The effect of intra-articular ozone injection combined with home-based exercise on pain and function in daily living activities of patients with mild to moderate knee osteoarthritis, a randomized double-blinded controlled clinical trial.

BACKGROUND: Knee osteoarthritis is the most common arthritis. Various treatments such as analgesics, exercise therapy, and surgery in high-grade OA have been shown to reduce pain and improve patients' function; however, determining the optimal treatment remains a challenge. Ozone therapy is one of the injection techniques used for symptom relief in these patients. Therefore, this study aimed to evaluate the effect of ozone injection in mild to moderate knee osteoarthritis. METHODS: Thirty-three patients with grade II-III knee osteoarthritis based on the Kellgren-Lawrence classification were involved in the study, by block randomisation. Totally 42 knees were included. All patients received exercise therapy, 500 mg of acetaminophen tablets (up to 2 g per day as needed), and healthy nutrition. In a double-blinded method, the intervention group received Ozone injections, but the control group received placebo injections. Functional tests, including timed-up-and-go and 6-min walk tests, were assessed at baseline and immediately after the 6-week intervention. In addition, the pain was measured by VAS score, and stiffness and activity of daily living (ADL) were evaluated by KOOS questionnaire before and after a 6-week intervention and then one and six months afterwards. FINDINGS: Improvements in pain and KOOS scores were seen in both groups in the 6th week of injections (p < 0.05), with significant differences between groups. However, the effects on pain and KOOS scores disappeared in the 1st and 6th months of follow-ups in the control group. Nevertheless, the effects persisted in the intervention group compared to the baseline and control group, which means that in the mentioned time points intervention group showed significant improvement compared to the control group (p < 0.05). In addition, functional tests showed significant differences between the two groups in the 6th week of injections (p < 0.001). INTERPRETATION: Ozone injection is a non-surgical treatment for mild to moderate knee osteoarthritis that could decrease pain and improve function and ADL of patients in the short to mid-term (3-6 months), so it seems that adding Ozone injection to the routine exercise therapy in management of patients with knee OA could improve outcomes.

Efficacy of Medical Ozone for Treatment of Chronic Musculoskeletal Pain with Abnormal Mitochondrial Redox State: Prospective Randomized Clinical Trial.

BACKGROUND: Chronic primary musculoskeletal pain is multifaceted and 20% of the adult population lives with severe chronic pain and experience symptoms such as intense pain, depression, weakness, sleep problems, decreased quality of life and decreased emotional well-being. OBJECTIVES: This paper studies the efficacy of trigger point injections with ozone compared to standard steroid injection or combination therapy for the treatment of chronic musculoskeletal pain in patients with abnormal mitochondrial redox state. STUDY DESIGN: This is a prospective randomized clinical study conducted with 51 patients experiencing chronic musculoskeletal pain. SETTING: Medical Research Institute Hospital, Alexandria University. METHODS: By computer-generated random numbers the 51 patients were divided into 3 groups. Group A (17 patients) received ozone injection, group B (17 patients) received betamethasone injection and group C (17 patients) received combined ozone and betamethasone injections. The groups were compared based on the intensity of pain and correction of mitochondrial redox state of the patients. RESULTS: Three days after intervention, the visual analog scale (VAS) scores reported by patients were lower in group A compared to group B (with a mean difference 1.27, 95% confidence interval (CI) of 0.15-2.39 (P < 0.02). One and 3 weeks after intervention, VAS scores of patients were lower in groups A and C compared to group B. At one week the mean difference between A and B was 1.2, with a 95% CI of 0.15-2.25 (P < 0.02) and the mean difference between C and B was 1.73 with a 95% CI of 0.69-2.78 (P < 0.001). At 3 weeks the mean difference between A and B was 1.5 with a 95% CI of 0.2-2.87 (P < 0.01) and the mean difference between C and B was 2.27 with a 95% CI of 0.93-3.60 (P < 0.0001). The reduced/oxidized glutathione ratio after intervention was higher in groups A and C compared to group B (P > 0.008). The mitochondrial copy number was higher in group A compared to group B (P < 0.002). LIMITATION: This study didn't allow for the comparison of the experimental groups with a placebo or control group for musculoskeletal pain conditions in orderto establish the role of an abnormal mitochondrial redox state on the pathogenesis of patients from an ethical view. CONCLUSIONS: Ozone therapy or combined ozone and betamethasone treatment are  effective techniques for management of pain since it produced a significant reduction of muscle pain and increase of the pain free interval experienced by patients. Ozone therapy causes pain improvement which increases with time and it improves muscle oxygenation and mitochondrial function. TRIAL REGISTRATION: This study was approved by the Ethics Committee of Medical Research Institute (IORH: IOR 00088812) and was registered at the Pan African Clinical Trial Registry (www.pactr.org) under the identification number PACTR201908620943471. The registration this experiment started on 07/08/2019. This study's protocol followed the CONSORT guidelines and was performed under the relevant guidelines.

Clinical Outcome for Lumbar Disc Herniation Treatment with Intradiscal Oxygen-ozone Therapy.

BACKGROUND: Low back pain due to disc herniation is a common problem causing frequent hospital visits and loss of working days with major socio-economic impact. Conservative treatments like analgesics, physiotherapy do not work in all patients. Surgical treatment has been the mainstay of treatment when indicated but is associated with anesthetic and surgical complications. Intradiscal oxygen-ozone chemonucleolysis is a minimally invasive procedure done under local anesthesia and has promising role in shrinking the bulged disc and reducing nerve root compression and related symptoms. This retrospective study was done to see how intradiscal oxygen-ozone chemonucleolysis reduces pain severity in patients with discogenic low back pain. METHODS: Retrospective data were retrieved of those patients who underwent fluoroscopy guided intradiscal oxygen-ozone chemonucleolysis with 5-6 ml of an O2-O3 mixture (concentration of 30 microgram/ml) during a period of two years in Nepal pain care and research center. Numerical pain scale (NRS) at various follow ups were compared to preprocedural NRS. RESULTS: Preprocedural NRS was 8± 13. NRS at three hours, one week, one month, three months and six months were 2± 13 (73 percent reduction), 2± 53 (68 percent reduction), 2± 27 (72 percent reduction), 1± 08 (77 percent reduction) and 1± 67 (79 percent reduction) respectively. CONCLUSIONS: Intradiscal oxygen-ozone chemonucleolysis can be a useful modality of treatment for discogenic low back pain in patients who fail to respond to conservative management and in whom surgery is not indicated.

Adjunct treatment with ozone to enhance therapy of knee osteoarthritis: preliminary results.

Knee osteoarthritis (knee OA), commonly known as gonarthrosis, is a chronic pathology involving knee at the joint level causing progressive pain, stiffness and difficulty in ambulation and leg movements. So far in situ infiltration therapies such as platelet rich plasma, conditioned autologous serum or hyaluronic acid, provided some encouraging though limited hopes for a routinely recommended therapy for knee OA. Recent clinical successful observations about the use of whole autologous blood ozonated with a calibrated mixture of oxygen and ozone, has promoted the present research study, in order to treat knee OA. A number of 250 patients suffering with knee OA of different Ahlback scores, were treated with infiltration of ozonated blood and evaluated for their WOMAC and Lequesne indexes, pre- and post-treatment, to evaluate pain, disability and stiffness. Patients recovered about 50% of their health status, reducing pain, stiffness and disability by only 5 sessions, one/week, with 20 µg/ml O3 ozonated autologous blood knee infiltrations. The evidence asks for further supporting results yet encourages our efforts to go ahead in this research issue. Key Points •The oxygen-ozone therapy via ozonated blood infiltration was used in this study. •Ozone reduced pain, disability, and stiffness in both female and male patients. •The treatment with ozone improved WOMAC both in type I and type II Ahlback knee OA. •The oxygen-ozone therapy via ozonated blood ameliorated Lequesne functional index.

Complementary and alternative therapies for managing postoperative pain after lower third molar surgery: a systematic review and network meta-analysis.

OBJECTIVE: The objective of this study was to evaluate the impact of complementary and alternative treatments on postoperative pain following lower third molar surgeries. METHODS: A comprehensive search of Electronic databases (Embase, MEDLINE via PubMed, and Cochrane Library) and grey literature was conducted up until May 2022. Randomized clinical trials investigating the effect of acupuncture, ozone therapy, laser (LLLT), drainage tube, kinesio-taping, ice therapy, and compressions on pain after LTM surgeries were included. The estimated mean differences (MD) for alternative therapies were pooled using the frequentist approach to random-model network meta-analysis NMA. RESULTS: Eighty-two papers were included in the qualitative analysis; 33 of them were included in the quantitative analyzes. NMA revealed that drainage tube and kinesio-taping were superior in controlling pain 24-hours postoperatively than no-treatment. At 48-hours follow-up, kinesio-taping and LLLT more effective than placebo and drainage tube; and kinesio-taping and LLLT were superior to no treatment. At 72 h postoperatively, ozone therapy was superior to placebo; and drainage tube, kinesio-taping, and LLLT were better than no treatment. At 7-days follow-up, ozone and LLLT were superior to placebo; and LLLT and kinesio-taping were superior to no treatment. The SUCRA-ranking placed drainage tube as top-ranking intervention at 48-hours (98.2%) and 72-hours (96%) follow-ups, and ozone (83.5%) at 7-days follow-up. CONCLUSION: The study findings suggest that these alternative and complementary therapies may be useful in reducing postoperative pain after LTM surgeries, and may offer advantages when combined to traditional pain management methods. CLINICAL RELEVANCE: Non-pharmacological therapies are gaining popularity among healthcare professionals and patients. This study found that some of these therapies, specifically kinesio-taping and drainage tube were effective in controlling postoperative pain after third molar surgeries. These findings have important implications for clinical practice, as they highlight the potential benefits of incorporating these therapies into postoperative pain management plans.

Topical application of ozonated sunflower oil accelerates the healing of lesions of cutaneous leishmaniasis in mice under meglumine antimoniate treatment.

Besides being scarce, the drugs available for treating cutaneous leishmaniasis have many adverse effects. Ozone is an option to enhance the standard treatment due to the wound-healing activity reported in the literature. In this study, we evaluated the efficiency of ozonated sunflower oil as an adjuvant in treating cutaneous lesions caused by Leishmania amazonensis. BALB/c mice were infected with L. amazonensis, and after the lesions appeared, they were treated in four different schedules using the drug treatment with meglumine antimoniate (Glucantime®), with or without ozonated oil. After thirty days of treatment, the lesions' thickness and their parasitic burden, blood leukocytes, production of NO and cytokines from peritoneal macrophages and lymph node cells were analyzed. The group treated with ozonated oil plus meglumine antimoniate showed the best performance, improving the lesion significantly. The parasitic burden showed that ozonated oil enhanced the leishmanicidal activity of the treatment, eliminating the parasites in the lesion. Besides, a decrease in the TNF levels from peritoneal macrophages and blood leukocytes demonstrated an immunomodulatory action of ozone in the ozonated oil-treated animals compared to the untreated group. Thus, ozonated sunflower oil therapy has been shown as an adjuvant in treating Leishmania lesions since this treatment enhanced the leishmanicidal and wound healing effects of meglumine antimoniate.

Ozone Therapy for a Soccer Player With Osteitis Pubis: A Case Report.

CONTEXT: Osteitis pubis (OP), which occurs as a result of excessive use of the symphysis pubis and parasymphysis bones, is more common in long-distance runners and kicking athletes, especially football players. Due to the poor results of commonly used treatments for OP, there is a need for investigation of more effective treatments, such as ozone therapy. Ozone therapy is used to treat a variety of diseases, including musculoskeletal conditions. CASE PRESENTATION: A 30-year-old amateur soccer player diagnosed with OP received conservative treatment with traditional physiotherapy and analgesic medications. After 6 months and no resolution of symptoms, the patient presented to the sports medicine outpatient clinic seeking alternative therapy options. MANAGEMENT AND OUTCOMES: The patient received ozone injections in 3 sessions administered at 10-day intervals. At 1, 3, 6 and 12 months after the treatment, the patient's complaints and pain levels were re-evaluated and examined. The patient was able to return to competition at the same level after the first injection. No recurrence was revealed at a minimum of 12 months of follow-up. CONCLUSION: In this article, we present a case in which OP was successfully treated with ozone injection.

Ozone and Laser Effects on Dentin Hypersensitivity Treatment: A Randomized Clinical Study.

INTRODUCTION: The aim of this study was to evaluate and compare the clinical efficacy of diode laser and ozone gas in the treatment of dentin hypersensitivity (DHS). METHODS: One hundred thirty-two teeth from 44 patients with moderate DHS were randomized into 3 groups according to a split-mouth design. In the diode laser group, the operator irradiated the superficial dentin exposed with an 808-nm wavelength and incremental power from 0.2 to 0.6 W with a 20-second interval. In the ozone gas group, the operator applied a high dose of ozone (32 g/m3) for 30 seconds using a silicon cup. In the placebo group, no therapy was applied. The dentin sensitivity level was evaluated upon enrollment (T0), immediately after treatment (T1), 3 months post-treatment (T2), and 6 months post-treatment (T3) with a cold air blast challenge and tactile stimuli. The pain severity was quantified according to the visual analogue scale. The Wilcoxon signed rank test was used to scrutinize potential statistical disparities among the treatments. Statistical significance was predetermined at P < .05. RESULTS: A significant decrease of DHS was observed in the ozone gas group and the `diode laser group immediately after treatment and after 3 and 6 months of the therapy. After 6 months from the therapy, the sensitivity values in the teeth treated with ozone gas remained statistically lower than those treated with diode lasers (P < .05). CONCLUSIONS: A laser diode and ozone gas are both efficient as dentin sensitivity treatment. Ozone maintains an invariable effectiveness after 6 months.

Ozone Therapy for Breast Cancer: An Integrative Literature Review.

Breast cancer is the most prevalent form of cancer in women. Despite significant advances in conventional treatment, additional safer complementary treatment options are needed. Recently, ozone therapy has been considered as a type of medical adjunctive treatment that could inhibit cancer cell survival and reduce chemoresistance. However, only a few studies have been conducted on its use in breast cancer, and the optimal dosage and time of administration are unknown. Currently, preclinical studies suggest that ozone alone or in combination with chemotherapy is an effective method for inhibiting breast cancer cell growth. However, rather than investigating the effects of ozone as an antitumor therapy, current clinical trials have generally assessed its effect as an adjunctive therapy for reducing chemotherapy-induced side effects, increasing oxygen tension, normalizing blood flow, restoring blood lymphocytes more rapidly, and reducing fatigue symptoms. In this article, the use of ozone as a medical adjunctive treatment for breast cancer and its role in integrative therapy are summarized and discussed.

Use of oxygen-ozone therapy to improve the effectiveness of antibiotic treatment on infected arthroplasty: protocol for a superiority, open-label, multicentre, randomised, parallel trial.

INTRODUCTION: Surgical site infections still remain a major public health challenge and have become an increasing universal risk, especially for the implantation of orthopaedic devices.Unfortunately, the discovery and increasingly widespread use (especially the misuse) of antibiotics have led to the rapid appearance of antibiotic-resistant strains today; more and more infections are caused by microorganisms that fail to respond to conventional treatments.Oxygen-ozone therapy has been extensively used and studied for decades across various potential medical applications and has provided consistent effects with minimal side effects.This study aims to determine the superiority of oxygen-ozone therapy in combination with oral antibiotic therapy in patients with wound infections after an orthopaedic device implantation when compared with antibiotic therapy alone. METHODS AND ANALYSIS: This is an open-label, multicentre, randomised, parallel-group study that aims to assess the efficacy and safety of oxygen-ozone therapy in combination with oral antibiotic therapy to treat infections in patients (male or female aged ≥18 years) having undergone surgery for the implant of an orthopaedic device. Patients must have at least one (but no more than three) postoperative wounds in the site of surgery (ulcers, eschars and sores) and at least one symptom (pain, burning, redness and malodour) and at least one sign (erythema, local warmth, swelling and purulent secretion) of infection of at least moderate intensity (score ≥2) in the target lesion at the screening visit (patients with wounds without signs of localised infection or with undermining wounds will be excluded).Patients (n=186) will be recruited from five Italian hospitals and studied for 7 weeks. All will be assigned to one of the two treatment groups according to a web-based, centralised randomisation procedure and placed into either the (1) intervention: oxygen-ozone therapy 2-3 times a week for 6 weeks (for a maximum of 15 sessions) simultaneously with an appropriate oral antibiotic therapy prescribed at baseline or (2) control: oral antibiotic therapy prescribed at baseline.The primary outcome is the efficacy and superiority of the treatment (ozone and oral antibiotic therapies); secondary outcomes include the resolution of signs and symptoms, modifications in lesion size and the treatment's safety and tolerability. ETHICS AND DISSEMINATION: This study has been reviewed and approved by the responsible Independent Ethics Committee (IEC) of COMITATO ETICO CAMPANIA NORD, located at 'Azienda Ospedaliera San Giuseppe Moscati di Avellino'.After completion of the study, the project coordinator will prepare a draft manuscript containing the final results of the study on the basis of the statistical analysis. The manuscript will be derived by the co-authors for comments, and after revision, it will be sent to a major scientific journal. Findings will be disseminated via online and print media, events and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04787575.

No-ozone cold plasma induces apoptosis in human neuroblastoma cell line via increased intracellular reactive oxygen species (ROS).

BACKGROUND: This study aimed to evaluate the effect of argon-based No-ozone Cold Plasma (NCP) on neuroblastoma cancer cell apoptosis. METHODS: Experiments were performed with SK-N-SH and HS 68. Cell cultures were treated with NCP for 1, 3, and 5 min. NCP was applied using three different strategies: direct NCP application to cell cultures, to only media, and to only cells. Evaluation of cell viability and the level of the reactive oxygen species (ROS) was performed. N-acetyl-L-cysteine (NAC) was also used to antagonize intracellular ROS. Cleaved caspase 3, PARP, aquaporin (AQP) 3 and 8 were detected. RESULTS: NCP induced a gradual decrease in the SK-N-SH cell viability. In contrast, the viability of HS 68 cells did not change. SK-N-SH cells viability was reduced the most when the only media-NCP application strategy was employed. Intracellular ROS levels were significantly increased with time. Cleaved caspase 3 and PARP were increased at 6 h after NCP application. SK-N-SH cells remained viable with NAC after NCP application. AQP 3 and 8 were over-expressed in SK-N-SH cells. CONCLUSION: These findings demonstrate the anti-cancer effect of NCP on neuroblastoma cells. NCP enhanced the selective apoptosis of neuroblastoma cells due to the increased intracellular ROS.

Healing refractory livedoid vasculopathy-related skin ulcers by ozone therapy: a case-based review.

Chronic skin wounds represent a prominent etiological factor in the occurrence of non-traumatic foot amputations on a global scale and pose a substantial threat to the patient's well-being and mortality in the absence of effective treatment strategies. There exists a subset of patients that exhibit an insufficient response to different treatment options, comprising antibiotics, dressings, gauze bandages, debridement, rehabilitation, collagen patch, and vacuum-assisted closure. In this patient group, distinct treatment strategies emerge before surgery and amputation. Ozone therapy is one of them. Ozone exhibits a wide variety of effects such as antimicrobial, anti-inflammatory, antioxidant, and trophic. Its trophic effect is mediated by disinfection, stimulation of granulation tissue, acceleration of the angiogenesis process, and detoxification mechanisms. In this article, we presented the beneficial effect of ozone therapy in a case of chronic skin ulcer associated with livedoid vasculopathy. In this context, we aimed to discuss the role of ozone therapy in the management of chronic skin ulcers. Finally, we focused on ozone therapy as a promising method in inflammatory rheumatic diseases.

Evaluation of the Usefulness of Ozone - O3 in the Treatment of Low Back Pain. Is it Really Something more than an Empirical Concept? Systematic Review of the Literature.

OBJECTIVE: Low back pain (LBP) is a common pathology, and its high prevalence has led to the emergence of alternative options that have gained popularity without objective epidemiological evaluations. This work seeks to clarify the utility of ozone in the treatment of LBP. METHODS: A systematic literature search was conducted following the principles by PRISMA. The search included articles published up to June 2023. Each of the authors reviewed the abstract of the articles and applied the inclusion and exclusion criteria. RESULTS: A total of 28 articles were selected: 18 prospective randomized clinical studies, 3 systematic reviews plus meta-analysis, and 6 retrospective case series studies. CONCLUSIONS: The treatment of LBP is complex. Advancements have been made in recent years from biomechanical and pathophysiological perspectives, but ozone therapy is not considered a treatment option. Techniques that involve the use of ozone fall into the category of empirical options. International guidelines for LBP exclude ozone therapy. It is advisable to conduct further studies under strict parameters to better evaluate its outcomes.

Intramuscular paravertebral oxygen-ozone therapy for chronic neck pain and low back pain: evaluation of 6-month clinical outcomes.

Spinal pain is recognized as the most common cause of disability, work absenteeism and need of healthcare services worldwide. Although many strategies have been developed for conservative treatment of spinal pain, its increasing prevalence diagnosis highlights the need for new treatments. Oxygen-ozone (O2-O3) therapy is considered to be an alternative therapy due to its analgesic and anti-inflammatory effects. This retrospective study evaluated the effects of O2-O3 intramuscular paravertebral injections in 76 patients with chronic neck pain or low back pain, in terms of pain and disability reduction, quality of life improvement, and analgesic drug intake. Patients were evaluated before, at the end of the treatment, and at 1, 3 and 6 months after the last treatment, using Numeric Rating Scale, Neck Disability Index or Oswestry Disability Index, and Short Form-12 Health Survey. There were significant beneficial effects of O2-O3 therapy in reducing pain and disability reduction and improving quality of life during the 6-month follow-up period. O2-O3 therapy was associated with a reduction in analgesic drug intake at each assessment. Our results allow us not only to support treatment with O2-O3 intramuscular paravertebral injections as a safe and beneficial treatment for chronic low back pain, but also to consider it as a valuable conservative therapy for patients with chronic neck pain.

Ozone in the adjunct medical treatment. The round personality of a molecule with hormetic properties.

Ozone, an allotrope of oxygen, is enjoying an increasing interest in the setting and management of the medical adjunct treatment, which is called, maybe too simplistically, "ozone therapy". Ozone is not a medicine, so the word therapy does not properly fit this gaseous molecule. Like many natural compounds, for example plant flavonoids, even ozone interacts with aryl hydrocarbon receptors (AhRs) and, at low doses, it works according to the paradoxical mechanism of hormesis, involving mitochondria (mitohormesis). Ozone, in the hormetic range, exerts cell protective functions via the Nrf2-mediated activation of the anti-oxidant system, then leading to anti-inflammatory effects, also via the triggering of low doses of 4-HNE. Moreover, its interaction with plasma and lipids forms reactive oxygen species (ROS) and lipoperoxides (LPOs), generally called ozonides, which are enabled to rule the major molecular actions of ozone in the cell. Ozone behaves as a bioregulator, by activating a wide population of reactive intermediates, which usually target mitochondria and their turnover/biogenesis, often leading to a pleiotropic spectrum of actions and behaving as a tuner of the fundamental mechanisms of survival in the cell. In this sense, ozone can be considered a novelty in the medical sciences and in the clinical approach to pharmacology and medical therapy, due to its ability to target complex regulatory systems and not simple receptors.

Oxygen-ozone autohemotherapy in breast cancer patients suffering from fatigue and musculoskeletal pain upon aromatase inhibitors treatment: a case-series study.

OBJECTIVE: In patients with breast cancer and positive hormone receptors, aromatase inhibitors are effective in reducing the risk of recurrences and are active in progressing the disease in this setting. On the other hand, fatigue and painful musculoskeletal side effects can significantly reduce treatment compliance. With no further treatment options to control these symptoms, non-pharmaceutical interventions, such as oxygen-ozone therapy, may play a role in managing rheumatologic symptomatology inasmuch. We have previously reported evidence on the effectiveness of oxygen-ozone in the treatment of pain and fatigue in chronic fatigue syndrome and fibromyalgia patients and in oncological patients as well. PATIENTS AND METHODS: In this study, we reported 6 cases of patients (mean age 64 yrs, all Caucasian females) with breast cancer upon treatment with anastrozole (Arimidex®), suffering from musculoskeletal pain, weakness and fatigue, and therefore treated with oxygen-ozone major autohemotherapy according to the Italian Scientific Society of Oxygen Ozone Therapy (SIOOT) protocol. Pain was measured with a 10-item Numerical Rating Scale (NRS) and fatigue with a 7-item Fatigue Scoring Scale (FSS). RESULTS: A reduction of at least 66% of pain (from 9.43 ±0.54 SD to 2.36 ±1.32 SD, p<0.001) and 66.26% of fatigue were obtained for all the cases. Pain and fatigue disappeared within one month from ozone therapy, and a healthy painless state lasted for many months following the oxygen-ozone therapy. CONCLUSIONS: The oxygen-ozone therapy is a sound opportunity for breast cancer patients to reduce anti-aromatase-induced pain, fatigue, and musculoskeletal symptoms.

Ozone alleviates MSU-induced acute gout pain via upregulating AMPK/GAS6/MerTK/SOCS3 signaling pathway.

BACKGROUND: Gout pain seriously affects the quality of patients' life. There is still no effective treatment. The inflammatory response is the main mechanism of gout. Here, we found that ozone can reduce the inflammatory reaction in the joints of gouty mice and relieve gout pain, and we further explore its protective mechanism. METHODS: MSU was used to establish the gouty mice model. Nociception was assessed by Von Frey hairs. Cell signaling assays were performed by western blotting and immunohistochemistry. The mouse leukemia cells of monocyte macrophage line RAW264.7 were cultured to investigate the effects of ozone administration on macrophage. RESULTS: Ozone reduced inflammation, relieved gout pain and improved the paw mean intensity and duty cycle of the gouty mice. Ozone increased the phosphorylation of AMP-activated protein kinase (AMPK), induced suppressor of cytokine signaling 3 (SOCS3) expression and inhibited metallopeptidase 9 (MMP9) expression. In vivo, ozone activated AMPK to induce Gas6 release, and upregulated MerTK/SOCS3 signaling pathway to reduce inflammation in mouse macrophage line RAW264.7. Inhibitors of AMPK and MerTK, respectively abolished the analgesic and anti-inflammatory effects of ozone in vivo and in vitro. Gas6 knockout cancelled the protectively effects of ozone on gout pain and the paw mean intensity and duty cycle of gouty mice. Additionally, the level of Gas6 and protein S in plasma of patients with hyperuricemia was significantly higher than that of healthy contrast group. CONCLUSION: Ozone reduces inflammation and alleviates gout pain by activating AMPK to up-regulate Gas6/MerTK/SOCS3 signaling pathway.