Ozone: a natural bioactive molecule with antioxidant property as potential new strategy in aging and in neurodegenerative disorders

Catia Scassellati, Antonio Carlo Galoforo, Cristian Bonvicini, Ciro Esposito, Giovanni Ricevuti, Catia Scassellati, Antonio Carlo Galoforo, Cristian Bonvicini, Ciro Esposito, Giovanni Ricevuti

Abstract

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 factor (erythroid-derived 2)-like 2 (Nrf2). Nrf2 plays a central role in different pathologies including neurodegenerative disorders (NDs), which are characterized by common pathogenetic 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 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 found a significant modulation of O3 on endogenous antioxidant-Nrf2 (p < 0.00001, Odd Ratio (OR) = 1.71 95%CI:1.17-2.25) and vitagene-Nrf2 systems (p < 0.00001, OR = 1.80 95%CI:1.05-2.55). O3 activates also immune, anti-inflammatory signalling, proteasome, releases growth factors, improves blood circulation, and has antimicrobial activity, with potential effects on gut microbiota. Thus, we provide 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 other antioxidants (polyphenols, mushrooms) implicated in the same Nrf2-mechanisms, can show neurogenic potential, providing evidence as new preventive strategies in aging and in NDs.

Keywords: Neurodegenerative Disorders; Oxygen-Ozone (O(2)-O(3)) therapy; Ozone (O(3)); antioxidant system; nuclear factor (erythroid-derived 2)–like 2 (Nrf2); stress oxidative biomarkers.

Conflict of interest statement

The authors have declared no conflict of interest.

Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
Molecular mechanisms linked to antioxidant/pro-authophagy activities of ozone (O3) via Nfr2 signalling. In the absence of stimuli, Nrf2 (nuclear factor erythroid 2–related factor 2) binds to its repressor Keap1 (kelch-like ECH-associated protein), an adapter between Nrf2 and Cullin 3 (Cul3) protein, which leads to ubiquitination followed by proteasome degradation. When O3 is administrated, it dissolves immediately and it reacts with PUFA (Poly-Unsaturated Fatty Acids) leading to the formation of fundamental messengers such as 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 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 Oxygenase 1 (HO-1), Superoxide dismutases (SOD), Glutathione peroxidase (GSH-Px), Glutathione-S-Transferase (GST), Catalase (CAT), GSH-reductase (GR), NADPH quinone oxidoreductase 1 (NQO1), Heat Shock Proteins (HSPs), Cytochrome P450 monooxygenase (CYP450), Thioredoxin reductase (TrxR), phase II enzymes (UDP-glucuronosyltransferases, UGTs; N-acetyltransferases, NATs, sulfotransferases, SULTs). A) O3 involves casein kinase 2 (CK2), a regulator of the Nrf2 activity through its phosphorylation, and MAPK (mitogen-activated protein kinase) signalling pathway, that is inhibited with consequent inactivation of oxidative stress and apoptosis by O3 administration. B) O3 modulates the degradation protein systems (autophagy), via activation of the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway. C) O3 downregulates inducible nitric oxide synthase (iNOS), which generates nitric oxide (NO) via NF-κB (Nuclear Factor Kappa B Subunit 1) pathway. (CO = carbon monoxide).
Fig. 2
Fig. 2
Molecular mechanisms linked to anti-apoptotic property of ozone (O3) via pro-apoptotic molecules inactivation. Various apoptotic stimuli, ischemia, Reactive Oxygen 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 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 (BH3-interacting domain death agonist), Nrf2 (Nuclear Factor Erytroid 2-related factor 2), CUL3 (Cullin 3), Keap 1 (Kelch-like ECH-associated Protein), H2O2 (Hydrogen Peroxide), 4HNE (4-hydroxynonenal), LOPs (Lipid Oxidation Products), Cyt C (Cytochrome C), PUFAs (Poly-Unsaturated Fatty Acid), AREs (Antioxidant Response Elements)).
Fig. 3
Fig. 3
Forest plot for odds ratio from meta-analysis of the endogenous Nrf2- antioxidant pathway before and after ozone (O3) treatment. CI, confidence interval; Chi2, χ2 test of goodness of fit; Tau2, estimate of the between-study variance in a random-effects meta-analysis. Superoxide dismutase (SOD), catalase (CAT), Glutathione peroxidase (GSH-Px), Glutathione (GSH), Glutathione S-transferase (GST), Glutathione reductase (GR). RI = rectal insufflations; MATH = major autohemotherapy
Fig. 4
Fig. 4
Forest plot for odds ratio from meta-analysis of the endogenous Nrf2- vitagene pathway before and after ozone (O3) treatment. CI, confidence interval; Chi2, χ2 test of goodness of fit; Tau2, estimate of the between-study variance in a random-effects meta-analysis. Nuclear factor Nrf2, heme-oxigenase (HO-1), heat shock protein (HSP)

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