Multiple roles have been indicated for reactive oxygen species (ROS) in the immune system in recent years. ROS have been extensively studied due to their ability to damage DNA and other subcellular structures. Noticeably, they have been identified as a pivotal second messenger for T-cell receptor signaling and T-cell activation and participate in antigen cross-presentation and chemotaxis. As an agent with direct toxic effects on cells, ROS lead to the initiation of the autoimmune response. Moreover, ROS levels are regulated by antioxidant systems, which include enzymatic and nonenzymatic antioxidants. Enzymatic antioxidants include superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Nonenzymatic antioxidants contain vitamins C, A, and E, glutathione, and thioredoxin. Particularly, cellular antioxidant systems have important functions in maintaining the redox system homeostasis. This review will discuss the significant roles of ROS generation and antioxidant systems under normal conditions, in the immune system, and pathogenesis of 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.
Background Lactic acid produced by tumors has been shown to overcome immune surveillance, by suppressing the activation and function of T cells in the tumor microenvironment. The strategies employed to impair tumor cell glycolysis could improve immunosurveillance and tumor growth regulation. Dichloroacetate (DCA) limits the tumor-derived lactic acid by altering the cancer cell metabolism. In this study, the effects of lactic acid on the activation and function of T cells, were analyzed by assessing T cell proliferation, cytokine production and the cellular redox state of T cells. We examined the redox system in T cells by analyzing the intracellular level of reactive oxygen species (ROS), superoxide and glutathione and gene expression of some proteins that have a role in the redox system. Then we co-cultured DCA-treated tumor cells with T cells to examine the effect of reduced tumor-derived lactic acid on proliferative response, cytokine secretion and viability of T cells. Result We found that lactic acid could dampen T cell function through suppression of T cell proliferation and cytokine production as well as restrain the redox system of T cells by decreasing the production of oxidant and antioxidant molecules. DCA decreased the concentration of tumor lactic acid by manipulating glucose metabolism in tumor cells. This led to increases in T cell proliferation and cytokine production and also rescued the T cells from apoptosis. Conclusion Taken together, our results suggest accumulation of lactic acid in the tumor microenvironment restricts T cell responses and could prevent the success of T cell therapy. DCA supports anti-tumor responses of T cells by metabolic reprogramming of tumor cells.
Background: Crohn's disease (CD) is a chronic inflammatory disease without a specific cause. Inflammation in these patients can disturb the oxidants/antioxidants balance and results in oxidative stress that plays a destructive role. This study aimed to evaluate the gene expression of sod1, sod2, cat, nrf2 and gp91phox in CD patients before and after Azathioprine (Aza) consumption. Method: Peripheral bloodmononuclear cells (PBMCs) were separated from CD patients (n= 15, mean age = 33.6 ± 1.8) before and after treatment with Aza and healthy controls (n= 15, mean age = 31.5 ± 1.2). The expression levels of sod1, sod2, cat, nrf2 and gp91phox were measured in byusing real-time qRT-PCR technique. Result: The expression levels of gp91phox (P-value < 0.001), cat (P-value < 0.05), sod1 (P-value < 0.001), nrf2 (P-value < 0.001) were significantly increased compared to control group. Following treatment with Aza, the decreased expression levels of gp91phox (P-value < 0.05), cat (P-value < 0.05), sod1(P-value < 0.001) and nrf2 (P-value < 0.001) were observed in CD patients. Conclusion: Overall, our results showed that prescription of Azathioprine can lead to the altered expression of redox system-related genes in patients with CD.
Background Regardless of improvements in controlling the COVID-19 pandemic, the lack of comprehensive insight into SARS-COV-2 pathogenesis is still a sophisticated challenge. In order to deal with this challenge, we utilized advanced bioinformatics and machine learning algorithms to reveal more characteristics of SARS-COV-2 pathogenesis and introduce novel host response-based diagnostic biomarker panels. Methods In the present study, eight published RNA-Seq datasets related to whole-blood (WB) and nasopharyngeal (NP) swab samples of patients with COVID-19, other viral and non-viral acute respiratory illnesses (ARIs), and healthy controls (HCs) were integrated. To define COVID-19 meta-signatures, Gene Ontology and pathway enrichment analyses were applied to compare COVID-19 with other similar diseases. Additionally, CIBERSORTx was executed in WB samples to detect the immune cell landscape. Furthermore, the optimum WB- and NP-based diagnostic biomarkers were identified via all the combinations of 3 to 9 selected features and the 2-phases machine learning (ML) method which implemented k-fold cross validation and independent test set validation. Results The host gene meta-signatures obtained for SARS-COV-2 infection were different in the WB and NP samples. The gene ontology and enrichment results of the WB dataset represented the enhancement in inflammatory host response, cell cycle, and interferon signature in COVID-19 patients. Furthermore, NP samples of COVID-19 in comparison with HC and non-viral ARIs showed the significant upregulation of genes associated with cytokine production and defense response to the virus. In contrast, these pathways in COVID-19 compared to other viral ARIs were strikingly attenuated. Notably, immune cell proportions of WB samples altered in COVID-19 versus HC. Moreover, the optimum WB- and NP-based diagnostic panels after two phases of ML-based validation included 6 and 8 markers with an accuracy of 97% and 88%, respectively. Conclusions Based on the distinct gene expression profiles of WB and NP, our results indicated that SARS-COV-2 function is body-site-specific, although according to the common signature in WB and NP COVID-19 samples versus controls, this virus also induces a global and systematic host response to some extent. We also introduced and validated WB- and NP-based diagnostic biomarkers using ML methods which can be applied as a complementary tool to diagnose the COVID-19 infection from non-COVID cases.
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