The Effects of Mesenchymal Stem Cells Loaded with Oncolytic Coxsackievirus A21 on Mouse Models of Colorectal Cancer.

BACKGROUND: Cancer is a major cause of death worldwide. Colorectal cancer is the second most common type. Additional treatments like chemotherapy and radiation therapy may be recommended. Developing new techniques is vital due to drug resistance and a lack of targeted therapies. OBJECTIVE: In this study, the effects of mesenchymal stem cells (MSCs) loaded with oncolytic Coxsackievirus A21 (CVA21) on a mouse model of CRC were investigated. METHODS: The therapeutic potency of MSCs loaded with oncolytic CVA21 was evaluated in an experimental mouse model of colorectal cancer which received an injection CT26 cells per mouse subcutaneously. Splenocyte proliferation index, lactate dehydrogenase (LDH) assay, nitric oxide (NO) production assessment, and cytokine assay (IFN-γ, IL-4, IL-10, and TGF-ß) in the splenocyte supernatant were all used to evaluate the impact of MSCs loaded with CVA21. RESULTS: The results of this study showed that the treatment of a mouse model of colorectal cancer with MSCs loaded with oncolytic CVA21 could significantly suppress the tumor growth, which was accompanied by stimulation of splenocytes proliferation index, an increase of NO and LDH. Also, MSCs loaded with oncolytic CVA21 increased the secretion of IFN-γ and decreased the secretion of IL-4, IL-10, and TGF-ß. CONCLUSION: The results of the current study suggest that MSCs loaded with oncolytic CVA21 therapy for the CRC mouse model may have some potential advantages. On the other hand, the results of the study showed that, in addition to activating the acquired immune system, the use of MSCs loaded with oncolytic CVA21 also stimulates the innate immune system by increasing levels of nitric oxide.

Exosomes from Adipose Tissue-derived Mesenchymal Stem Cells Induce Regulatory T Cells in COVID-19 Patients.

An imbalance between regulatory T (Treg) and T-helper (Th)-17 cells has been implicated in the pathogenesis of coronavirus disease 2019 (COVID-19). Mesenchymal stem cells (MSCs) exert immunomodulatory properties through secreting exosomes. This study aimed to assess the effect of MSC-derived exosomes (MSC-Exo) on the differentiation of peripheral blood mononuclear cells (PBMCs) into  Tregs from patients with COVID-19. Exosomes were isolated from adipose tissue-derived MSCs. PBMCs were separated from the whole blood of COVID-19 patients (n=20). Treg frequency was assessed before and 48 hours after treatment of PBMCs with MSC-Exo using flow cytometry. Expression of FOXP3 and cytokine genes, and the concentration of cytokines associated with Tregs, were assessed before and after treatment with MSC-Exo. The frequency of CD4+CD25+CD127-  Tregs was significantly higher after treating PBMCs with MSC-Exo (6.695±2.528) compared to before treatment (4.981±2.068). The expressions of transforming growth factor (TGF)-ß1, interleukin (IL)-10, and FOXP3 were significantly upregulated in MSC-Exo-treated PBMCs. The concentration of IL-10 increased significantly after treatment (994.7±543.9 pg/mL) of PBMCs with MSC-Exo compared with before treatment (563.5±408.6 pg/mL). The concentration of TGF-ß was significantly higher in the supernatant of PBMCs after treatment with MSC-Exo (477.0±391.1 pg/mL) than PBMCs before treatment (257.7±226.3 pg/mL). MSC-Exo has the potential to raise anti-inflammatory responses by induction of  Tregs, potentiating its therapeutic effects in COVID-19.

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.

Efficacy of ozone therapy on visual evoked potentials in diabetic patients.

BACKGROUND: The involvement of the central nervous system is a frequent yet underestimated complication of diabetes mellitus. Visual evoked potentials (VEP) are a simple, sensitive, and noninvasive method for detecting early alterations in central optic pathways. The objective of this paralleled randomized controlled trial was to evaluate the impact of ozone therapy on visual pathways in diabetic patients. METHODS: Sixty patients with type 2 diabetes visiting clinics of Baqiyatallah university in Tehran (Iran) hospital were randomly assigned to two experimental groups: Group 1 (N = 30) undergoing a cycle of 20 sessions of systemic oxygen-ozone therapy in addition to standard therapy for metabolic control; Group 2 (N = 30)-serving as control-receiving only standard therapy against diabetes. The primary study endpoints were two VEP parameters; P100 wave latency and P100 amplitude at 3 months. Moreover, HbA1c levels were measured before the start of treatment and three months later as secondary study endpoint. RESULTS: All 60 patients completed the clinical trial. P100 latency significantly reduced at 3 months since baseline. No correlation was found between repeated measures of P100 wave latency and HbA1c (Pearson's r = 0.169, p = 0.291). There was no significant difference between baseline values and repeated measures of P100 wave amplitude over time in either group. No adverse effects were recorded. CONCLUSIONS: Ozone therapy improved the conduction of impulses in optic pathways of diabetic patients. The improved glycemic control following ozone therpay may not fully explain the reduction of P100 wave latency though; other mechanistic effects of ozone may be involved.

Oncolytic viruses: A novel treatment strategy for breast cancer.

Breast cancer, an unceasingly occurring neoplasm, is one of the major determinants of mortality in women. Several ineffective attempts have been pursued using with conventional therapies against breast cancer. Resistance to existing therapies and their respective debilitating adverse effects have led research toward a new era of cancer treatment using viruses. Virotherapy constitutes a developing treatment modality with multiple mechanisms of therapeutic activity in which the viruses can be directly oncolyticand can express transgenes or induce host immune response against tumor cells. Several different DNA- and RNA-containing viruses have been considered for virotherapy of breast cancer including adenovirus, herpes virus, vaccinia, reovirus, Newcastle Disease virus, measles virus and vesicular stomatitis virus. This review aims to summarize the viro-therapeutical agents against breast malignancies. Key Scientific Concepts of Review: In this review paper, we proposed a new strategy to virus's combinatorial treatments using several kinds of transgenes and drugs. These recombinant viruses have provided evidence of treatment efficacy against human breast cancer.

Potential therapeutic applications of extracellular vesicles in the immunopathogenesis of COVID-19.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19) which has emerged as a global health crisis. Recently, more than 50 different types of potential COVID-19 vaccines have been developed to elicit a strong immune response against SARS-CoV-2. However, genetic mutations give rise to the new variants of SARS-CoV-2 which is highly associated with the reduced effectiveness of COVID-19 vaccines. There is still no efficient antiviral agent to specifically target the SARS-CoV-2 infection and treatment of COVID-19. Therefore, understanding the molecular mechanisms underlying the pathogenesis of SARS-CoV-2 may contribute to discovering a novel potential therapeutic approach to the management of COVID-19. Recently, extracellular vesicle (EV)-based therapeutic strategies have received great attention on account of their potential benefits in the administration of viral diseases. EVs are extracellular vesicles containing specific biomolecules which play an important role in cell-to-cell communications. It has been revealed that EVs are involved in the pathogenesis of different inflammatory diseases such as cancer and viral infections. EVs are released from virus-infected cells which could mediate the interaction of infected and uninfected host cells. Hence, these extracellular nanoparticles have been considered a novel approach for drug delivery to mediate the treatment of a wide range of diseases including, COVID-19. EVs are considered a cell-free therapeutic strategy that could ameliorate the cytokine storm and its complications in COVID-19 patients. Furthermore, EV-based cargo delivery such as immunomodulatory agents in combination with antiviral drugs may have therapeutic benefits in patients with SARS-CoV-2 infection. In this review, we will highlight the potential of EVs as a therapeutic candidate in the diagnosis and treatment of COVID-19. Also, we will discuss the future perspectives regarding the beneficial effects of Evs in the development of COVID-19 vaccines.

Reduce the risk of ventilator-associated pneumonia in ICU patients by Ozonated water mouthwash: A double-blind randomized clinical trial.

BACKGROUND: The aim of this study was to compare the 2 mouthwash solutions, including chlorhexidine (CHG) and ozonated water (OZW) to reduce the risk of ventilator-associated pneumonia (VAP) in patients on mechanical ventilation in intensive care unit (ICU). METHODS: This randomized double-blind clinical trial was performed in ICU units of hospitals. Patients (n=73) were selected and divided into 2 groups of CHG (n=37) and OZW mouthwash (n=36). Mouthwash was performed by trained nurses. Chi-square test, independent t-test, paired t-test, Mann-Whitney U-test, and Repeated Measure ANOVA was used to evaluate the effect of CHG and OZW mouthwash on the risk of VAP occurrence by Clinical Pulmonary Infection Score (CPIS) checklists and swab culture. RESULTS: Both CHG and OZW mouthwash reduced the risk of VAP differ at different time points (the first, the third and the fifth days). There was also difference in the incidence of VAP in terms of culture of pulmonary secretions in the 2 groups. Incidence of VAP in the CHG mouthwash group was 45.9%, and also 25% in the OZW mouthwash group. Most pathogens, that found in the culture of pulmonary secretions in the CHG mouthwash was Acinetobacter baumannii; also, in the OZW mouthwash, A baumannii and Pseudomonas aeruginosa were the most frequent ones. CONCLUSIONS: OZW mouthwash was more effective than CHG mouthwash to reduce the risk of VAP.

Advances in early diagnosis of cervical cancer based on biosensors.

Human papillomavirus (HPV) is a causative agent of cervical cancer among women worldwide. Serological and molecular tests are commonly used to detect and identify HPV, but all the detection methods for HPV have some limitations. Nowadays, considerable advancements in nanosensors have enabled monitoring of hybridization procedures dynamically for HPV detection. Biosensors, as effective, quick, economical, and highly sensitive tools, can be used in the diagnosis of HPV as an alternative technique instead of other detection methods. Biosensor detection methods of HPV in use from 2000 to 2021 were investigated using several databases such as Google Scholar, Scopus, PubMed, and the Scientific Information Database. Furthermore, a manual search of the references of the retrieved articles was performed. On analyzing the most recently developed biosensors for HPV identification, we observed that three biosensor systems, electrochemical, optical, and piezoelectric systems, are the main transducers used in the development of HPV biosensors. The aim of this review is to examine recent research on biosensors for the detection of HPV and perform a comparison with other diagnostic methods. Considering the importance of rapid HPV detection in the control of infection and development of public health measures, improvement of biosensors as an economical and quick method can be very useful in the diagnosis of HPV.

Iranian patients co-infected with COVID-19 and mucormycosis: the most common predisposing factor, clinical outcomes, laboratory markers and diagnosis, and drug therapies.

BACKGROUND: The newly emerged pandemic of coronavirus disease-2019 (COVID-19) is the world's main health challenge because infected patients become vulnerable to a variety of opportunistic diseases. OBJECTIVE: This study aimed to assess clinical outcomes, diagnosis, utilized drug therapies, and ongoing COVID-19 practices in Iranian cases co-infected with COVID-19 and mucormycosis. PARTICIPANTS AND METHODS: A case-series analysis was conducted in the presence of 10 patients with COVID-19 and mucormycosis co-infection (two men and eight women; mean age of 48.8 years) from March to October 2020. Demographic variables, signs/symptoms, and comorbidities of all patients were recorded. COVID-19 was confirmed with reverse transcription polymerase chain reaction (RT-PCR) nasopharyngeal swab tests and high-resolution computed tomography (HR-CT)_ scans. RESULTS: All patients had a positive RT-PCR for SARS-CoV-2. Eight patients had a history of diabetes, while three of them exhibited a hypertension history. Remarkable laboratory findings were elevated fasting blood sugar in 6 cases and anaemia in four patients. A rhino-orbital-cerebral of mucormycosis in all patients was detected based on HR-CT scans and otorhinolaryngological or ophthalmological examinations. Neurological disorders including facial, trigeminal, optic, and oculomotor nerve involvement resulted in paraesthesia, pain, ptosis, no light perception, blurred vision, and papilledema in five cases. Maxillary and ethmoid sinuses were the most common sites of involvement. CONCLUSION: Vulnerable COVID-19 patients with comorbidities, any facial involvements, or treated by excessive doses of glucocorticoids and antibiotics should undergo precise examinations during the appearance of early signs and hospitalization to diagnose and treat mucormycosis using the standard care and antifungal treatments.

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.

Gastrointestinal cancers, ACE-2/TMPRSS2 expression and susceptibility to COVID-19.

Recent studies on the pathophysiology of COVID-19 are indicating that the Angiotensin convertase enzyme 2 (ACE-2) and transmembrane serine protease 2 (TMPRSS2) can act as a major component in the fusion of SARS-Cov-2 with target cells. It has also been observed that the expression of ACE-2 and TMPRSS2 can be altered in malignancies. Shedding light on this matter could be crucial since the COVID-19 pandemic interfered with many gastrointestinal cancer screening programs. Herein we discuss the possibility of severe forms of COVID-19 in patients with gastrointestinal cancers due to the gastrointestinal entry route of SARS-CoV-2 into the human body. The disruption of cancer screening programs caused by the current COVID-19 pandemic could therefore have massive negative health impact on patients affected by gastrointestinal malignancies.

The effects of oxygen-ozone therapy on regulatory T-cell responses in multiple sclerosis patients.

Multiple sclerosis (MS) is a common degenerative disorder of the central nervous system. The decreased frequency and dysfunction of Treg cells cause inflammation and disease progression. Ozone autohemotherapy can be used as a potential therapeutic approach to regulate the immune system responses and inflammation in MS. For this purpose, 20 relapsing-remitting multiple sclerosis patients were under treatment with ozone twice weekly for 6 months. The frequency of Treg cell, the expression levels of the Treg cell-related factors (FoxP3, IL-10, TGF-ß, miR-17, miR-27, and miR-146A), and the secretion levels of IL-10 and TGF-ß were assessed. We found a significant increase in the number of Treg cells, expression levels of FoxP3, miRNAs (miR-17 and miR-27), IL-10, and TGF-ß factors in patients after oxygen-ozone (O2 -O3 ) therapy compared to before treatment. In contrast, oxygen-ozone therapy notably decreased the expression level of miR-146a in treated patients. Interestingly, the secretion levels of both IL-10 and TGF-ß cytokines were considerably increased in both serum and supernatant of cultured peripheral blood mononuclear cells in posttreatment condition compared to pretreatment condition. According to results, oxygen-ozone therapy raised the frequency of Treg cell and its relevant factors in treated MS patients. Oxygen-ozone therapy would contribute to improving the MS patients by elevating the Treg cell responses.

The Primary Outcomes and Epidemiological and Clinical Features of Coronavirus Disease 2019 (COVID-19) in Iran.

AIM: We aimed to describe the epidemiological and clinical characteristics of Iranian patients with COVID-19. METHODS: In this single-center and retrospective study, patients with confirmed COVID-19 infections were enrolled. Univariate and multivariate logistic regression methods were used to explore the risk factors associated with outcomes. RESULTS: Of 179 patients with confirmed COVID-19 infection, 12 remained hospitalized at the end of the study and 167 were included in the final analysis. Of these, 153 (91.6%) were discharged and 14 (8.38%) died in hospital. Approximately half (50.9%) of patients suffered from a comorbidity, with diabetes or coronary heart disease being the most common in 20 patients. The most common symptoms on admission were fever, dyspnea, and cough. The mean durations from first symptoms to hospital admission was 8.64 ± 4.14 days, whereas the mean hospitalization time to discharge or death was 5.19 ± 2.42 and 4.35 ± 2.70 days, respectively. There was a significantly higher age in non-survivor patients compared with survivor patients. Multivariate regression showed increasing odds ratio (OR) of in-hospital death associated with respiratory rates >20 breaths/min (OR: 5.14, 95% CI: 1.19-22.15, p = 0.028) and blood urea nitrogen (BUN) >19 mg/dL (OR: 4.54, 95% CI: 1.30-15.85, p = 0.017) on admission. In addition, higher respiratory rate was associated with continuous fever (OR: 4.08, 95% CI: 1.18-14.08, p = 0.026) and other clinical symptoms (OR: 3.52, 95% CI: 1.05-11.87, p = 0.04). CONCLUSION: The potential risk factors including high respiratory rate and BUN levels could help to identify COVID-19 patients with poor prognosis at an early stage in the Iranian population.

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.

Changes in Th17 cells frequency and function after ozone therapy used to treat multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) is a neurodegenerative autoimmune disease with chronic inflammation. In the course of the disease, the increased levels of Th17 cell, and its relevant inflammatory factors, may cause disease inflammation and progression. Ozone therapy with anti-oxidant and anti-inflammatory functions is known as a beneficial therapeutic approach. The current non-controlled study aimed to evaluate the therapeutic implications of ozone autohemotherapy on Th17 responses in MS patients. METHODS: 20 MS patients as the experimental group received ozone therapy (100 ml of O2/O3 compound (25 ugs/ml concentration) with 100 ml of autologous blood) twice per week for 6 months. The frequency of Th17 cells, gene expression of the relevant factors (RORÉ£t, IL-17, IL-23, miR-141, miR-155, and miR-200), as well as the secretion levels of IL-17 and IL-23 cytokines, were compared between the patient and control groups, as well as the group of patients before and after ozone therapy using the flow cytometry, Real-time PCR, and ELISA techniques, respectively. RESULTS: Findings indicated the significant decrease in the frequency of Th17 cells (P = 0.0002), the expression levels of RORÉ£t and IL-17 (P = 0.0001 and P = 0.0004, respectively), as well as miR-141 and miR-155 (P<0.0001 and P<0.0001, respectively) in post-treatment condition with Ozone compared to pre-treatment condition. Also, the significant reduction in the secretion level of IL-17 (P = 0.043) was detected in treated patients. DISCUSSION: Since increased levels and responses of Th17 cells may have critical roles in MS pathogenesis and inflammation, our findings revealed that ozone autohemotherapy could lower the Th17 responses in peripheral blood of MS patients and can be a beneficial approach in MS treatment.

The clinical value of two combination regimens in the Management of Patients Suffering from Covid-19 pneumonia: a single centered, retrospective, observational study.

BACKGROUND: There is no identified pharmacological therapy for COVID-19 patients, where potential therapeutic strategies are underway to determine effective therapy under such unprecedented pandemic. Therefore, combination therapies may have the potential of alleviating the patient's outcome. This study aimed at comparing the efficacy of two different combination regimens in improving outcomes of patients infected by novel coronavirus (COVID-19). METHODS: This is a single centered, retrospective, observational study of 60 laboratory-confirmed COVID-19 positive inpatients (≥18 years old) at two wards of the Baqiyatallah Hospital, Tehran, Iran. Patient's data including clinical and laboratory parameters were recorded. According to the drug regimen, the patients were divided into two groups; group I who received regimen I consisting azithromycin, prednisolone, naproxen, and lopinavir/ritonavir and group II who received regimen II including meropenem, levofloxacin, vancomycin, hydroxychloroquine, and oseltamivir. RESULTS: The oxygen saturation (SpO2) and temperature were positively changed in patients receiving regimen I compared to regimen II (P = 0.013 and P = 0.012, respectively). The serum level of C-reactive protein (CRP) changed positively in group I (P < 0.001). Although there was a significant difference in platelets between both groups (75.44 vs 51.62, P < 0.001), their change did not clinically differ between two groups. The findings indicated a significant difference of the average length of stay in hospitals (ALOS) between two groups, where the patients under regimen I showed a shorter ALOS (6.97 vs 9.93, P = 0.001). CONCLUSION: This study revealed the beneficial effect of the short-term use of low-dose prednisolone in combination with azithromycin, naproxen and lopinavir/ritonavir (regimen I), in decreasing ALOS compared to regimen II. Since there is still lack of evidence for safety of this regimen, further investigation in our ongoing follow-up to deal with COVID-19 pneumonia is underway. Graphical abstract.

Early manifestation of ARDS in COVID-19 infection in a 51- year-old man affected by Mounier-Kuhn syndrome.

A 51-year-old man known to be affected by Mounier-Kuhn syndrome (MKS). presented to Accident & Emergecy (A&E) with fever, dyspnea and deterioration of his chronic coughs. Increased diameters of his trachea (39 mm), right (30 mm) and left (26 mm) main bronchi were revealed by chest computerized tomography (CT) scan. CT scan showed also ground-glass opacities (GGO) and bronchiectasis in the mid and lower zones of both lungs. COIVD-19 infection was eventually confirmed by RT-PCR. A severe form of COVID-19 could occur even in the early stages of the disease in presence of underlying co-morbidities including MKS, which increases the susceptibility to more recurrent and severe respiratory infections.