Treatment of case
治疗案例

  Oxygen-ozone immunoceutical therapy in COVID-19 outbreak: facts and figures

  COVID-19爆发的氧-臭氧免疫治疗:事实与数据

  

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  Giovanni Ricevuti,1 Marianno Franzini,2 Luigi Valdenassi3

  1Department of Drug Science, University of Pavia, Italy, High School in Oxygen Ozone Therapy, University of Pavia;

  2SIOOT International, Comunian Clinic, Gorle (BG), High School in Oxygen Ozone Therapy, University of Pavia;

  3SIOOT, Italian Society of Oxygen Ozone Therapy, High School in Oxygen Ozone Therapy, University of Pavia, Italy

  The problems related to the approach to the outbreak of COVID-19 in the world require that all possible effective treatment options be explored. The clinical criterion of the researcher is not to refuse a priori, but to verify and evaluate the proposals that are made. Italian Society of Oxygen Ozone Therapy (SIOOT) proposed to the Italian ISS (Italian Institute of Health) to use oxygen ozone therapy (O2O3) in patients with COVID-19. The ISS has said on 24 March 2020 that it is possible to use it in the light of scientific considerations:

  世界范围内与COVID-19爆发途径有关的问题要求探索所有可能的有效治疗方案。研究者的临床标准不是拒绝先验,而是验证和评估提出的建议。意大利氧臭氧治疗协会(SIOOT)向意大利ISS(意大利卫生研究所)提议,对COVID-19患者使用臭氧治疗(O2O3)。意大利卫生研究所在2020年3月24日曾表示,从科学角度考虑,有可能使用它:

  


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  Although the proposal is supported by a certain rational basis, the data actually available in relation to the proposed indication consist essentially in demonstrating the effectiveness of ozone in killing SARS virus in monkey cells, and clinical experience of the benefit in patients with bronchopulmonia. However, as the proposal appears to be shared and supported by clinical centers experienced in the treatment of viral pneumonia, treatment could, if deemed appropriate, be carried out under the responsibility of the physician, after obtaining the informed consent of the patient. Considering the “experimental” character of the use this indication, which also requires specific medical experience and the availability of appropriate instruments, it is considered appropriate to acquire also the opinion of the Ethics Committee.

  虽然该建议有一定的合理依据,但与建议适应症相关的实际可用数据基本上包括证明臭氧在猴细胞中杀灭SARS病毒的有效性,以及在支气管肺疾病患者中受益的临床经验。然而,由于该提案似乎得到了在治疗病毒性肺炎方面经验丰富的临床中心的赞同和支持,如果认为适当,在获得患者的知情同意后,可以由医生负责进行治疗。考虑到使用该适应症的“实验性”特点,这也需要特定的医疗经验和适当的器械,也可以考虑征求伦理委员会的意见。

  

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  Some hospitals in Lombardy, the region most affected by COVID-19 in Italy, have already started its use with initial positive results.

  As little is known about O2O3 in the world, although there is a lot of scientific evidence published in the recent years on the anti-inflammatory, immunomodulatory and organ-protective validity of O2O3 therapy, we consider useful to follow the suggestions of the article Activating Immunity to Fight a Foe – A New path, by Richard S. Hotchkiss and Steven M. Opal, and proposing the O2O3 therapy as immunoceutical therapy according to the indications of the article. The O2O3 therapy has many biological effects, but the most relevant is its ability to modulate the activation of Nrf2 (an important nuclear message transductor), the downregulation of NFkB, and it also modulates the NLRP3 inflammasome.

  意大利受COVID-19影响最大的伦巴第地区的一些医院已经开始使用COVID-19,并取得了初步的积极成果。世界上对三氧知之甚少,虽然近年来发表了大量关于三氧治疗的抗炎、免疫调节和器官保护有效性的科学证据,但我们认为遵循Richard S.Hotchkiss和并根据本文的适应症提出了三氧作为免疫药物治疗。三氧治疗有许多生物学效应,但最相关的是它能调节Nrf2(一种重要的核信息传导器)的激活,NFkB的下调,它还调节NLRP3炎症。

  In this letter, I wish to present this therapeutic opportunity, outline the important activities of the Oxygen Ozone Therapy (O2O3) and explain the rationale for this treatment in COVID-19 patients.

  Spike protein and Angiotensin-Converting Enzyme 2 (ACE2) cell receptors have been identified as putative receptors for SARS-CoV-2; they could promote the proliferation of COVID-19 (Figure 1). It is known that these receptors can be blocked with some specific monoclonals but also through the control of Nrf2 that regulates and blocks the activity of Spike and ACE2. Because O2O3 acts directly on Nrf2, stimulating them, it seems very likely that this is the most important physiological mechanism to block endogenous COVID-19 reduplication by preventing contact with putative receptors of SARS-CoV-19.

  在这封信中,我想介绍这一治疗机会,概述氧臭氧疗法的重要活动,并解释在COVID-19患者中进行这一治疗的理由。棘突蛋白和血管紧张素转换酶2(ACE2)细胞受体被认为是SARS-CoV-2的假定受体;它们可以促进COVID-19的增殖(图1)。已知这些受体可以被一些特定的单克隆阻断,但也可以通过调节和阻断Spike和ACE2活性的Nrf2的控制。由于三氧直接作用于Nrf2,刺激Nrf2,这很可能是通过阻止与SARS-CoV-19受体的接触来阻断内源性COVID-19重叠的最重要的生理机制。

  

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  Oxygen-ozone has a high solubility in plasma and induces formation of two second messengers, H2O2 and ozonoids and alchenals (Figure 2). These are the ones who are mainly competent, interacts with the membrain proteins and receptors of the cells, especially the immunocompetent ones, and enter the cells and interact with signal transduction proteins on the nucleus and mitochondria level. The key action mechanism of O2O3 therapy is its action on proteasome and inflammation cascade, to control inflammatory process, by stimulating the nuclear factor Nrf2 and by inhibiting nuclear factor NFkB (Figure 3).

  氧-臭氧在等离子体中具有高溶解度,并诱导形成两个第二信使,H2O2和类臭氧化合物以及alchenals(图2)。它们主要是有能力的,与细胞的膜脑蛋白和受体,特别是免疫能力的膜脑蛋白和受体相互作用,在细胞核和线粒体水平上进入细胞并与信号转导蛋白相互作用。三氧治疗的关键作用机制是其对蛋白酶体和炎症级联反应的作用,通过刺激核因子Nrf2和抑制核因子NFkB来控制炎症过程(图3)。

  

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  The O2O3 therapy can restore the right immune response by stimulating signal transduction molecules via Nrf2 and thus stimulating the nuclear transduction via specific microRNAs restoring the normal antioxidant and immunostimulating reaction. The action mechanism of O2O3 therapy has very well summarized by Noel L. Smith et al. in 2017 By reacting with Polyunsaturated Fatty Acids (PUFA) and water, O3 creates hydrogen peroxide (H2O2), a Reactive Oxygen Species (ROS). Simultaneously, O3 forms a mixture of Lipid Ozonation Products (LOP).

  三氧治疗可通过Nrf2刺激信号转导分子,从而通过特定的microRNAs刺激核转导,恢复正常的抗氧化和免疫刺激反应,从而恢复正常的免疫应答。Noel L.Smith等人对三氧治疗的作用机制进行了很好的总结。2017年通过与多不饱和脂肪酸(PUFA)和水反应,三氧生成过氧化氢(H2O2),一种活性氧物种(ROS)。同时,O3形成脂质臭氧氧化产物(LOP)的混合物。

  The LOPs created after O3 exposure include lipoperoxyl radicals, hydroperoxides, malonyldialdeyde, isoprostanes, the ozonide and alkenals, and 4-Hydroxynonenal (4-HNE). Moderate oxidative stress caused by O3 increases activation of the transcriptional factor mediating nuclear factor-erythroid 2-related factor 2 (Nrf2). Nrf2’s domain is responsible for activat ing the transcription of Antioxidant Response Elements (ARE). Upon induction of ARE transcription, an assortment of antioxidant enzymes gains increased concentration levels in response to the transient oxidative stress of O3. The antioxidants created include, but are not limited to, Superoxide Dismutase (SOD), Glutathione Peroxidase (GPx), Glutathione S-Transferase (GST), Catalase (CAT), Heme Oxygenase-1 (HO-1), NADPHquinone-Oxidoreductase (NQO-1), Heat Shock Proteins (HSP), and phase II enzymes of drug metabolism. Many of these enzymes act as free radical scavengers clinically relevant to a wide variety of diseases.

  臭氧暴露后产生的LOPs包括脂质过氧化物自由基、过氧化氢、丙二酰二醛、异丙醇、臭氧酸和烯醛以及4-羟基壬醛(4-HNE)。三氧引起的中度氧化应激增加了介导核因子红系2相关因子2(Nrf2)的转录因子的激活。Nrf2的结构域负责激活抗氧化反应元件(ARE)的转录。在诱导ARE转录后,一系列抗氧化酶在三氧的短暂氧化应激反应中获得更高的浓度水平。产生的抗氧化剂包括但不限于超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GPx)、谷胱甘肽S-转移酶(GST)、过氧化氢酶(CAT)、血红素氧合酶-1(HO-1)、萘醌氧化还原酶(NQO-1)、热休克蛋白(HSP)和药物代谢II期酶。其中许多酶在临床上作为自由基清除剂与多种疾病相关。

  

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  Masaru Sagai et al. in 2011 described the biological responses induced via the activation of Nrf2/ARE with mild oxidative stress (O2O3 therapy) that can be summarized in:

  i) Increasing the levels of direct antioxidants, such as GSH, CO, and bilirubin;

  ii) Stimulating GSH regeneration via glutathione and thioredoxin reductase;

  iii) Increasing the levels of enzymes that detoxify oxidants and electrophils (i.e. catalase, SOD, GPx, GSTr, NADPHQuinone Oxidoreductase (NQO1), HO-1, HSP70, etc);

  iv) Increasing the levels of phase II enzymes;

  v) Inhibiting cytokine-mediated inflammation via the induction of leukotriene B4 reductase;

  vi) Reducing iron overload, and subsequent oxidative stress induced via elevated ferritin;

  vii) Recognizing, repairing, and removing damaged proteins;

  viii) Protection from apoptosis induced via oxidative stress;

  ix) Increasing DNA repair activity.

  Masaru Sagai等人,描述了通过激活Nrf2/ARE和轻度氧化应激(O2O3疗法)诱导的生物反应,可概括为:

  1) 提高直接抗氧化剂的水平,如GSH、CO和胆红素;

  2)通过谷胱甘肽和硫氧还蛋白还原酶促进GSH再生;

  3)提高氧化剂和电泳解毒酶(即过氧化氢酶、超氧化物歧化酶、GPx、GSTr、萘醌氧化还原酶(NQO1)、HO-1、HSP70等)的水平;

  4)提高II期酶的水平;

  5) 通过诱导白三烯B4还原酶抑制细胞因子介导的炎症反应;

  6)减少铁超载和随后通过铁蛋白升高引起的氧化应激;

  7)识别、修复和去除受损蛋白质;

  8)对氧化应激诱导的细胞凋亡的保护作用;

  9)增加DNA修复活性。

  In addition, Jacqueline Diaz-Luis et al. in 2015demonstrated that ozone was able to modulate the phagocytic cells in peripheral blood and the mechanisms on how messengers can activate immunological response leading to the therapeutic biological effects. Furthermore, it was demonstrated that there is a range of ozone concentrations where we can obtain the highest positive results, while lower doses are ineffective and higher doses can produce lower effects. Accordingly, ozone, in a dose-dependent behavior, may stimulate the phagocytic function of the peripheral blood cells.

  此外,Jacqueline Diaz Luis等人。2015年,证明臭氧能够调节外周血中的吞噬细胞,以及信使如何激活免疫反应从而产生治疗性生物效应的机制。此外,研究还表明,在臭氧浓度范围内,我们可以获得最高的阳性结果,而低剂量是无效的,高剂量可以产生较低的效果。因此,臭氧在剂量依赖性行为中,可能刺激外周血细胞的吞噬功能。

  Another important effect of O2O3 therapy than can explain its effects in improving the therapeutic approach to COVID-19 infected patients is its important action on NLRP3 inflammasome that is recognized to play a crucial part in the initiation and continuance of inflammation in various diseases. Gang Yu et al. in 2016 demonstrated that the protective effect of ozone therapy was achieved by its anti-inflammatory property through the modulation of the NLRP3 inflammasome. Ozone-oxygen mixture at low concentration could effectively improve organ ischemia-reperfusion that is what happens in the lungs of patients affected by COVID-19 infection.

  三氧治疗的另一个重要作用是它对NLRP3炎症的重要作用,而NLRP3炎症被认为在各种疾病炎症的起始和持续中起着关键的作用。刚玉等。2016年证明,臭氧治疗的保护作用是通过调节NLRP3炎症小体的抗炎特性实现的。低浓度臭氧-氧混合物能有效改善COVID-19感染患者肺组织的缺血再灌注。

  

  Ischemia-Reperfusion Injury (IRI) is a major cause of lung dysfunction during many pathological diseases. Zhiwen Wang et al. in 2018 demonstrated that ozone oxidative treatment protects the lung from IRI by attenuating nucleotide-binding oligomerization domainlike receptor containing pyrin domain 3 (NLRP3)-mediated inflammation, enhancing the antioxidant activity of Nrf2 and inhibiting apoptosis.

  缺血再灌注损伤(IRI)是许多病理性疾病肺功能不全的主要原因。王志文等。2018年的研究表明,臭氧氧化治疗通过减弱核苷酸结合寡聚类域受体(含吡喃结构域3(NLRP3)介导的炎症,增强Nrf2的抗氧化活性和抑制凋亡,保护肺免受IRI的影响。

  In conclusion, as systemic oxygen therapy has all these positive effects: control of inflammation, stimulation of immunity, antivirus ability, protection from ischemia-reperfusion damage, action on proteasome and inflammation.7,9 Oxygen-ozone therapy can be said to be a new method of immunoceutical therapy and therefore its use in combination with other treatments in COVID-19 positive patients may be justified, helpful and synergic.

  Further studies and tests are needed, but we hope to soon have confirmation that O2O3 therapy is synergistic and effective in controlling COVID-19-infection.

  综上所述,全身氧疗具有控制炎症、刺激免疫、抗病毒、保护缺血再灌注损伤、抑制蛋白酶体和炎症等积极作用。氧臭氧疗法可以说是一种新的免疫药物治疗方法,因此它与COVID-19阳性患者的其他治疗可能是合理的、有帮助的和协同的。

  还需要进一步的研究和试验,但我们希望很快证实,三氧疗法在控制COVID-19感染方面是协同和有效的。


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