Morphology: increased renal plasma flow (RPF), glomerular filtration rate (GFR).
Oxygen was used as further
e-
control.
Preconditioning: 0.8, 2.4, 4 Reduction: serum alanine amino transferase (ALT), aspartate amino transferase (AST), (Rodriguez et al.,
mg/kg, intraperitoneal, daily for 5 creatinine (CRE), thiobarbituric acid reactive substances (TBARS), myeloperoxidase 2009)
days, with/without sepsis. A (MPO). Increase: superoxide dismutase (SOD), glutathione peroxidase (GSH-Px).
Pr
control was performed with
Oxygen.
Preconditioning: 1mg/kg, Reduction: blood urea nitrogen (BUN), serum creatinine (Cr) (slightly), Jablonski grade, (Wang, Z. et al.,
transrectal insufflations, once a serum interleukin-6 (IL-6), IL-18, cyclooxygenase-2 (Cox-2), Malonaldehyde (MDA), 2018)
day, 15 treatments, before the nuclear factor NF-κBp65 and rabbit polyclonal anti-rat antibody (HMGB1)
l
kidney transplant procedure. expression/protein. Increase: Superoxide Dismutase (SOD), Glutathione peroxidase
na
(GSH-Px).
Morphology: alleviated the morphological damages, attenuated the injury of brush
border of proximal renal tubular, restrained the expression level of NF- κBp65 in renal
tissue, suppressed the expression of HMGB1 in renal tissue.
ur
150 mg/kg, intraperitoneally, Reduction: lactate dehydrogenase (LDH) (Liver, Kidney, Lungs, Heart). Increase: (Madej et al., 2007)
single dose for 10 days, at the Succinate Dehydrogenase (SDH) (Lungs, Heart), adenosine triphosphatase (ATPase) (no
same time Escherichia coli toxin Kidney), acid phosphatase (AcPase) (Liver, Kidney, Lungs, Heart), -Glucuronidase
(LPS) (20 mg/kg). (Liver, Kidney, Lungs).
Jo
f
tubular epithelial cells was slightly more pronounced (Kidney).
oo
Histochemically detected activity of lactic dehydrogenase (LDH): less pronounced
stimulation of enzyme in principal tubules and other portions of nephrons (Kidney).
Histochemically detected activity of adenosine triphosphatase (ATPase): decreased
intensity of the reaction in renal glomeruli and in walls of blood vessels, particularly
those of low caliper (Kidney).
pr
Histochemically detected activity of acid phosphatase (AcPase): decreased intensity of
the reaction pertained in principal tubuli and collecting duts (Kidney).
Histochemically detected activity of succinate dehydrogenase (SDH): no more
pronounced alterations (Lungs).
e-
Histochemically detected activity of lactate dehydrogenase (LDH): stimulation was less
pronounced (Lungs).
Histochemically detected activity of adenosine triphosphatase (ATPase): no changing
Pr
(Lungs).
Histochemically detected activity of acid phosphatase (AcPase): decreased activity
(Lungs).
Preconditioning: 0.2, 0.4, 1.2 Reduction dose-dependent manner: thiobarbituric acid reactive substances (TBARS). (Rodriguez et al.,
mg/kg intraperitoneally, once Increase dose-dependent manner: glutathione peroxidase (GPx). 2011)
l
daily, for 5 days, before
na
lipopolysaccharide (LPS)
injection (30 mg/kg).
Dexamethasone (30 mg/kg) used
as a reference drug.
Preconditioning: 0.2, 0.4, 1.2 Reduction dose-dependent manner: serum Tumor Necrosis Factor (TNF)-alpha, (Zamora et al.,
ur
mg/kg intraperitoneally, once thiobarbituric acid reactive substances (TBARS). Increase dose-dependent manner: 2005)
LIVER daily, for 5 days, before glutathion-S transferase (GST), glutathione peroxidase (GSH-Px).
lipopolysaccharide (LPS)
Jo
f
5.0 ml), 15 treatments, one per peroxidation (TBARS, thiobarbituric acid-reactive substances). Increase: cholinesterase
oo
day, before carbon tetrachloride (CHEase), superoxide dismutases (SODs), Catalase (CAT), Calcium-dependent (Ca-
(CCl4). ATPase), gluthatione (GSH), glucose-6-phosphate dehydrogenase (G6PD).
Ozone control groups were: 1. A Morpho-metric evaluation of the hepatic damage: reduction of the damage area.
control was with oxygen; 2.
another control was ozone without
pr
CCl4.
Preconditioning: 1 mg/kg, rectal Reduction: Aspartic alanine transaminase (AST), serum alanine aminotransferase (ALT), (Ajamieh, H. H. et
insufflation, 15 treatments, one malondialdehyde (MDA) + 4-hydroxyalkenals, nitrite/nitrate (NO2-/NO3-). Increase: al., 2004)
e-
per day, before ischaemia– superoxide dismutase (SOD), total hydroperoxide (TH), glutathione (GSH), Ratio
reperfusion. GSH/GSSG.
Preconditioning; 0.7 mg/kg, Reduction: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), (Gultekin, Cakmak
intraperitoneal, daily five times, tumor necrosis factor alpha (TNF-α). No alterations: interleukin-6 (IL-6). et al., 2013)
Pr
before 70% partial hepatectomy. Histopathological examination: improve in liver weight, mitotic index, proliferating cell
nuclear antigen (PCNA) labeling index.
Preconditioning: 0.7 mg/kg, Reduction time-dependent manner: serum alanine aminotransferase (ALT), aspartate (Gultekin, Bakkal
intraperitoneal, daily five times, aminotransferase (AST), tumor necrosis factor alpha (TNF-α), malondialdehyde (MDA). et al., 2013)
before total body irradiation with Increase time-dependent manner: superoxide dismutase (SOD).
l
a single dose of 6 Gy. Histopathological examination: reduction in hepatocellular degeneration, inflammation,
na
congestion and dilatation in both sinusoids and central veins; reduced inflammatory cell
infiltrate in the lamina propria; regular villous structure, abundant goblet cells in the
epithelium; reduced inflammatory cell infiltrate in the lamina propria.
Preconditioning: 0.5 mg/kg, Reduction: Nuclear factor κB (NF-κB) staining. (Sun, Pei, 2012)
ur
intraperitoneal, daily five times, Morphology/Immunohistochemistry parameters: intact hepatic architecture, normal liver
before lipopolysaccharide (LPS) cell membrane integrity, little inflammatory cell infiltration (low NF-kB-positive
injection (20 mg/kg). Ketamine (5 staining).
mg/kg) used as a reference drug.
Jo
Preconditioning: 1 mg/kg, rectal Reduction: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), (León Fernández et
insufflation, 15 treatments, one nitric oxide (NO) (nitrite/nitrate (NO-2)/NO-3), adenosine deaminase (ADA), al., 2008)
per day, before malondialdehyde (MAD), 4-hydroxyalkenals, attenuated GSSG increase, NF-kB (p65
ischemia/reperfusion. Agonist (2- subunit) expression, tumor necrosis factor alpha (TNF-α), heat shock protein-70
chloro N6 cyclo-pentyladenosine, (HSP70). Increase: glutathione (GSH).
CCPA), Antagonist (8- Immunohistochemistry: remarkable preservation of the liver parenchyma architecture,
cyclopentyl-1,3-dipropylxanthine, prevention of the inflammatory recruitment.
DPCPX) of A1 subtype receptor.
59
Preconditioning: 1 mg/kg, rectal Reduction: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), (Ajamieh, H. H. et
insufflation, 15 treatments, one malondialdehyde (MAD), 4-hydroxyalkenals. Increase: SOD (MnSOD), glutathione al., 2005)
f
per day, before (GSH), GSH/GSSG.
oo
ischemia/reperfusion. Histological lesions: normal morphology of the acinus like sham-operated.
Cycloheximide (CHX) to promote Ultrastructural analysis: normal appearance of mithocondrial, rough endoplasmatic
protein synthesis inhibition after reticulum and peroxisome, no alteration on nucleus structure.
OzoneOP treatment.
Preconditioning: 1 mg/kg, rectal Reduction: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), 5’- (Ajamieh, H. et al.,
pr
insufflation, 15 treatments, one NT, malondialdehyde (MDA), 4 hydroxyalkenals. calcium, calpain, total Xanthine 2002)
per day, before dehydrogenase (XDH), xanthine oxidase (XO). Increase: total sylfhydryl groups.
ischemia/reperfusion and/or Improvement in histological parameters: normal morphology of hepatic lobuli.
e-
ischaemic preconditioning.
Oxygen was another control
comparison.
Preconditioning: 1 mg/kg, rectal Reduction: uric acid, lactate, thiobarbituric acid-reactive substances (TBARS). Increase: (Candelario-Jalil et
Pr
insufflation, 15 treatments, one hepatic glycogen, liver weight (LW)/body weight (BW) ratios, superoxide dismutase al., 2001)
per day, before carbon (SOD), catalase (CAT).
tetrachloride (CCl4) (1ml/kg). An Histopathological findings: the permanence of glycogen deposits in hepatic cells was
ozone control group was ozone proved, only a minimal non-parenquimatous cell reaction co-existed around the central
without CCl4. vein.
Preconditioning: l 0.7 mg/kg, Reduction: malondialdehyde (MDA). Increase: superoxide dismutase (SOD), glutathione (Kesik et al., 2009)
na
intraperitoneal, 15 applications peroxidase (GSH-Px).
(once daily), before methotrexate Histologically: ILEUM: less inflammatory cell infiltration and edema, reduction in
(Mtx) (6 mg/kg). vacuolated cells in the epithelium; LIVER/KIDNEY: no significant change, due
probably to the cumulative prolonged effect of Mtx on these tissues.
Preconditioning: 10, 30, 50 μg/ml,
ur
f
same time Escherichia coli toxin
oo
(LPS) (20 mg/kg). (Liver, Kidney, Lungs).
Histochemically detected activity of succinate dehydrogenase (SDH): extinguished
enzymatic activity in central parts of the lobule and paralleled by narrowing of zone I
(Liver).
Histochemically detected activity of lactate dehydrogenase (LDH): increased activity
pr
(hepatocytes, Kupffer cells, Liver).
Histochemically detected activity of adenosine triphosphatase (ATPase): decrease
intensity of the reaction for ATPase (Liver).
e-
Histochemically detected activity of acid phosphatase (AcPase): lower decrease in
activity (Liver).
Histochemically detectable activity of succinate dehydrogenase (SDH): the reaction in
tubular epithelial cells was slightly more pronounced (Kidney).
Pr
Histochemically detected activity of lactic dehydrogenase (LDH): less pronounced
stimulation of enzyme in principal tubules and other portions of nephrons (Kidney).
Histochemically detected activity of adenosine triphosphatase (ATPase): decreased
intensity of the reaction in renal glomeruli and in walls of blood vessels, particularly
those of low caliper (Kidney).
l Histochemically detected activity of acid phosphatase (AcPase): decreased intensity of
na
the reaction pertained in principal tubuli and collecting duts (Kidney).
Histochemically detected activity of succinate dehydrogenase (SDH): no more
pronounced alterations (Lungs).
Histochemically detected activity of lactate dehydrogenase (LDH): stimulation was less
pronounced (Lungs).
ur
(Lungs),
Preconditioning: 0.7 mg/kg, Reduction: malondialdehyde (MDA), serum tumor necrosis factor alpha (TNF-a), (Bakkal et al.,
intraperitoneal, 5 applications interleukin-1 beta (IL-1). Increase: superoxide dismutase (SOD). 2013)
(once daily), before total body Histopathological evaluation: reduction in alveolar area, interstitial congestion, and
LUNG irradiation (TBI) (6 Gy). alveolar and bronchiolar hemorrhage.
Preconditioning: 100 μg/kg, Reduction: malondialdehyde (MDA), myeloperoxidase (MPO), inflammasome (Wang, Z., Zhang
intraperitoneal, once daily for 10 (NLRP3), apoptosis-associated speck-like protein containing a caspase activation and et al., 2018)
days, before ischemia/reperfusion. recruitment domain (ASC), un-cleavable cysteine-requiring aspartate protease-1
61
A control was performed with (procaspase-1), cysteine-requiring aspartate protease-1 (caspase-1), apoptotic index,
Oxygen. interleukin-1 beta (IL-1). Increase: transcription factor Nrf2, superoxide dismutase
f
(SOD).
oo
Macroscopic and histologic view: dark and edematous tissue, inter alveolar septum,
rupturing and alveolar space hemorrhage disappear.
Preconditioning: 0.8, 2.4, 4 Reduction: serum alanine amino transferase (ALT), aspartate amino transferase (AST), (Rodriguez et al.,
mg/kg, intraperitoneal, daily for 5 creatinine (CRE), thiobarbituric acid reactive substances (TBARS), myeloperoxidase 2009)
days, with/without sepsis. A (MPO). Increase: superoxide dismutase (SOD), glutathione peroxidase (GSH-Px).
pr
control was performed with
Oxygen.
Preconditioning: Reduction dose-dependent manner: bcl-2-associated X (BAX), nuclear factor NF-κβ, (Kucukgul et al.,
IN VITRO A549 cell lines, 1, 10, tumor necrosis factor alpha (TNF-α), Inducible nitric oxide synthase (iNOS), nitrite
e-
2016)
20, 80 mol/L, before H2O2. levels. Increase dose-dependent manner: catalase (CAT), glutathione peroxidase (GSH-
Px), superoxide dismutase (SOD), glutathione (GSH) expression.
Morphology: recovered the majority of cells from the toxicity, regenerated cell
Pr
proliferation, prevented 9.6% and 11.0% of cell loss.
Preconditioning: 10, 30, 50 μg/ml, Reduction dose-dependent manner in LIVER/LUNG: conjugated dienes (CD), (Guanche et al.,
intraperitoneal, 5 days, before thiobarbituric acid-reactive substances (TBARS), Total pro-oxidant activity (TOS). 2010)
sepsi induced by intraperitoneal Increase dose-dependent manner: superoxide dismutase (SOD), catalase (CAT),
injection of rat fecal material glutathione peroxidase (GSH-Px), Total antioxidant activity (TAC).
l
(0.5g per kg of animals weight)
na
extracted from another donor rat.
A control group was performed
with oxygen.
150 mg/kg, intraperitoneally, Reduction: lactate dehydrogenase (LDH) (Liver, Kidney, Lungs, Heart). Increase: (Madej et al., 2007)
ur
single dose for 10 days, at the Succinate Dehydrogenase (SDH) (Lungs, Heart), adenosine triphosphatase (ATPase) (no
same time Escherichia coli toxin Kidney), acid phosphatase (AcPase) (Liver, Kidney, Lungs, Heart), -Glucuronidase
(LPS) (20 mg/kg). (Liver, Kidney, Lungs).
Histochemically detected activity of succinate dehydrogenase (SDH): extinguished
Jo
enzymatic activity in central parts of the lobule and paralleled by narrowing of zone I
(Liver).
Histochemically detected activity of lactate dehydrogenase (LDH): increased activity
(hepatocytes, Kupffer cells, Liver).
Histochemically detected activity of adenosine triphosphatase (ATPase): decrease
intensity of the reaction for ATPase (Liver).
Histochemically detected activity of acid phosphatase (AcPase): lower decrease in
activity (Liver).
62
Histochemically detectable activity of succinate dehydrogenase (SDH): the reaction in
tubular epithelial cells was slightly more pronounced (Kidney).
f
Histochemically detected activity of lactic dehydrogenase (LDH): less pronounced
oo
stimulation of enzyme in principal tubules and other portions of nephrons (Kidney).
Histochemically detected activity of adenosine triphosphatase (ATPase): decreased
intensity of the reaction in renal glomeruli and in walls of blood vessels, particularly
those of low caliper (Kidney).
Histochemically detected activity of acid phosphatase (AcPase): decreased intensity of
pr
the reaction pertained in principal tubuli and collecting duts (Kidney).
Histochemically detected activity of succinate dehydrogenase (SDH): no more
pronounced alterations (Lungs).
Histochemically detected activity of lactate dehydrogenase (LDH): stimulation was less
e-
pronounced (Lungs).
Histochemically detected activity of adenosine triphosphatase (ATPase): no changing
(Lungs).
Pr
Histochemically detected activity of acid phosphatase (AcPase): decreased activity
(Lungs).
Preconditioning: rectal Reduction dose-dependent manner: creatine kinase-MB (CK-MB), lactate, (Ahmed, L. A. et
insufflations as five applications myeloperoxidase (MPO), total nitrate/nitrite (NOx), thiobarbituric acid reactive al., 2012)
per week. In a group: 0.3 substances (TBARS). Increase dose dependent manner: Myocardial adenine nucleotides
l
mg/kg/day in the first week, and (ATP, ADP, AMP, TAN), glutathione (GSH).
na
0.5 mg/kg/day in the second Histological examination, ultrastructural analyses: improvement in edema in between
week. In another group, 0.6 muscle fibers, and edema within muscle fibers, good myofibrillar arrangement with only
mg/kg/day in the first week, and 1 slight edema around muscle fibers, mild mitochondrial swelling with decreased matrix
mg/kg/day in the second week, density and mild disruption of mitochondrial cristae and vesiculation, slight margination
before ischemia/reperfusion. A of chromatin near nuclear membrane.
ur
intraperitoneally, once daily, 5 putative kinase 1 (PINK1), cytochrome c oxidase subunit IV (COX4), Caspase 3,
days, before ischemia/reperfusion. myocardial apoptosis. Increase: nuclear factor (erythroid-derived 2)-like 2 (Nrf2),
A control was performed with glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase modifier
Oxygen. subunit (GCLM), superoxide dismutases (SODs) expression.
Morphology: mild mitochondrial injury.
Validation of: 1. nuclear extracts (TATA-binding protein (TBP) in nuclear extracts), 2.
mitochondrial fractions separated from the cytoplasmic fraction (cytochrome c oxidase
subunit IV (COX4) detectable).
63
Preconditioning: 0.6 mg/kg, rectal Reduction: malondialdehyde (MDA), protein carbonyls (Pr Co), lipofuscin, cytosolic (El-Sawalhi et al.,
insufflations, twice/week for the Ca2+ (heart/hippocampus). Increase: glutathione (GSH), energy status (ATP, ADP) 2013)
f
first 3 months, then once/week till (heart/hippocampus), Na+, K+, ATPase (hippocampus).
oo
the age of 15 months, in aged rats.
A control was performed with
Oxygen.
Preconditioning: 50, 80 mL/kg, Prolonged cardiac allograft survival without any adjunctive immunosuppressive therapy, (Stadlbauer et al.,
single (1x) or repetitive (5x) not alternated number of red blood cells, decreased number of thrombocytes, increase of 2008)
pr
insufflation, in rat cardiac white blood cells, mostly granulocytes.
transplant model.
Preconditioning; 0.3 mg/kg, rectal Reduction: pro- brain natriuretic peptide (BNP), malondialdehyde (MDA), advanced (Delgado-Roche et
e-
insufflation, once on alternating oxidation protein products (AOPP). Increase: superoxide dismutase (SOD), catalase al., 2014)
days for 20 sessions, before (CAT).
doxorubicin (2 mg/kg). The Morphology: slight damage, normal morphology of cardiac fibres.
oxygen group was a further 90% survival rate, reduced loss of body weight.
Pr
control.
150 mg/kg, intraperitoneally, Reduction: lactate dehydrogenase (LDH) (Liver, Kidney, Lungs, Heart). Increase: (Madej et al., 2007)
single dose for 10 days, at the Succinate Dehydrogenase (SDH) (Lungs, Heart), adenosine triphosphatase (ATPase) (no
same time Escherichia coli toxin Kidney), acid phosphatase (AcPase) (Liver, Kidney, Lungs, Heart), -Glucuronidase
(LPS) (20 mg/kg). (Liver, Kidney, Lungs).
l Histochemically detected activity of succinate dehydrogenase (SDH): extinguished
na
enzymatic activity in central parts of the lobule and paralleled by narrowing of zone I
(Liver).
Histochemically detected activity of lactate dehydrogenase (LDH): increased activity
(hepatocytes, Kupffer cells, Liver).
ur
f
pronounced alterations (Lungs).
oo
Histochemically detected activity of lactate dehydrogenase (LDH): stimulation was less
pronounced (Lungs).
Histochemically detected activity of adenosine triphosphatase (ATPase): no changing
(Lungs).
Histochemically detected activity of acid phosphatase (AcPase): decreased activity
pr
(Lungs).
Preconditioning: 0.7 mg/kg, Reduction: malondialdehyde (MDA), myeloperoxidase (MPO). Increase: bursting (Tasdoven et al.,
intraperitoneal, daily five times, pressure values of anastomosis, Hydroxyproline (HPO), superoxide dismutase (SOD). 2019)
e-
before irradiation of 500 cGy. Histopathological evaluation: improving in anastomotic wound healing, granulation
tissue development and histological changes corresponding to the local inflammatory
response.
Preconditioning: 0.7 mg/kg, Reduction time-dependent manner: serum alanine aminotransferase (ALT), aspartate (Gultekin, Cakmak
Pr
intraperitoneal, daily five times, aminotransferase (AST), tumor necrosis factor alpha (TNF-α), malondialdehyde (MDA). et al., 2013)
before total body irradiation with Increase: superoxide dismutase (SOD).
a single dose of 6 Gy. Histopathological examination: reduction in hepatocellular degeneration, inflammation,
congestion and dilatation in both sinusoids and central veins, reduced inflammatory cell
infiltrate in the lamina propria, regular villous structure, abundant goblet cells in the
INTESTINE
l epithelium, reduced inflammatory cell infiltrate in the lamina propria.
na
Preconditioning: 0.7 mg/kg, Reduction: malondialdehyde (MDA). Increase: superoxide dismutase (SOD), glutathione (Kesik et al., 2009)
intraperitoneal, 15 applications peroxidase (GSH-Px).
(once daily), before methotrexate Histologically: ILEUM: less inflammatory cell infiltration and edema, reduction in
(Mtx) (6 mg/kg). vacuolated cells in the epithelium; LIVER/KIDNEY: no significant change, due
ur
ischemia/reperfusion. protein. Reduction: Park's Injury Score in jejunum and ileum, enterocyte apoptosis in
jejunum and ileum, caspase 3.
Preconditioning: 1 mg/kg, Reduction: apoptotic index, malondialdehyde (MDA), the total oxidant score (TOS). (Onal et al., 2017)
intraperitoneally, 7 days, before Increase: superoxide dismutase (SOD), glutathione peroxidase (GSH‐ Px), total
ischemia/reperfusion. antioxidant capacity (TAC), catalase (CAT).
COCHLEAR
Histological evaluation: increased numbers of glial cells in the spiral ganglion, reduced
level of vascularization.
Postconditioning: 60 ug/mL, Statistically significant differences in DPOAE results. (Koçak et al., 2016)
65
rectal and/or intratympanic, 7 Histopathological scoring: decreased stria vascularis damage, decreased inner–outer hair
days, after cisplatin-induced cell damage.
f
ototoxicity (5-mg/kg/day). The
oo
rats were tested with distortion
product otoacoustic emissions
(DPOAE).
Postconditioning: 30 µg/ml, Reduction: malondialdehyde (MDA), % mitochondrial swelling, mitochondrial (Nasezadeh et al.,
intravenous, daily administration membrane potential (MMP), Glutathione disulfide (GSSG), cytochrome c (Brain, 2017)
pr
for 14 days, at the same time with cochlear). Increase: glutathione (GSH), glutathione peroxidase (GSH‐ Px), superoxide
noise exposure. dismutase (SOD) (Brain, cochlear), ATP.
Histopathological findings: prevents mitochondrial membrane potential (MMP) collapse,
e-
mitochondrial swelling, cytochrome c release.
Preconditioning: 0.7 mg/kg, Reduction: malondialdehyde (MDA), Serum nitrite-nitrate (NOx), Inducible nitric oxide (Koca et al., 2010)
intraperitoneally; 4 doses, before synthase (iNOS) immunostaining. Increase: glutathione peroxidase (GSH‐ Px),
ischemia. superoxide dismutase (SOD).
Pr
SKELETAL Preconditioning: 0.7 mg/kg, 6 Reduction: malondialdehyde (MDA), interleukin-1β (IL-1β), creatinine kinase (CK), (Ozkan et al., 2015)
days, before ischemic period aspartate aminotransferase (AST), K+, nitric oxide (NO). Increase: glutathione
and/or hypothermia. peroxidase (GSH‐ Px), superoxide dismutase (SOD).
iNOS immunohistochemical staining: mild intensity.
Preconditioning: 50 μg/kg, Reduction: 4-hydroxynonenal (4-HNE), Poly(ADP-ribose) polymerase-1 (PARP-1), (Siniscalco et al.,
l
intraperitoneally, once a day for glucagon, glycemia. Increase: nuclear factor Nrf2, glutathione-s-transferase (GST), 2018)
na
seven days. Streptozotocin (STZ) insulin, leptin.
(2ml). A control was performed Immunohistochemistry: reduction in tissue degeneration evidenced by the partial
with Oxygen. restoration of normal cellular population size of islets of Langerhans and absence of islet
damage. Immunofluorescence: reduction in cell death, decreased DNA damage.
ur
PANCREAS Postconditioning: 0.7-mg/kg, Reduction: serum amylase, neopterin, lipase, aspartate aminotransferase (AST), alanine (Uysal et al., 2010)
intraperitoneally, daily for 3 days. amino transferase (ALT), -Glutamyl transferase (GT), malondialdehyde (MAD).
induction of acute necrotizing Increase: Alkaline phosphatase (AP), glutathione peroxidase (GSH-Px), superoxide
pancreatitis. A control was dismutase (SOD).
Jo
f
for 2 hours. Histopathological score: lower.
oo
OTHER Preconditioning: 1 mg/kg, rectal Reduction: malondialdehyde (MDA), peroxidation potential (PP), advanced oxidation (Delgado-Roche et
insufflation, 15 sessions in 5 protein products (AOPP), nitric oxide (NO). Increase: glutathione (GSH). al., 2013)
weeks, in alternated days, 2 Histopathology: minimal lesions in the aortas, smaller intima/media ratio.
mL/kg of lipofundin. A control
group was performed with
pr
Oxygen.
e-
l Pr
na
ur
Jo
67