Medical Ozone. Redox regulation and a new mechanism in the treatment of rheumatoid arthritis

Olga Sonia León Fernández * , Gabriel Takon Oru , Renate Viebahn-Haensler , Gilberto López Cabreja ,
Irainis Serrano Espinosa , María Elena Corrales Vázquez
Posted Date: 4 October 2024
doi: 10.20944/preprints202410.0288.v1
Keywords: Ozone; Reactive Oxygen Species; Rheumatoid Arthritis; Methotrexate; A1 Adenosine Receptors

Medical Ozone. Redox regulation and a new
mechanism in the treatment of rheumatoid arthritis
Olga Sonia León Fernández 1
, *, Gabriel Takon Oru 1 , Renate Viebahn-Haensler 2
, Gilberto
López Cabreja 3
, Irainis Serrano Espinosa 3
and María Elena Corrales Vázquez 4
1 Pharmacy and Food Institute, University of Havana, Havana 13603, Cuba; orugabriel@yahoo.com
2 Medical Society for the Use of Ozone in Prevention and Therapy, D-76473 Iffezheim, Germany;
renateviebahn@t-online.de
3 National Institute of Rheumatology, Ministry of Public Health, Havana 19210, Cuba;
gilberto.lopez@infomed.sld.cu; serranoespinosairainis@gmail.com
4 Clinical Laboratory of the Surgical and Clinical Teaching Hospital “10 de Octubre”, Faculty of Medical
Sciences, Ministry of Public Health, Havana 19210, Cuba; mariaelenacorralesvazques@gmail.com

  • Correspondence: olgasonia204@gmail.com; Tel.: +53-72727726.
  • Abstract: Medical ozone is a redox regulator with beneficial effects in oxidative etiology diseases such as
    rheumatoid arthritis (RA). The aim of this study was to conduct a holistic review from different
    pharmacological trials involving ozone in model diseases as well as the clinical response of RA patients. The
    ROS involved in RA and its relationship to the main pathological pathways of this autoimmune disease were
    here considered. The integrator analysis of experimental results from animals with clinical findings have
    revealed that both methotrexate (MTX) and medical ozone share common mechanisms via adenosinergic
    regulation. This finding has enabled us to propose a new pharmacological mechanism in the treatment of RA.
    We concluded that MTX + medical ozone combined therapy reduces ROS overproduction and the generation
    of proinflammatory cytokines, and decreases anti-cyclic citrullinate peptide levels by a mutual mechanism
    involving adenosine A1 receptors.
    Keywords: ozone; reactive oxygen species; rheumatoid arthritis; methotrexate; a1 adenosine receptors
  1. Introduction
    The loss of cellular redox balance leads to oxidative stress (OS) as a result of an excessive
    production of Reactive Oxygen Species (ROS) that exceed antioxidant defenses [1] and cause cellular
    damage with loss of vital functions.
    It is important to note that OS does not always promote damage. Some ROS participate in signaling mechanisms and regulate processes essential for life. A good example is nitric oxide, a free radical and vasodilator, released by endothelial cells; its deficit is associated with cardiovascular and other diseases. OS is involved in a variety of autoimmune diseases of oxidative etiology [2,3], particularly rheumatoid arthritis (RA). RA is a chronic systemic autoimmune disease causing progressive disability and premature death [4]. It is a symmetric peripheral disease involving bone erosion, proximal involvement and destructive bone lesions. In addition to this, RA patients display
    synovitis, morning stiffness and/or immobility of their proximal interphalangeal joints [5]. Finally, such patients suffer joint failure due to cartilage damage and severely weakened tendons and ligaments [6].
    In the development of RA, a proinflammatory and hypoxic scenario is generated in the synovial tissue, which leads to an overproduction of Reactive Oxygen Species (ROS) with DNA damage and mitochondrial dysfunction. The synovium is the principal target as it is associated with the degree of RA activity. This compartment is severely infiltrated by immune system cells leading to neovascularization [7]. The joints of patients affected by RA show inflammation, edematous synovial tissue with hyperemia and other alterations [8].
    Disclaimer/Publisher’s Note: The statements, opinions, and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions, or products referred to in the content.
    Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 4 October 2024 doi:10.20944/preprints202410.0288.v1

    One important source of ROS in RA is the mitochondria. In particular, the superoxide anion radical is generated in the mitochondrial electron transport chain with the participation of complexes I, II and III [9]. This ROS is a precursor of other ROS, such as hydrogen peroxide, which triggers a cascade of reactions giving rise to different molecules involved in RA. The accumulation of ROS in the mitochondria leads to the modification of functions such as the activation of the mitochondrial permeability transition pore. An extension of the opening time of these pores can induce an explosive increase of ROS that damage the mitochondria itself which is linked to different pathological
    conditions expressed in the form of comorbidities of RA [10,11]. On the other hand, the joints of patients with RA are in a state of hypoxia, which is linked, as an additional factor, to the production of ROS [12]. ROS levels have been correlated with the degree of RA activity, C-reactive protein and antibodies against cyclic citrullinated peptides in the blood of patients with RA, with ROS being reported as an indirect indicator of the degree of synovial inflammation in these patients [13,14].
    Neutrophils represent 60% of total leukocytes. These cells are part of the innate immunity, constituting the first lines of defense against infections and orchestrating adaptive immune responses. It has been suggested that neutrophil extracellular traps (NETs), activation of peptidyl arginine deiminase (PAD), and generation of citrullinated peptides are at the core of RA pathogenesis. Activated neutrophils accumulate in synovial fluid and tissue. Moreover, fibroblasts such as synoviocytes internalize NET-associated citrullinated peptides, recruit antigen-presenting
    cells that present this peptide-NET complex to CD4+ T cells to produce an autoimmune response [16].
    Neutrophil levels in RA patients are significantly higher than in subjects with other arthritic diseases. Their concentrations were positively correlated with inflammation and disease severity. ROS are released by neutrophil degranulation, including superoxide anion radical, increased mitochondrial and extracellular oxidative stress with a decrease in antioxidant defense mechanisms in RA [17,18].
    Macrophages, together with neutrophils, belong to the set of cells that constitute innate immunity. Macrophages release high levels of ROS produced by different sources and sites of formation. The first identified source of superoxide anion radical generation by macrophages was NADPH Oxidase located in the plasma membrane, which produces the superoxide radical by transfer of an electron from NADPH to oxygen. It is worth noting that, in the macrophage, we find other sites of ROS production – of mitochondrial origin – such as the formation of hydrogen peroxide by monoamine oxidase (MAO) in the outer membrane of the mitochondria; a superoxide anion
    radical, hydrogen peroxide and hydroxyl radical in the mitochondrial matrix, through the electron transport chain. In addition to this we also find hydrogen peroxide with a participation of cytochrome C in the inner membrane of the mitochondria, plus superoxide anion radical and hydrogen peroxide in the cytosol due to the metabolism of xanthine via xanthine oxidase [19]. From the above, it is evident that the superoxide anion radical is released by macrophages from different sites and by different enzymes and can play a central role in the triggering of RA..

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