Harnessing the therapeutic potential of mesenchymal stem/stromal cell-derived extracellular vesicles as a novel cell-free therapy for animal models of multiple sclerosis.

Multiple sclerosis (MS) is a chronic, neuroinflammatory, and demyelinating disease of the central nervous system (CNS). Current treatments offer only limited relief from symptoms, and there is no cure. Mesenchymal stem/stromal cells (MSCs) have demonstrated therapeutic potential for MS. However, their clinical application faces challenges, including immune rejection and the potential for tumor formation. Recent studies suggest that MSCs exert their effects through extracellular vesicles (EVs) released from the cells, rather than direct cellular engraftment or differentiation. This discovery has sparked interest in the potential of MSC-derived EVs as a cell-free therapy for MS. This review explores the existing literature on the effects of MSC-EVs in animal models of MS. Administration of MSC-EVs from various tissue sources, such as bone marrow, adipose tissue, and umbilical cord, was found to reduce clinical scores and slow down disease progression in experimental autoimmune encephalomyelitis (EAE), the primary mouse model of MS. The mechanisms involved immunomodulation through effects on T cells, cytokines, CNS inflammation, and demyelination. Although the impact on CNS repair markers remained unclear, MSC-EVs exhibited the potential to modulate neuroinflammation and suppress harmful immune responses in EAE. Further studies are still required, but MSC-EVs demonstrate promising therapeutic effects for MS and warrant further exploration as a novel treatment approach.

Effect of Disease-Modifying Therapies on COVID-19 Vaccination Efficacy in Multiple Sclerosis Patients: A Comprehensive Review.

According to current knowledge, the etiopathogenesis of multiple sclerosis (MS) is complex, involving genetic background as well as several environmental factors that result in dysimmunity in the central nervous system (CNS). MS is an immune-mediated, inflammatory neurological disease affecting the CNS. As part of its attack on the axons of the CNS, MS witnesses varying degrees of myelin and axonal loss. A total of about 20 disease-modifying therapies (DMTs) are available today that, both in clinical trials and in real-world studies, reduce disease activity, such as relapses, magnetic resonance imaging lesions, and disability accumulation. Currently, the world is facing an outbreak of the new coronavirus disease 2019 (COVID-19), which originated in Wuhan, Hubei Province, China, in December 2019 and spread rapidly around the globe. Viral infections play an important role in triggering and maintaining neuroinflammation through direct and indirect mechanisms. There is an old association between MS and viral infections. In the context of MS-related chronic inflammatory damage within the CNS, there has been concern regarding COVID-19 worsening neurological damage. A high rate of disability and increased susceptibility to infection have made MS patients particularly vulnerable. In addition, DMTs have been a concern during the pandemic since many DMTs have immunosuppressive properties. In this article, we discuss the impact of DMTs on COVID-19 risks and the effect of DMTs on COVID-19 vaccination efficacy and outcome in MS patients.

Gene expression of semaphorin-3A, semaphorin-7A, neuropilin-1, plexin-C1, and ß1 integrin in treated-multiple sclerosis patients.

OBJECTIVE: Recently, members of the semaphorin family have received major attention in various medical fields, especially autoimmunity. In this study, we selected semaphorin-3A (Sema3A), semaphorin-7A (Sema7A), and their receptors to determine the possible relationship between these molecules and multiple sclerosis (MS). METHOD: We measured the gene expression of Sema3A, Sema7A, neuropilin-1 (NP-1), plexin-C1, and ß1 integrin in the blood samples of relapsing-remitting multiple sclerosis (RRMS) patients, treated with high-dose interferon-ß1a (IFN-ß1a), low-dose IFN-ß1a, IFN-ß1b, and glatiramer acetate (GA) via quantitative real-time polymerase chain reaction (qRT-PCR) assay, and then, compared the results of treatment-naive patients with the healthy controls. RESULTS: The gene expression of Sema3A (P = 0.02), NP-1 (P < 0.001), and plexin-C1 (P < 0.01) significantly decreased in the treatment-naive group, compared to the healthy controls. Sema3A significantly increased in all treated patients, compared to the treatment-naive patients (P < 0.001). However, expression of NP-1 (P < 0.001), plexin-C1 (P < 0.001), and ß1 integrin (P < 0.05) only increased in patients receiving high-dose IFN-ß1a, IFN-ß1b, and GA. Expression of Sema7A increased in only two groups of patients treated with IFN-ß1b (P < 0.001) and GA (P = 0.018), without any significant decrease in the treatment-naive group, compared to the healthy controls (P > 0.05). CONCLUSION: Our findings confirm that the presence of Sema3A, Sema7A, and their receptors can play critical roles in the treatment of MS patients. Therefore, they can be potential target molecules for MS treatment in the future.

Effects of interferon and glatiramer acetate on cytokine patterns in multiple sclerosis patients.

Multiple sclerosis (MS) is an unpredictable autoimmune disease, which causes neurodegeneration in the central nervous system. Since the main cause of MS remains obscure, in this study, we aimed to evaluate the serum levels of some cytokines, including interleukin-5 (IL-5), IL-8, IL-9, IL-17A, transforming growth factor-beta (TGF-ß), and interferon-gamma (IFN-γ) in relapsing-remitting (RR)-MS patients, treated with IFN-ß and glatiramer acetate (GA). Serum samples of RR-MS patients, treated with high-dose IFN-ß1a, low-dose IFN-ß1a, IFN-ß1b, and GA, were assessed by ELISA assay and then compared with the results of treatment-naive patients and healthy controls. The findings showed that the serum levels of IL-8, IL-9, and IFN-γ in treatment-naive patients were significantly higher than the healthy controls, while there was no significant difference in terms of other cytokines between the groups. A significant reduction was observed in the levels of IL-9 and IFN-γ, while there was a significant increase in TGF-ß level among patients treated with GA. IFN-ß1b resulted in a significant decline in the levels of IL-9 and TGF-ß. In addition to these findings, some cytokines were positively correlated in different groups. Overall, the present results support the inflammatory and aggravating effects of IL-8, IL-9, and IFN-γ on MS. Furthermore, based on the results reported in the GA treatment group, we suggest GA as an effective treatment for RR-MS patients.

Negative Regulation of Semaphorin-3A Expression in Peripheral Blood Mononuclear Cells Using MicroRNA-497-5p.

BACKGROUND: Semaphorin-3A (Sema3A), as a secreted semaphorin, is an immune modulator molecule participating in the pathogenesis of autoimmune diseases. MicroRNAs (miRNAs) modulate the target-gene expression at the post-transcriptional level. It has been proposed that miRNAs may be crucial to the modulation of the function of semaphorins. Previous findings have proven that miR-497-5p is upregulated and Sema3A is downregulated in some autoimmune disorders. Thus, we aimed to examine the presence of any correlation between Sema3A and miR-497-5p in peripheral blood mononuclear cells (PBMCs). METHODS: PBMCs were cultured and transfected with miR-497-5p mimic using the X-tremeGENE™ reagent. The expression level of Sema3A was assessed after 48 hours in supernatants and cells via the enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction, respectively. Cell viability was evaluated using the methylthiazol tetrazolium assay. All the experiments were done in triplicate, and the statistical analyses were performed with SPSS, version 20. P values equal to or less than 0.05 were considered significant. RESULTS: We observed downregulation of the Sema3A gene (P=0.0001) and its secretion (P=0.032) in the PBMCs through miR-497-5p transfection. Moreover, transfection with miR-497-5p mimic and downregulation of Sema3A did not affect the viability of the PBMCs (P=0.061). CONCLUSION: Based on the obtained results, we suggest that miR-497-5p has a high suppressive effect on Sema3A expression and both Sema3A and miR-497-5p can be considered critical targets for further studies on future therapeutic attempts for the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

High Mobility Group box-1 (HMGB1) Protein As a Biomarker for Acute Cholecystitis.

BACKGROUND: Acute cholecystitis is defined as gallbladder inflammation caused by obstruction of the cystic duct. The pro-inflammatory cytokine, high mobility group box-1 (HMGB1), has been found to hold critical roles in the pathogenesis of several different inflammatory diseases. This study aimed to determine the relationship between HMGB1 and acute cholecystitis, and examine the potential for this cytokine as a biomarker for clinical diagnosis. METHODS: The serum of 23 patients with severe acute cholecystitis, 45 patients with mild acute cholecystitis and 35 healthy subjects was collected and isolated from peripheral blood. The serum levels of HMGB1, CRP, amylase, lipase and the number of white blood cells were measured prior to the patient's cholecystectomy and 48 hours following the procedure. RESULTS: A significant increase in the levels of HMGB1 were observed in both patient groups with mild or severe acute cholecystitis compared with normal group. ROC analysis determined a cut-off point of 2.34 for HMGB1 serum levels to discriminate between the normal group and acute cholecystitis patients with a sensitivity of 79.41% and a specificity of 54.3%. The area under the ROC curve was 0.71. Furthermore, a positive correlation was observed between CRP and HMGB1 levels and no significant difference in the levels of amylase and lipase was observed between groups. CONCLUSION: These findings suggest a potential role for HMGB1 as an effective biomarker in improving the diagnostic accuracy of acute cholecystitis when used in conjunction with the standard diagnostic tests.

Assessment of CCL27 and IL-11 in Multiple Sclerosis Patients Treated with Interferon-ß and Glatiramer Acetate.

INTRODUCTION: Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease which involves the central nervous -system. Although the primary cause of MS is obscure, effects of some cytokine and chemokine patterns in both innate and adaptive immune systems have been described. -Objectives: Since limited studies have examined the role of interleukin (IL)-11 and chemokine CCL27 in MS, we aimed to identify changes in IL-11 and CCL27 gene expression and serum levels in relapsing-remitting MS (RRMS) patients, treated with interferon (IFN)-ß and glatiramer acetate (GA). METHODS: The serum level and gene expression of IL-11 and CCL27 were measured and compared between treatment-naïve MS patients and RRMS patients who were treated with high-dose IFN-ß1a, low-dose IFN-ß1a, IFN-ß1b, and GA via enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction. RESULTS: A significant decrease was observed in the serum level of CCL27 in treatment-naïve patients and IFN-ß1b-treated patients compared to the healthy controls. On the other hand, a significant increase was found in the protein level of CCL27 in low-dose and high-dose IFN-ß1a groups compared to the treatment-naïve group. In addition, CCL27 gene expression was higher in patients treated with GA than in the treatment-naïve group. There were no significant changes in the gene expression or protein level of IL-11 in all experimental groups. Additionally, a positive correlation was found between IL-11 and CCL-27. CONCLUSION: Our results suggest the inflammatory role of CCL27 in MS patients, while IFN-ß1a seems to play a compensatory role for this chemokine.

Semaphorin-3A as An Immune Modulator Is Suppressed by MicroRNA-145-5p.

OBJECTIVES: Semaphorin-3A (SEMA3A) and its receptors are found on some immune cells and act as suppressors of immune cells over-activation. Considering the role of SEMA3A and its down-regulation in some autoimmune diseases, as well as our bioinformatics predictions, we assumed that miR-145-5p might affect SEMA3A expression. So, we aimed to determine the effect of miR-145-5p on SEMA3A gene expression level. MATERIALS AND METHODS: In this experimental study, we evaluated the effect of miR-145-5p transfection on SEMA3A expression in peripheral blood mononuclear cells (PBMCs) using ELISA and quantitative real-time polymerase chain reaction (PCR) methods. RESULTS: Our results showed that miR-145-5p is able to decrease SEMA3A expression at both protein and mRNA levels. These data confirmed our previous bioinformatic prediction about the inhibitory effect of miR-145-5p on SEMA3A expression. CONCLUSIONS: These results enlightened us about an unknown aspect of SEMA3A role in some autoimmune disorders like multiple sclerosis (MS) and rheumatoid arthritis (RA) and also proposed SEMA3A as a potential therapeutic approach.

Decreased expression of Sema3A, an immune modulator, in blood sample of multiple sclerosis patients.

Semaphorin 3A (Sema3A) as an immune modulator could participate in the pathogenesis of autoimmune diseases. In the current study, we aimed to investigate Sema3A expression in peripheral blood mononuclear cells (PBMCs) and its serum level in relapsing-remitting multiple sclerosis (RRMS) patients. Fifteen newly determined and untreated RRMS patients were chosen and assessed in relapsing and remitting phases in compare with fifteen healthy individuals. In consistent with previous findings in other autoimmune diseases, our results revealed that serum level of Sema3A and its expression in PBMCs of RRMS patients were significantly lower than in normal subjects. We also evaluated this down regulation predictive value with ROC analysis. According to our data, we suggest that Sema3A could be involved in pathogenesis of MS and might be a potential diagnostic biomarker for the disease.