Nucleic Acids as Novel Therapeutic Modalities to Address Multiple Sclerosis Onset and Progression.

The issue of treating Multiple Sclerosis (MS) begins with disease-modifying treatments (DMTs) which may cause lymphopenia, dyspnea, and many other adverse effects. Consequently, further identification and evaluation of alternative treatments are crucial to monitoring their long-term outcomes and hopefully, moving toward personalized approaches that can be translated into clinical treatments. In this article, we focused on the novel therapeutic modalities that alter the interaction between the cellular constituents contributing to MS onset and progression. Furthermore, the studies that have been performed to evaluate and optimize drugs' efficacy, and particularly, to show their limitations and strengths are also presented. The preclinical trials of novel approaches for multiple sclerosis treatment provide promising prospects to cure the disease with pinpoint precision. Considering the fact that not a single treatment could be effective enough to cover all aspects of MS treatment, additional researches and therapies need to be developed in the future. Since the pathophysiology of MS resembles a jigsaw puzzle, researchers need to put a host of pieces together to create a promising window towards MS treatment. Thus, a combination therapy encompassing all these modules is highly likely to succeed in dealing with the disease. The use of different therapeutic approaches to re-induce self-tolerance in autoreactive cells contributing to MS pathogenesis is presented. A Combination therapy using these tools may help to deal with the clinical disabilities and symptoms of the disease in the future.

Umbilical cord mesenchymal stem cells as well as their released exosomes suppress proliferation of activated PBMCs in multiple sclerosis.

Multiple sclerosis (MS) is a central nervous system (CNS) degenerative disorder which is caused by a targeted autoimmune-mediated attack on myelin proteins. Previously, mesenchymal stem cells were considered as a novel and successful treatment of MS. One of the underlying mechanisms behind their immunomodulatory function is the release of extracellular vesicles, particularly exosomes. In this study, we aimed to evaluate the suppressive efficacy of MSCs and their exosomes on the proliferation of peripheral mononuclear blood cells (PBMC) in relapsing-remitting MS (RRMS) patients and healthy subjects. To do, mesenchymal stem cells were derived from human umbilical cord tissues and used for exosome isolation through ultracentrifugation. Suppressive function of MSCs and MSC-derived exosomes was examined in a coculture with CFSE-labelled PBMCs in vitro. PBMC proliferation of the patients and healthy individuals was measured using flow cytometry. We first demonstrated that proliferation of PBMCs decreased in the presence of MSCs and suppression was more efficient by MSC-derived exosomes, with a minimum alloreaction rate. However, suppression capacity of MSCs and their exosomes significantly decreased during extensive sub-culturing. The present study showed that MSC-derived exosomes as an effective cell-free therapy could prevent proliferation of PBMCs. However, further evaluations are need to move towards a functional approach that can be translated to the clinic.

Beneficial impact of exercise on bone mass in individuals under calorie restriction: a systematic review and Meta-analysis of randomized clinical trials.

Background: A major therapeutic goal in weight management should be total body fat reduction whereas as preserving lean body mass and bone mass density. It is uncertain if an exercise program reduces the adverse effects of calorie restriction-induced weight loss in adults.Objective: The aim of the present study was to evaluate the differences in bone mass between adults who enrolled in a calorie restriction or an exercise-calorie restriction induced weight loss program.Data sources: Both PubMed and Scopus libraries were searched up to February 2020.Methods: Systematic reviews and a meta-analysis were carried out of randomized clinical trials (published to February 2020) on differences in bone mineral density and content (BMD and BMC) of adults who lost weight by calorie restriction alone (CR) or exercise-calorie restriction (CR-E). The study quality was calculated using the Cochrane scoring system. Retrieved data were pooled when weight mean differences (WMDs) were computed between two groups for BMD and BMC at various sites of the body.Results: Thirteen studies, with a total of 852 participants were included. Available evidence found significantly higher BMD at the hip (WMD: 0.03 g/cm2, 95%CI: 0.01 to 0.04, p < 0.001) and femoral neck WMD: 0.03 g/cm2, 95%CI: 0.01 to 0.05, p < 0.001) and total body BMC (WMD: 0.13 kg/cm2, 95%CI: -0.10 to 0.36, p < 0.001) in the CR-E compared to the CR weight loss group. In contrast, all changes in total body BMD (WMD: 0.00 g/cm2, 95%CI: -0.01 to 0.02, p = 0.57) and lumbar spine BMD (WMD: 0.00 g/cm2, 95%CI: -0.01 to 0.01, p = 0.89) were not statistically significant.Limitations: Little evidence was available for different sexes separately. Most individuals were postmenopausal females and no subgroup analysis could be conducted based on menopausal status.Conclusion: This study suggests that physical training can preserve and even significantly increase the bone mass of the hip and femoral neck during weight reduction. Of note, various exercise modalities affected BMD at different sites. Similar results were not found for lumbar spine and total body BMD.

The Effect of L-Carnitine Supplementation on Exercise-Induced Muscle Damage: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Accumulating evidence of previous experimental studies indicated that L-Carnitine positively ameliorates muscle damage. However, findings from trials vary substantially across studies. Therefore, current meta-analysis aimed to examine the effects of L-Carnitine supplementation on exercise-induced muscle damage. An electronic search of the online literature databases (Medline (PubMed), Scopus and Google Scholar) was performed up to November 2018. Either a fixed-effects model or a random-effects model (Diasorin-Liard) was used in order to estimate the effects size. Cochran's Q test and I2 tests were used to assess the heterogeneity among the studies. Funnel plot and Egger's regression test were also employed in order to assess the publication bias. Of 604 studies, seven eligible randomized controlled trials (RCTs) were included in this meta-analysis. Pooled data from seven studies showed that L-Carnitine resulted in significant improvements in muscle soreness (MS) at the five follow-up time points (0, 24, 48, 72 and 96 hours (h)) compared to placebo. Also, pooled data indicated that L-Carnitine significantly reduced creatine kinase (CK), myoglobin (Mb), and lactate dehydrogenase (LDH) levels at one follow-up period (24 h). However, no effects have been observed beyond this period. Our outcomes indicate that L-Carnitine supplementation improves delayed-onset muscle soreness (DOMS) and markers of muscle damage. Further research is needed to clarify impacts of L-Carnitine on DOMS after different types of mechanical or chemical damages.Key teaching pointsThe effect of L-Carnitine supplementation on exercise-induced muscle damage has come under scrutiny over many years.This systematic review and meta-analyses study investigated the effects of L-Carnitine supplementation on exercise-induced muscle damage.Overall, summary results indicate that L-Carnitine supplementation improves muscle soreness and markers of muscle damage (CK, LDH, and Mb).Overall, L-carnitine supplementation ameliorated muscle damage only in resistance training groups and untrained population.

Immunomodulatory Potential of Human Mesenchymal Stem Cells and their Exosomes on Multiple Sclerosis.

Purpose: Promising advances have been made in mesenchymal stem cell transplantation to reinducethe immune tolerance in neuroinflammatory animal models and multiple sclerosis (MS)patients. The available evidence demonstrated that immunomodulatory effects of mesenchymalstem cell are particularly exerted through releasing exosomes to their environment. Wetherefore, aimed to comparatively assess the potential effect of mesenchymal stem cells andmesenchymal stem cells-derived exosomes on proliferation and function of the CD4+CD25- conventional T cells, isolated from relapsing-remitting MS patients. Methods: Mesenchymal stem cells were isolated from human umbilical cord tissues and usedfor exosome isolation via ultracentrifugation. Both mesenchymal stem cells and mesenchymalstem cells-derived exosomes were evaluated for their anti-inflammatory effects againstthe proliferation of T cells isolated from two groups of individuals in vitro, MS patients andhealthy subjects. Cytokine production of conventional T cells (interferon-γ, interleukin-10, andinterleukin-17) was also assessed, using flow cytometry for the patients and healthy individuals. Results: Here, evidence shows that MSCs and MSC-derived exosomes dampen proliferationand percentage of conventional T cells that produce IFN-γ (healthy control: P < 0.001) andinterleukin-17 (healthy control: P <0.001, MS patients: P < 0.001), with a significant increaseof IL-10 producing cells in the patients and healthy individuals. Surprisingly, MSC-derivedexosomes demonstrated higher immune-modulating properties on conventional T cellsresponses, compared to mesenchymal stem cells (MSCs). Conclusion: The current study, provides a novel approach of exocytosis on autoimmune therapy.In particular, Mesenchymal stem cell -derived exosomes, which are cell-derived biologics,could be considered as an alternative for Mesenchymal stem cells in treating MS.

Prophylactic and Therapeutic Effects of MOG-Conjugated PLGA Nanoparticles in C57Bl/6 Mouse Model of Multiple Sclerosis.

Purpose: Multiple sclerosis (MS) is a debilitating neuroinflammatory disorder of the central nervous system. It is believed to result from an impaired immune response against myelin components especially myelin oligodendrocyte glycoprotein (MOG). Some efforts have been made to bioconjugate the MOG peptides to tolerogenic particles like poly (lactic-co-glycolic acid) (PLGA) for treating animal models of autoimmune disorders. Accordingly, we aimed to elucidate the tolerogenic effects of MOG-PLGA particles on experimental autoimmune encephalomyelitis (EAE). Methods: PGLA nanoparticles were synthesized using water/oil/water procedure. Next, the MOG or ovalbumin (OVA) peptides covalently linked to the PLGA particles. These particles were then intravenously or subcutaneously administered to nine groups of C57BL/6 mice before and after EAE induction. The brain tissues were assessed for the infiltration of immune cells. The Tolerogenic effect of the vaccine was also assessed on the quantity of the Treg cells. Moreover, the amount of interferon-γ (IFN-γ), interleukin-10 (IL-10), and interleukin-17 levels produced by splenic lymphocytes were then quantified by ELISA. Results: Intravenous administration of PLGA500-MOG35-55 nanoparticles before EAE induction ameliorated EAE clinical scores as well as infiltration of immune cells into the brain. In the spleen, the treatment increased CD4+CD25+FoxP3+ Treg population and restored the homeostasis of IFN-γ, IL-10, and IL-17 (all P values <0.0001) among splenocytes. Conclusion: The conjugation of MOG peptides to the PLGA nanoparticles significantly recovered clinical symptoms and the autoimmune response of EAE. The MOG-PGLA particles are potentially valuable for further evaluations, hopefully progressing toward an optimal approach that can be translated to the clinic.

The Effects of Omega-3 Supplementation on Resting Metabolic Rate: A Systematic Review and Meta-Analysis of Clinical Trials.

BACKGROUND: It is uncertain if omega-3 polyunsaturated fatty acids are associated with increase in resting metabolic rate (RMR) in adults. OBJECTIVE: The aim of the present study was to evaluate the overall effects of omega-3 on RMR. METHODS: Both PubMed and Scopus libraries were searched up to April 2021. Study quality was assessed using the Jadad scale. Random- and fixed-effects models were utilized in order to obtain pooled estimates of omega-3 supplementation impacts on RMR, using weight mean difference (WMD). RESULTS: Seven studies including a total of 245 participants were included. There was significantly higher FFM-adjusted RMR in the intervention group than the control group (WMD: 26.666 kcal/kg/day, 95% CI: 9.010 to 44.322, p=0.003). Study quality showed that four of seven included studies were of high quality. However, there was no significant difference in results in the subgroup analysis according to the quality of studies. Subgroup analyses revealed significant changes for sex (for women: WMD = 151.793 kcal/day, 95% CI = 62.249 to 241.337, p=0.001) and BMI (for BMI > 25: WMD = 82.208 kcal/day, 95% CI = 0.937 to 163.480, p=0.047). Influence analysis indicated no outlier among inclusions. CONCLUSION: The current study depicted that omega-3 polyunsaturated acids can significantly increase RMR in adults. However, further assessments of omega-3 supplementation therapy are critical to monitor its long-term outcomes and potential clinical application.

Mesenchymal Stem Cell-Derived Exosomes: A Promising Therapeutic Ace Card to Address Autoimmune Diseases.

With the development of novel treatments for autoimmune disorders, it has become a popular research focus which mesenchymal stem cells (MSCs) have the capacity to counteract with autoimmune diseases progression. One of the underlying mechanisms behind their activities is the release of extracellular vesicles especially exosomes. MSC-derived exosomes are hypoimmunogenic nanocarriers which contain numerous immunoregulatory factors and similar to other exosomes, are able to pass through boundaries like the blood-brain barrier (BBB). Accumulating evidence provided by animal studies has demonstrated that MSC-derived exosomes, as a novel therapy, can re-induce self-tolerance, without subsequent complications reported for other treatments. Therefore, therapeutic applications of MSC-derived exosomes are contributing to core advances in the field of autoimmune diseases. Here, we briefly describe the biological characteristics of MSC-derived exosomes and review the experimentally verified outcomes for autoimmune disease therapy purposes.