Therapeutic Effects of IL-1RA, M2 Cells, and Their Synergistic Impact on a Mouse Model of Rheumatoid Arthritis.

Purpose: Rheumatoid arthritis (RA) is a type of autoimmune disease that results in chronic inflammation of the joint synovial tissue, leading to joint damage and significant disability. Despite ongoing research, the exact cause of RA remains unclear, and current treatments have limitations. This study explores the potential of utilizing interleukin-1 receptor antagonist (IL-1RA) and anti-inflammatory macrophages polarized in the vicinity of the supernatant from allogeneic mesenchymal stem cells (MSCs) as a novel therapeutic approach for RA. Methods: An expression cassette containing the IL-1RA gene was constructed and expressed in E. coli BL21. The resulting protein was purified and stabilized for use in in vivo experiments. Bone marrow MSCs were isolated and used to produce anti-inflammatory M2 macrophages from the isolated peripheral blood monocytes. The macrophages were then used to treat mice with RA induced by collagen type II. Results: The combination of IL-1RA and M2 macrophages improved clinical and histopathological symptoms of the disease, reduced levels of inflammatory factors, and modulated the immune system in the treated mouse groups. The results showed that this combinatory therapy had a synergistic effect for RA treatment. Conclusion: The simultaneous use of IL-1RA and M2 cells could be a promising approach for the treatment of RA. This combinatory therapy has the potential to improve the disease and decrease the severity of inflammation in patients with RA.

Cytokine profile and antioxidants status in the moderate and severe COVID-19 patients: a trial of ozone therapy impact as a medicinal supplement.

BACKGROUND: Complementary ozone therapy has been identified as a revolutionary medical technique for a number of goals and ailments. At the present, it has been shown that ozone has medicinal qualities, such as antibacterial, antifungal, and antiparasitic properties. Coronavirus (SARS-CoV-2) is quickly spread over the globe. Cytokine storms and oxidative stress seem to play a substantial role in the most of acute attacks of the disease. The aim of this research was to assess the therapeutic advantages of complementary ozone therapy on the cytokine profile and antioxidant status in COVID-19 patients. METHODS: The statistical sample of this study included two hundred patients with COVID-19. One hundred COVID-19 patients (treatment group) received 240 ml of the patient's blood and an equal volume of O2/O3 gas at a concentration of 35-50 µg/ml daily, which gradually increased in concentration, and were kept for 5-10 days and one hundred patients (control group) received standard treatment. The secretion levels of IL-6, TNF-α, IL-1ß, IL-10 cytokines, SOD, CAT and GPx were compared between control patients (standard treatment) and standard treatment plus intervention (ozone) before and after treatment. RESULTS: The findings indicated a significant decrease in the level of IL-6, TNF-α, IL-1ß in group receiving complementary ozone therapy in compared with control group. Furthermore, a significant increase was found in the level of IL-10 cytokine. Moreover, SOD, CAT and GPx levels revealed a significant increase in complementary ozone therapy group compared to control group. CONCLUSIONS: Our results revealed that complementary ozone therapy can be used as a medicinal complementary therapy to reduce and control inflammatory cytokines and oxidative stress status in patients with COVID-19 as revealed its antioxidant and anti-inflammatory effects.

Safety and immunogenicity of a recombinant receptor-binding domain-based protein subunit vaccine (Noora vaccine™) against COVID-19 in adults: A randomized, double-blind, placebo-controlled, Phase 1 trial.

The development of a safe and effective vaccine is essential to protect populations against coronavirus disease 2019 (COVID-19). There are several vaccine candidates under investigation with different mechanisms of action. In the present study, we have evaluated the safety and immunogenicity of a recombinant receptor-binding domain (RBD)-based protein subunit vaccine (Noora vaccine) against COVID-19 in adults. This Phase 1 trial is a randomized, double-blind, placebo-controlled study to evaluate the safety and immunogenicity of the recombinant RBD-based protein subunit vaccine (Noora vaccine) against COVID-19 in healthy adults volunteers. Eligible participants were included in this study after evaluating their health status and considering the exclusion criteria. They were then randomized into three groups and received three doses of vaccine (80 µg, 120 µg, and placebo) on Days 0, 21, and 35. Primary outcomes including solicited, unsolicited, and medically attended adverse events were recorded during this study. Secondary outcomes including the humoral and cellular immunity (including anti-RBD IgG antibody and neutralizing antibody) were measured on Days 0, 21, 28, 35, 42, and 49 by using the ELISA kit and the Virus Neutralization Test (VNT) was performed on day 49. Totally 70 cases were included in this Phase 1 trial and 60 of them completed the study. Safety assessments showed no severe adverse events. Local pain at the vaccine injection site occurred in 80% of the vaccinated volunteers. Induration and redness at the injection site were the other adverse reactions of this vaccine. There was no significant difference between the studied groups regarding adverse reactions. Anti-RBD IgG antibody and neutralizing antibody assessment showed significant seroconversion in comparison to the placebo group (80%, and 100% respectively, p < 0.001). The cellular immunity panel also showed mild to moderate induction of TH1 responses and the VNT showed 78% of seroprotection. The results of this Phase 1 trial showed acceptable safety without serious adverse events and significant seroconversions in the humoral and cellular immunity panel. The dose of 80 µg is an appropriate dose for injection in the next phases of the trial.

Melatonin as a complementary and prophylactic agent against COVID-19 in high-risk populations: A narrative review of recent findings from clinical and preclinical studies.

The coronavirus disease 2019 (COVID-19) pandemic has been going on around the world for more than a year and has cost a lot, as well as affected the quality of life of many. The psychological stress like delirium and sleep disturbances caused by the COVID-19 has affected many people in direct or indirect way by the disease. Insomnia and sleep deprivation have a negative effect on the immune system as well as disorders of the hormonal system, including the production and secretion of melatonin, known as the sleep hormone. Melatonin is a known anti-inflammatory and antioxidant agent in addition to its role in regulating circadian rhythms. In this review, we investigated the relationship between the effect of psychological stress caused by COVID-19 on patients, their families, health care workers, and occupations as well as how melatonin might act as a prophylactic agent with sedative effects and sleep enhancement potential. Search terms "melatonin" and "COVID-19" were manually searched on PubMed or other electronic database and relevant articles were included. Based on the review of scholarly articles, it can be inferred that melatonin, as an endogenous hormone controlling and regulating sleep and wakefulness in various researches, has a good potential due to its antioxidant and anti-inflammatory with minimal side effects. These beneficial effects highlight the impact of melatonin as an adjuvant and a potential alternative for the better management of SARS-CoV-2 infection in high-risk populations.

NLRP3 inflammasome activation and oxidative stress status in the mild and moderate SARS-CoV-2 infected patients: impact of melatonin as a medicinal supplement.

The inflammasome as a multiprotein complex has a role in activating ASC and caspase-1 resulting in activating IL-1ß in various infections and diseases like corona virus infection in various tissues. It was shown that these tissues are affected by COVID-19 patients. According to the current evidence, melatonin is not veridical while possessing a high safety profile, however, it possesses indirect anti-viral actions owing to its anti-oxidation, anti-inflammation, and immune improving properties. This study aims to assess the impacts of melatonin as the complementary treatments on oxidative stress agents and inflammasome activation in patients with COVID-19. Melatonin supplement (9 mg daily, orally) was provided for the patients hospitalized with a COVID-19 analysis for 14 days. For measuring IL-10, IL-1ß, and TNF-α cytokines and malondialdehyde (MDA), nitric oxide (NO), and superoxide dismutase (SOD) level and the expression of CASP1 and ASC genes, blood samples were gathered from the individuals at the start and termination of the therapy. Our findings indicated that melatonin is used as a complementary treatment to reduce the levels of TNF-α and IL-1ß cytokines, MDA, and NO levels in COVID-19 patients and significantly increase SOD level, however, the levels of IL-10 cytokine possesses no considerable changes. The findings revealed that genes of CASP1 and ASC were dysregulated by melatonin regulating the inflammasome complex. Based on the findings of the current study, it is found that melatonin can be effective as a medicinal supplement in decreasing the inflammasome multiprotein complex and oxidative stress along with beneficial impacts on lung cytokine storm of COVID-19 patients.

Efficacy of a Low Dose of Melatonin as an Adjunctive Therapy in Hospitalized Patients with COVID-19: A Randomized, Double-blind Clinical Trial.

BACKGROUND: Melatonin has been known as an anti-inflammatory agent and immune modulator that may address progressive pathophysiology of coronavirus disease 2019 (COVID-19). AIM OF THE STUDY: To evaluate the clinical efficacy of adjuvant, use of melatonin in patients with COVID-19. METHODS: This single-center, double-blind, randomized clinical trial included 74 hospitalized patients with confirmed mild to moderate COVID-19 at Baqiyatallah Hospital in Tehran, Iran, from April 25, 2020-June 5, 2020. Patients were randomly assigned in a 1:1 ratio to receive standard of care and standard of care plus melatonin at a dose of 3 mg three times daily for 14 d. Clinical characteristics, laboratory, and radiological findings were assessed and compared between two study groups at baseline and post-intervention. Safety and clinical outcomes were followed up for four weeks. RESULTS: A total of 24 patients in the intervention group and 20 patients in the control group completed the treatment. Compared with the control group, the clinical symptoms such as cough, dyspnea, and fatigue, as well as the level of CRP and the pulmonary involvement in the intervention group had significantly improved (p <0.05). The mean time of hospital discharge of patients and return to baseline health was significantly shorter in the intervention group compared to the control group (p <0.05). No deaths and adverse events were observed in both groups. CONCLUSIONS: Adjuvant use of melatonin has a potential to improve clinical symptoms of COVID-19 patients and contribute to a faster return of patients to baseline health.

Evaluation of Th1 and Th2 mediated cellular and humoral immunity in patients with COVID-19 following the use of melatonin as an adjunctive treatment.

Coronavirus (SARS-CoV-2) is spreading rapidly in the world and is still taking a heavy toll. Studies show that cytokine storms and imbalances in T-helper (Th)1/Th2 play a significant role in most acute cases of the disease. A number of medications have been suggested to treat or control the disease but have been discontinued due to their side effects. Melatonin, as an intrinsic molecule, possesses pharmacological anti-inflammatory and antioxidant properties that decreases in concentration with age; as a result, older people are more prone to various diseases. In this study, patients who were hospitalized with a diagnosis of coronavirus disease 2019 (COVID-19) were given a melatonin adjuvant (9 mg daily, orally) for fourteen days. In order to measure markers of Th1 and Th2 inflammatory cytokines (such as interleukin (IL)-2, IL-4, and interferon (IFN)-γ) as well as the expression of Th1 and Th2 regulatory genes (signal transducer and activator of transcription (STAT)4, STAT6, GATA binding protein 3 (GATA3), and T-box expressed in T cell (T-bet)), blood samples were taken from patients at the beginning and end of the treatment. Adjuvant therapy with melatonin controlled and reduced inflammatory cytokines in patients with COVID-19. Melatonin also controlled and modulated the dysregulated genes that regulate the humoral and cellular immune systems mediated by Th1 and Th2. In this study, it was shown for the first time that melatonin can be used as a medicinal adjuvant with anti-inflammatory mechanism to reduce and control inflammatory cytokines by regulating the expression of Th1 and Th2 regulatory genes in patients with COVID-19.

Ozone therapy for the treatment of COVID-19 pneumonia: A scoping review.

Severe forms of COVID-19 can evolve into pneumonia, featured by acute respiratory failure due to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In viral diseases, the replication of viruses is seemingly stimulated by an imbalance between pro-oxidant and antioxidant activity as well as by the deprivation of antioxidant mechanisms. In COVID-19 pneumonia, oxidative stress also appears to be highly detrimental to lung tissues. Although inhaling ozone (O3) gas has been shown to be toxic to the lungs, recent evidence suggests that its administration via appropriate routes and at small doses can paradoxically induce an adaptive reaction capable of decreasing the endogenous oxidative stress. Ozone therapy is recommended to counter the disruptive effects of severe COVID-19 on lung tissues, especially if administered in early stages of the disease, thereby preventing the progression to ARDS.

Evaluation of Disease Severity and Health-Related Quality of Life in Patients with Rheumatoid Arthritis Undergoing Total Knee Arthroplasty.

;Background: The Total Knee Arthroplasty (TKA) is one of the most common surgical intervention in patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Previous studies suggested a significant improvement in health status after TKA surgery. But we have little data about the Iranian population undergone TKA. In the current clinical study, we evaluated postoperatively health status using reliable tools of MOS SF-36 and WOMAC in OA and RA patients undergoing TKA. METHODS: In this cohort study, patients with OA and/or RA who were candidates for TKA surgery were included. Using two reliable questionnaires, i.e., WOMAC and SF-36, the quality of life of patients was examined during a period of six months (three monthly intervals) after the surgery. All data were analyzed using IBM SPSS Statistics. Kolmogrov-Smirnov, Kendall's tau, chi-square test and K-related Non-parametric tests were used. RESULTS: Of the 2126 patients who underwent TKA, there were 2024 diagnosed osteoarthritis and 102 validated RA over one year. The mean ± SD of age and the average BMI were 68.0 ± 7.0 BMI 28.5 kg/m2, respectively. Regarding comorbidities and concurrent disorders, about 14% of cases were diabetic, 42% had cardiovascular diseases, 3% had respiratory diseases, and 12% involved with gastrointestinal diseases. The result of SF-36 dramatically increased during follow up. The central distributions of all domains in the SF-36 questionnaire indicated that most scores increased during the time after surgery. As a consequence, WOMAC and MOS FS-36 indicated statistically significant changes after TKA for those who are suffering from RA or OA. CONCLUSION: TKA is an effective surgical process, which improves the quality of life in OA and/or RA. In addition, WOMAC and SF-36 examining tools are likely reliable tools with similar results to assess patients' quality of life after TKA surgery.

Alendronate slows down aortic stenosis progression in osteoporotic patients: An observational prospective study.

BACKGROUND: Aortic stenosis (AS) is the most common primary valvular disease. Currently, there is no pharmacological approach for the medical management of AS. We investigated the effect of osteoporosis therapy with alendronate on hemodynamic progression in patients concurrently affected by AS and osteoporosis. MATERIALS AND METHODS: In this observational prospective study, we enrolled 37 women more than 60 years old with diagnosis of AS and concurrent osteoporosis from August 2017 to December 2019. These patients were treated with alendronate 70 mg every week added to their routine treatment for AS, and their outcomes were compared with 33 patients only affected by AS. Echocardiographic changes and N-terminal-prohormone of brain natriuretic peptide (NT-pro-BNP) level were evaluated during about 2 years of follow-up. RESULTS: The mean follow-up time for the treated and nontreated groups was 20.89 ± 2.73 and 20.84 ± 2.76 months, respectively. Mean gradient (P = 0.02) and peak gradient (P = 0.04) of aortic valve were significantly different between the groups after follow-up. Aortic valve area was decreased 0.09 cm2 in the treated group by alendronate and 0.23 cm2 in the other group (P = 0.001). Furthermore, NT-pro-BNP was significantly decreased in patients treated by alendronate (P = 0.01), but it was increased in nontreated patients (P = 0.04). CONCLUSION: Treatment with alendronate in patients with AS and concurrent osteoporosis slows down the progression of stenosis and improves their prognosis. This study could open a new pathway for the treatment of AS. Further studies, particularly randomized controlled clinical trial, should be done for providing more evidence.

Are Iranian Sulfur Mustard Gas-Exposed Survivors More Vulnerable to SARS-CoV-2? Some Similarity in Their Pathogenesis.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged as a health problem worldwide. It seems that COVID-19 is more lethal for Iranian veterans with a history of exposure to mustard gas. There are some similarities in the pathogenesis of SARS-CoV-2 and mustard gas in immune system disruption and pulmonary infection. SARS-CoV-2 and mustard gas inducing oxidative stress, immune system dysregulation, cytokine storm, and overexpression of angiotensin-converting enzyme II (ACE2) receptor in lungs that act as functional entry receptors for SARS-CoV-2. Moreover, Iranian survivors of mustard gas exposure are more susceptible and vulnerable to COVID-19. It is suggested that the principles of COVID-19 infection prevention and control be adhered to more stringently in Iranian survivors of mustard gas exposure than others who have not been exposed to mustard gas. Therefore, in this review, we discuss the different pathologic aspects of lung injury caused by mustard gas and also the relationship between this damage and the increased susceptibility of Iranian mustard gas exposed survivors to COVID-19.

Epidemiological characteristics of coronavirus disease 2019 (COVID-19) patients in IRAN: A single center study.

BACKGROUND: An outbreak of COVID-19 in Iran has spread throughout the country. Identifying the epidemiological characteristics of this disease will help to make appropriate decisions and thus control the epidemic. The aim of this study was characterization of the epidemiological features of COVID-19 in Iran. METHODS: In this retrospective study, data related to the epidemiological characteristics of COVID-19 patients admitted to Baqiyatallah Hospital in Tehran, Iran, from 19 February 2020 to 15 April 2020 have been analyzed and reported. Patient characteristics including age, gender and underlying diseases were investigated. Data were collected through patient records. Sex ratio, Case Fatality Rate (CFR) and daily trend of cases were also determined. A multiple logistic regression analysis was also performed to assess affecting factors on mortality. RESULTS: From February 19, 2020 to April 15, 2020, 12870 patients referred to the hospital emergency department, of which 2968 were hospitalized with COVID-19 diagnosis. The majority of cases were in the age group of 50 to 60 years of old. The male-to-female ratio was 1.93:1. A total of 239 deaths occurred among all cases for an overall CFR of 1.85% based on the total number of patients (both outpatient and inpatient) and 8.06% among hospitalized patients. Out of all patients 10.89% had comorbidity. Diabetes, chronic respiratory diseases, hypertension, cardiovascular diseases, chronic Kidney diseases and cancer were the most common comorbidities with 3.81, 2.02 , 1.99 , 1.25, 0.60 and 0.57 %, respectively. Male gender (OR=1.45, 95% CI: 1.08-1.96), older age (OR=1.05, 95% CI: 1.04-1.06) and having underlying diseases (OR=1.53, 95% CI: 1.04-2.24) were significantly associated with mortality. CONCLUSIONS: The results of this study showed that Male gender, older age and having comorbidities were significantly associated with the risk of death among COVID-19 patients. It is important to pay special attention to male elderly patients with underlying diseases.

The frequency of anti-phospholipid antibody syndrome in patients with premature coronary artery disease.

Introduction: Coronary Artery Disease (CAD) is known as the major cause of morbidity and mortality in the world with a growing trend, especially in some developing countries. CAD commonly observed in elderly cases, however; recently it is usually found in young adults. In this study, we aimed to evaluate the prevalence of anti-phospholipid antibody syndrome (APS) in patients with premature CAD. Methods: The cross-sectional study was conducted in Baqiyatallah hospital from April 2012 to April 2016. Patients with premature CAD were included in the study. The data regarding the laboratory tests, echocardiography, and angiography were obtained from all cases. Results: Overall 133 eligible patients were included in the study. In the first set of the laboratory test, 18 patients were recognized to have APS (13.53%). The second confirmatory APA test was showing 3 of 18 patients were considered to have APS (2.25%). Conclusion: The results showed there is an association between the risk of developing Premature CAD and APS could potentially. The APS may have significant effects on the risk of coronary heart disease, especially in young adults.

Curcuminoid treatment for knee osteoarthritis: a randomized double-blind placebo-controlled trial.

Treatment of osteoarthritis (OA) is challenging owing to the inefficacy and long-term adverse events of currently available medications including non-steroidal anti-inflammatory drugs. Curcuminoids are polyphenolic phytochemicals with established anti-inflammatory properties and protective effects on chondrocytes. The aim of this study is to investigate the clinical efficacy of curcuminoids in patients suffering from knee OA. A pilot randomized double-blind placebo-control parallel-group clinical trial was conducted among patients with mild-to-moderate knee OA. Patients were assigned to curcuminoids (1500 mg/day in 3 divided doses; n = 19) or matched placebo (n = 21) for 6 weeks. Efficacy measures were changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analogue scale (VAS) and Lequesne's pain functional index (LPFI) scores during the study. There was no significant difference in age, gender, body mass index, and VAS, WOMAC and LPFI scores between the study groups at baseline (p > 0.05). Treatment with curcuminoids was associated with significantly greater reductions in WOMAC (p = 0.001), VAS (p < 0.001) and LPFI (p = 0.013) scores compared with placebo. With respect to WOMAC subscales, there were significant improvements in the pain and physical function scores (p < 0.001) but not stiffness score (p > 0.05). There was no considerable adverse effect in both groups. To conclude, curcuminoids represent an effective and safe alternative treatment for OA.

Mutation Detection in Activin A Receptor, Type I (ACVR1) Gene in Fibrodysplasia Ossificans Progressiva in An Iranian Family.

Fibrodysplasia Ossificans Progressiva (FOP, MIM 135100) is a rare genetic disease that is often inherited sporadically in an autosomal dominant pattern. The disease manifests in early life with malformed great toes and, its episodic and progressive bone formation in skeletal muscle after trauma is led to extra-articular ankylosis. In this study, a 17 year-old affected girl born to a father with chemical injury due to exposure to Mustard gas during the Iran-Iraq war, and her first degree relatives were examined to find the genetic cause of the disease. The mutation c.617G>A in the Activin A receptor, type I (ACVR1) gene was found in all previously reported patients with FOP. Therefore, peripheral blood samples were taken from the patient and her first-degree relatives. DNA was extracted and PCR amplification for ACVR1 was performed. The sequencing of ACVR1 showed the existence of the heterozygous c.617G>A mutation in the patient and the lack of it in her relatives. Normal result of genetic evaluation in relatives of the patient, ruled out the possibility of the mutation being inherited from parents. Therefore, the mutation causing disease in the child, whether is a new mutation with no relation to the father's exposure to chemical gas, or in case of somatic mutation due to exposure to chemical gas, the mutant cells were created in father's germ cells and were not detectable in his blood sample.

The initial presentation of systemic lupus erythematosis with aplastic anemia successfully treated with rituximab.

Hematologic disorders are common in autoimmune diseases. First presentation of systemic lupus erythematosis with aplastic anemia is extremely rare. We report a patient with the diagnosis of secondary aplastic anemia associated with lupus. All routine medications were not effective. She received Rituximab and her response was satisfactory. Her hematologic parameters were within normal range until last follow-up, six months after therapy was initiated with Rituximab. Review of literature displayed 23 cases of acquired aplastic anemia secondary to systemic lupus erythematosis; however, this is the first time the new drug therapy was used for the treatment.

Acute pancreatitis: an initial presentation of systemic lupus erythematosus.

Acute pancreatitis is a rare, but fatal, manifestation of systemic lupus erythematosus. Only 10 systemic lupus erythematosus-associated pancreatitis cases were found in a search of published articles. We report a 24-year-old woman without significant medical history, who was admitted with abdominal pain, nausea and vomiting, which was diagnosed as pancreatitis. It was discovered to be the initial presentation of systemic lupus erythematosus. The first time she was admitted, she recovered with conservative management and steroid therapy. Two months later, she was readmitted to our hospital with symptoms and signs of acute abdomen, which was attributed to her discontinuation of the therapeutic regimen with corticosteroids just after her previous discharge. She underwent laparotomy twice for signs of peritonitis. Despite administration of a monoclonal antibody, rituximab, she died due to the progression of systemic lupus erythematosus activity.