More balance toward activating receptors and cytotoxic activity of NK cells ex vivo differentiated from human umbilical cord blood-derived CD34+ stem cells in comparison with peripheral blood NK cells.

Adoptive immunotherapies that use functional NK cells depend on the availability of sufficient numbers of these cells. We expanded umbilical cord blood (UCB)-CD34+ HSCs for 2 weeks and then differentiated them into NK cells and compared their function to peripheral blood (PB) NK cells. We assessed NKG2D, NKG2A, NKp30, NKp44, NKp46, and the expression of CD107a, CD57, CD69, FasL, PD-1, and IFN-γ level in two groups after co-culture with K562 cell line. We found that UCB-CD34+-derived NK cells express significantly more NKG2D, NKp44, and NKp46 receptors than PB NK cells. PB NK cells expressed significantly higher NKG2A and CD57 than UCB-CD34+-derived NK cells. In addition, UCB-CD34+-derived NK cells significantly expressed CD107a more than PB NK cells. Based on our findings, UCB-CD34+ cells can be a potentially advantageous source with strong cytotoxic function to produce allogeneic NK cells for adoptive cancer immunotherapy.

Strong capacity of differentiated PD-L1 CAR-modified UCB-CD34+ cells and PD-L1 CAR-modified UCB-CD34+-derived NK cells in killing target cells and restoration of the anti-tumor function of PD-1-high exhausted T Cells.

BACKGROUND: Using natural killer (NK) cells to treat hematopoietic and solid tumors has great promise. Despite their availability from peripheral blood and cord blood, stem cell-derived NK cells provide an "off-the-shelf" solution. METHODS: In this study, we developed two CAR-NK cells targeting PD-L1 derived from lentiviral transduction of human umbilical cord blood (UCB)-CD34+ cells and UCB-CD34+-derived NK cells. The transduction efficiencies and in vitro cytotoxic functions including degranulation, cytokine production, and cancer cell necrosis of both resultants PD-L1 CAR-NK cells were tested in vitro on two different PD-L1 low and high-expressing solid tumor cell lines. RESULTS: Differentiated CAR­modified UCB-CD34+ cells exhibited enhanced transduction efficiency. The expression of anti-PD-L1 CAR significantly (P < 0.05) enhanced the cytotoxicity of differentiated CAR­modified UCB-CD34+ cells and CAR-modified UCB-CD34+-derived NK cells against PD-L1 high-expressing tumor cell line. In addition, CAR-modified UCB-CD34+-derived NK cells significantly (P < 0.05) restored the tumor-killing ability of exhausted PD-1 high T cells. CONCLUSION: Considering the more efficient transduction in stem cells and the possibility of producing CAR-NK cell products with higher yields, this approach is recommended for studies in the field of CAR-NK cells. Also, a pre-clinical study is now necessary to evaluate the safety and efficacy of these two CAR-NK cells individually and in combination with other therapeutic approaches.

Pathway-Based Mendelian Randomization for Pre-Infection IL-6 Levels Highlights Its Role in Coronavirus Disease.

OBJECTIVES: Interleukin 6 (IL-6) levels at hospital admission have been suggested for disease prognosis, and IL-6 antagonists have been suggested for the treatment of patients with severe COVID-19. However, less is known about the relationship between pre-COVID-19 IL-6 levels and the risk of severe COVID-19. To fill in this gap, here we extensively investigated the association of genetically instrumented IL-6 pathway components with the risk of severe COVID-19. METHODS: We used a two-sample Mendelian randomization study design and retrieved genetic instruments for blood biomarkers of IL-6 activation, including IL-6, soluble IL-6 receptor, IL-6 signal transducer, and CRP, from respective large available GWASs. To establish associations of these instruments with COVID-19 outcomes, we used data from the Host Genetics Initiative and GenOMICC studies. RESULTS: Our analyses revealed inverse associations of genetically instrumented levels of IL-6 and its soluble receptor with the risk of developing severe disease (OR = 0.60 and 0.94, respectively). They also demonstrated a positive association of severe disease with the soluble signal transducer level (OR = 1.13). Only IL-6 associations with severe COVID-19 outcomes reached the significance threshold corrected for multiple testing (p < 0.003; with COVID-19 hospitalization and critical illness). CONCLUSIONS: These potential causal relationships for pre-COVID-19 IL-6 levels with the risk of developing severe symptoms provide opportunities for further evaluation of these factors as prognostic/preventive markers of severe COVID-19. Further studies will need to clarify whether the higher risk for a severe disease course with lower baseline IL-6 levels may also extend to other infectious diseases.

Investigating the effect of Fusobacterium nucleatum on the aggressive behavior of cancer-associated fibroblasts in colorectal cancer.

Fusobacterium nucleatum, (F. nucleatum) as a known factor in inducing oncogenic, invasive, and inflammatory responses, can lead to an increase in the incidence and progression of colorectal cancer (CRC). Cancer-associated fibroblasts (CAF) are also one of the key components of the tumor microenvironment (TME), which lead to resistance to treatment, metastasis, and disease recurrence with their markers, secretions, and functions. This study aimed to investigate the effect of F. nucleatum on the invasive phenotype and function of fibroblast cells isolated from normal and cancerous colorectal tissue. F. nucleatum bacteria were isolated from deep periodontal pockets and confirmed by various tests. CAF cells from tumor tissue and normal fibroblasts (NF) from a distance of 10 cm of tumor tissue were isolated from 5 patients by the explant method and were exposed to secretions and ghosts of F. nucleatum. The expression level of two markers, fibroblast activation protein (FAP), and α-smooth muscle actin (α-SMA), and the amount of production of two cytokines TGF-ß and IL-6 from fibroblast cells were measured by flow cytometry and ELISA test, respectively before and after exposure to different bacterial components. The expression of the FAP marker was significantly higher in CAF cells compared to NF cells (P < 0.05). Also, the expression of IL-6 in CAF cells was higher than that of NF cells. In investigating the effect of bacterial components on the function of fibroblastic cells, after comparing the amount of IL-6 produced between the normal tissue of each patient and his tumoral tissue under 4 treated conditions, it was found that the amount of IL-6 production from the CAF cells of patients in the control group, treated with heat-killed ghosts and treated with paraformaldehyde-fixed ghosts had a significant increase compared to NF cells (P < 0.05). Due to the significant increase in FAP marker expression in fibroblast cells of tumor tissue compared to normal tissue, it seems that FAP can be used as a very good therapeutic marker, especially in patients with high levels of CAF cells. Various components of F. nucleatum could affect fibroblast cells differentially and at least part of the effect of this bacterium in the TME is mediated by CAF cells.

Harnessing IL-10 induced anti-inflammatory response in maturing macrophages in presence of electrospun dexamethasone-loaded PLLA scaffold.

The ultimate goal of tissue engineering is to repair and regenerate damaged tissue or organ. Achieving this goal requires blood vessel networks to supply oxygen and nutrients to new forming tissues. Macrophages are part of the immune system whose behavior plays a significant role in angiogenesis and blood vessel formation. On the other hand, macrophages are versatile cells that change their behavior in response to environmental stimuli. Given that implantation of a biomaterial is followed by inflammation; therefore, we reasoned that this inflammatory condition in tissue spaces modulates the final phenotype of macrophages. Also, we hypothesized that anti-inflammatory glucocorticoid dexamethasone improves modulating macrophages behavior. To check these concepts, we investigated the macrophages that had matured in an inflammatory media. Furthermore, we examined macrophages' behavior after maturation on a dexamethasone-containing scaffold and analyzed how the behavioral change of maturing macrophages stimulates other macrophages in the same environment. In this study, the expression of pro-inflammatory markers TNFa and NFκB1 along with pro-healing markers IL-10 and CD163 were investigated to study the behavior of macrophages. Our results showed that macrophages that were matured in the inflammatory media in vitro increase expression of IL-10, which in turn decreased the expression of pro-inflammatory markers TNFa and NFκB in maturing macrophages. Also, macrophages that were matured on dexamethasone-containing scaffolds decreased the expression of IL-10, TNFa, and NFκB and increase the expression of CD163 compared to the control group. Moreover, the modulation of anti-inflammatory response in maturing macrophages on dexamethasone-containing scaffold resulted in increased expression of TNFa and CD163 by other macrophages in the same media. The results obtained in this study, proposing strategies to improve healing through controlling the behavior of maturing macrophages and present a promising perspective for inflammation control using tissue engineering scaffolds.

Contradictory Effect of Lymphocyte Therapy and Prednisolone Therapy on CD3+CD8+CD56+ Natural Killer T Population in Women with Recurrent Spontaneous Abortion.

Background: Natural killer T (NKT) cells are influential immune cells in pregnancy failures, including recurrent spontaneous abortion (RSA). Different approaches are used for these disorders due to their effects on maternal immunomodulation. Aims: In the present study, we compared the effects of two typical immunotherapies (lymphocyte immunotherapy [LIT] and low-dose prednisolone) on CD3+CD56+CD16+ and CD3+CD56+CD8+ cells as two distinct subsets of NKT cells in Women with RSA. Settings and Design: This study was a comparative cohort study conducted from 2021 to 2022. One hundred and five women with RSA were distributed into three treatment groups randomly. Materials and Methods: Fifty women in the group of low-dose prednisolone therapy, fifty women in the LIT group and five women without any treatment as the control group were included in the study. NK and NKT cell subsets were assessed using flow cytometry. Furthermore, the concentration of interferon-gamma (IFN-γ), transforming growth factor-beta (TGF-ß) and interleukin-10 (IL-10) was measured quantitatively using the enzyme-linked immunosorbent assay technique. Statistical Analysis Used: Normality and comparisons between study groups were performed by non-parametric unpaired Mann-Whitney, Kruskal-Wallis rank sum test, and one-way ANOVA. Results: The percentage of CD56dim NK cells was increased after prednisolone therapy, while this population significantly decreased in the LIT group. In contrast to the LIT group, the administration of prednisolone increased CD3+CD8+CD56+ NKT cells (P < 0.0001), which is helpful for pregnancy. The effect of the investigated treatment approaches on the population of peripheral CD3+CD56+CD16+ NKT cells of women with RSA was not adequately significant. The same situation was also observed regarding the serum level of IFN-γ. However, a significant decrease in serum levels of IL-10 and TGF-ß was observed after prednisolone therapy. Conclusion: The lower capability of LIT in changing the population of NKT cells compared to prednisolone therapy may be due to its mechanism of action, which is related to the production of blocking antibodies. These treatment approaches had different effects on NKT cells, indicating that NKT cell population and function can be affected using LIT and prednisolone therapy distinctly. In addition, prednisolone therapy and LIT in women with normal serum levels of IFN-γ have no harmful effects in changing the production of this critical cytokine.

Resistance exercise training augments the immunomodulatory adaptations to aerobic high-intensity interval training.

To compare the effectiveness of different types of high-intensity interval training (HIIT) on meta-inflammation during obesity, TLR4 pathway activities were assessed following a 10-week randomized trial. 30 young females with overweight and obesity were randomly allocated to aerobic HIIT (HIIT/AE) or resistance exercise in HIIT (HIIT/RE) and performed a 28-minute (4 × 4 min) in each session. During each interval, the HIIT/AE performed four minutes of all-extremity cycling, whereas the HIIT/RE completed four minutes of combined resistance exercises and all-extremity cycling. The TLR4 pathway gene expression was measured for the TLR4 receptor, downstream adaptors (TIR domain-containing adaptor-inducing interferon-ß (TRIF) and myeloid differentiation factor (MYD) 88), transcriptional factors (nuclear factor kappa B (NF-κB), and interferon regulatory factor (IRF) 3), and its negative regulator (tumor necrosis factor (TNF) a-induced protein 3 (TNFAIP3)). The serum levels of TNFα, interferon (IFN) γ, interleukin (IL)-10, and adiponectin were measured. We found that TLR4 (HIIT/RE: 0.6 ± 0.43 vs. HIIT/AE: 1.24 ± 0.82, p = 0.02), TRIF (HIIT/RE: 0.51 ± 0.4 vs. HIIT/AE: 3.56 ± 0.52, p = 0.001), and IRF3 (HIIT/RE: 0.49 ± 0.42 vs. HIIT/AE: 0.6 ± 0.89; p = 0.04) levels were significantly downregulated in HIIT/RE compared to the HIIT/AE, with a significant reduction in serum levels of TNFα (pg/ml) (HIIT/RE: 22.5 ± 11.3 to 6.3 ± 5.3 vs. HIIT/AE: 19.16 ± 20.8 to 13.48 ± 21.7, p = 0.04) and IFNγ (pg/ml) (HIIT/RE: 43.5 ± 20.6 to 37.5 ± 4.3 vs. HIIT/AE: 37.6 ± 5.6 to 68.1 ± 22.5, p = 0.03). Adiponectin and IL-10 levels did not significantly differ between the two groups. Thus, resistance exercise training augments the immunomodulatory adaptations to HIIT and should be prescribed to people at risk of cardiometabolic disease.Highlights HIIT in combination with resistance exercise looks more effective than HIIT alone to target TLR4-mediated inflammation in individuals with overweight and obesity.HIIT/RE induces a different effect on two downstream cascades of TLR4, leading to a greater overall reduction of TRIF-dependent pathway activities compared to MYD88.Both HIIT protocols show comparable effects on the negative regulatory protein TNFAIP3 gene expression.

Human recombinant soluble PD1 can interference in T cells and Treg cells function in response to MDA-MB-231 cancer cell line.

OBJECTIVES: PD1/PDL1 pathway targeting using antibodies shows immune related adverse events in patients with tumors. The masking of PD1 ligand by soluble human PD-1 (shPD-1) probably inhibits the PD1/PDL1 interaction between T cells and tumor cells. Accordingly, the goal of this study was to produce human recombinant PD-1-secreting cells and find out how soluble human PD-1 affects T lymphocyte function. METHODS: An inducible construct of the human PD-1 secreting gene under hypoxia condition was synthesized. The construct was transfected into the MDA-MB-231 cell line. In six groups exhausted T lymphocytes were co-cultured with transfected or non-transfected MDA-MB-231 cell lines. The effect of shPD-1 on IFNγ production, Treg cell's function, CD107a expression, apoptosis, and proliferation was assessed by ELISA and flow cytometry, respectively. RESULTS: The results of this study showed that shPD-1 inhibits PD-1/PD-L1 interaction and enhances T lymphocyte responses through a significant increase in IFNγ production and CD107a expression. In addition, in the presence of shPD-1, the percentage of Treg cells decreased, while MDA-MB-231 cell apoptosis increased. CONCLUSIONS: We concluded that the human PD-1 secreting construct induced under hypoxia condition inhibits the interaction of PD-1/PD-L1 and enhances T lymphocyte responses in tumor environments and chronic infections.

Sodium-borohydride exfoliated bismuthene loaded with Mitomycin C for chemo-photo-radiotherapy of triple negative breast cancer.

In current study, a new remotely controlled drug delivery, radio-sensitizing, and photothermal therapy agent based on thioglycolic acid modified bismuth nanosheets is thoroughly evaluated. Bismuth nanosheets were synthesized using sodium borohydride (NaBH4) and Tween 20 through low energy (400 W) sonication within 2 h. The resultant nanosheets were 40-60 nm in size and 1-3 atomic layers in thickness. The morphological and structural characteristics of the nanosheets were studied using transmission electron microscopy, high-resolution transmission electron microscopy, X-ray diffraction, Raman spectroscopy and ultraviolet spectroscopy. The surface of the nanosheets was modified using thioglycolic acid, which resulted in enhanced Mitomycin C loading capacity to 274.35% and circumvented the burst drug release due to the improved electrostatic interactions. At pH 7.4 and 5.0, the drug release was significantly boosted from 45.1 to 69.8%, respectively. Thioglycolic acid modified bismuth nanosheets under 1064 nm laser irradiation possessed photothermal conversion efficiency of η=51.4% enabling a temperature rise of 24.9 °C at 100 µg/ml in 5 min. The combination of drug delivery, photothermal therapy, and radio-sensitization greatly damaged the MDA-MB-231 cells through apoptosis and diminished their colony forming.

Targeting immune checkpoints: how to use natural killer cells for fighting against solid tumors.

Natural killer (NK) cells are unique innate immune cells that mediate anti-viral and anti-tumor responses. Thus, they might hold great potential for cancer immunotherapy. NK cell adoptive immunotherapy in humans has shown modest efficacy. In particular, it has failed to demonstrate therapeutic efficiency in the treatment of solid tumors, possibly due in part to the immunosuppressive tumor microenvironment (TME), which reduces NK cell immunotherapy's efficiencies. It is known that immune checkpoints play a prominent role in creating an immunosuppressive TME, leading to NK cell exhaustion and tumor immune escape. Therefore, NK cells must be reversed from their dysfunctional status and increased in their effector roles in order to improve the efficiency of cancer immunotherapy. Blockade of immune checkpoints can not only rescue NK cells from exhaustion but also augment their robust anti-tumor activity. In this review, we discussed immune checkpoint blockade strategies with a focus on chimeric antigen receptor (CAR)-NK cells to redirect NK cells to cancer cells in the treatment of solid tumors.

Potential Therapeutic Effects of Human Amniotic Epithelial Cells on Gynecological Disorders Leading to Infertility or Abortion.

The induction of feto-maternal tolerance, fetal non-immunogenicity, and the regulation of mother's immune system are essential variables in a successful pregnancy. Fetal membranes have been used as a source of stem cells and biological components in recent decades. Human amniotic epithelial cells (hAEC) have stem/progenitor characteristics like those found in the amniotic membrane. Based on their immunomodulatory capabilities, recent studies have focused on the experimental and therapeutic applications of hAECs in allograft transplantation, autoimmune disorders, and gynecological problems such as recurrent spontaneous abortion (RSA), recurrent implantation failure (RIF), and premature ovarian failure (POF). This review discusses some of the immunomodulatory features and therapeutic potential of hAECs in preventing infertility, miscarriage, and implantation failure by controlling the maternal immune system.

Diagnostic Value of Natural Killer Cells, CD56+ CD16+ Natural Killer Cells, NLRP3, and Lactate Dehydrogenase in Severe/Critical COVID-19: A Prospective Longitudinal Study According to the Severe/Critical COVID-19 Definitions.

Innate immunity, as the first line of defense of our immune system, plays a crucial role in defending against SARS-CoV-2 infection and also its immunopathogenesis. We aim to investigate the immune status of natural killer (NK) cells, natural killer T (NKT) cells, and NLRP3 gene expression in COVID-19 patient blood samples. The immunophenotype of NK cell subsets and NKT cells was detected by flow cytometry and the expression of NLRP3 gene assessed by reverse transcriptase real-time polymerase chain reaction in 44 COVID-19 patients and 20 healthy individuals. The percentage of most of NK cell subpopulation and NKT cells was significantly decreased in COVID-19 patients. The percentage of CD56dim CD16- NK cell subsets, and NLRP3 gene expression increased. The percentage of total NK cells, CD56+ CD16+ NK cells, and NLRP3 gene expression had acceptable sensitivity and specificity for assisting diagnosis of severe/critical COVID-19. O2 saturation% and lactate dehydrogenase levels showed valuable diagnostic value to identify critical cases. The declined NK and NKT cells in COVID-19 patients and enhanced NLRP3 gene expression were associated with disease severity. Total NK cells, CD56+ CD16+ NK cells, and NLRP3 gene expression might be used as meaningful indicators for assisting diagnosis of severe/critical COVID-19.

Supplementation of Carvacrol Attenuates Hippocampal Tumor Necrosis Factor-Alpha Level, Oxidative Stress, and Learning and Memory Dysfunction in Lipopolysaccharide-Exposed Rats.

Background: Carvacrol is a natural phenolic monoterpene with anti-inflammatory and antioxidant bioactivities. Neuroinflammatory and oxidative stress responses play a crucial role in the pathogenesis of Alzheimer's disease. The present study examined the effect of carvacrol on brain tumor necrosis factor-alpha (TNF-α) level and oxidative stress as well as spatial learning and memory performances in lipopolysaccharide (LPS)-exposed rats. Materials and Methods: The rats were treated with either carvacrol (25 and 50 mg/kg) or Tween 80 for 2 weeks. Thereafter, LPS (1 mg/kg) or saline was intraperitoneally administered on days 15-19, 2 h before Morris water maze task, and treatments with carvacrol or Tween 80 were performed 30 min prior to behavioral testing. The level of TNF-α, lipid peroxidation, and total thiol concentration were measured in the hippocampus and cerebral cortex at the end of the experiment. Results: It was found that LPS-exposed rats exhibited spatial learning and memory dysfunction, which was accompanied by increased TNF-α level and lipid peroxidation, and decreased total thiol concentration in the hippocampus and/or cortex. Moreover, treatment with carvacrol at a dose of 25 mg/kg attenuated learning and memory impairments, decreased TNF-α and lipid peroxidation level in the hippocampus and cortex, and increased total thiol concentration in the cortex. Conclusion: Carvacrol exerts neuroprotective effects against LPS-induced spatial memory deficits through attenuating hippocampal TNF-α level and oxidative stress in rats.

Comparison of follicular T helper cells, monocytes, and T cells priming between newly diagnosed and rituximab-treated MS patients and healthy controls.

Background and purpose: The use of anti-CD20 monoclonal antibodies like rituximab (RTX) to deplete B cells has practical therapeutic implications in multiple sclerosis (MS) patients. However, the therapy's impact on other immune cells is also important. Therefore, in this study, we assessed the effects of RTX therapy on Tfh cells, T cells, T cells priming, and monocytes in MS patients compared to newly-diagnosed MS patients and healthy subjects. Experimental approach: Thirty newly-diagnosed and RTX-treated MS patients and healthy control were included. Peripheral blood mononuclear cells were isolated from whole blood for assessment of Tfh cells, CD4+, CD8+, CD4+CD45RA+, CD3+HLA-DR+, and CD3+CD4+CD25+ T cells by flow cytometry. Whole blood was lysed by lysis solution to assess CD45+CD14+ monocytes by flow cytometry. Also, the serum level of interleukin 21 was measured by the ELISA method. Findings / Results: We showed that RTX treatment led to a decrease in Tfh cells and their predominant cytokine, interleukin 21. Also, we found a statistically significant reduction in CD3+HLA-DR+ and CD3+CD4+CD25+ T cells in RTX-treated patients compared to new cases and healthy control. Moreover, we found a decrease in the CD45+ CD14+ monocyte population in the RTX-treated group compared to the healthy control. Conclusion and implications: Our data suggest that following treatment with RTX, Tfh cells, monocytes, and T cells priming declined happened, and fewer T cells were activated. Also, due to the interaction between B cells and Tfh cells, Tfh targeting could be assessed as a therapeutic strategy in MS.

Therapeutic potential of silymarin as a natural iron-chelating agent in ß-thalassemia intermedia.

Abnormal iron accumulation in vital organs is one of the major complications of ß-thalassemia intermedia (ß-TI). Silymarin, a flavonolignan isolated from Silybum marianum, significantly decreases the serum ferritin levels of ß-TI patients. This finding suggests silymarin as a safe and effective natural iron-chelating agent for the treatment of iron-overloaded conditions.

Comparison of four methods of colon cancer cell lysates preparation for ex vivo maturation of dendritic cells.

BACKGROUND AND PURPOSE: One of the most effective methods for the development of dendritic cell (DC)-based cancer immunotherapy is ex vivo pulsing of DCs with tumor cell lysates (TCLs). However, antitumor immune responses of DCs are significantly influenced by how TCLs were prepared. Here, we compared four strategies of TCL preparation derived from colon cancer cells, HT-29, for ex vivo maturation of DCs. EXPERIMENTAL APPROACH: Peripheral blood monocytes were isolated from healthy volunteers and incubated with granulocyte macrophage colony-stimulating factor and interleukin (IL)-4 to differentiate into DCs in 10 days. Morphological properties, phenotype characteristics (i.e. CD83 and CD86), and cytokine production (i.e. IL-10 and interferon gamma) of DCs loaded with four different TCLs (i.e. freeze-thaw, hypochlorous acid (HOCl), hyperthermia, and UV irradiation) were evaluated. FINDINGS/RESULTS: HOCl preparations led to the generation of DCs with higher surface expression of maturation biomarkers (particularly CD83), while UV preparations resulted in DCs with lower levels of surface biomarkers compared to freeze-thawed preparations. The supernatant of DCs pulsed with HOCl preparation showed significantly higher levels of interferon gamma and lower levels of IL-10 compared with the other groups. CONCLUSION AND IMPLICATIONS: Our results suggest that pulsing DCs with HOCl preparation may be superior to other TCLs preparation strategies, possibly due to induction of rapid necrotic cell death.

Association of Exposure to Particulate Matters and Multiple Sclerosis: A Systematic Review and Meta-Analysis.

The association between air pollution and multiple sclerosis (MS) is not entirely clear. This meta-analysis was aimed at determining the correlation between particulate matter (PM)2.5, PM10, and MS incidence/relapse. The literature search was performed in EMBASE, Web of Science, PubMed, and the gray literature. Sixteen articles were retrieved, and ten articles were included and evaluated. Three measures of association were used for the meta-analysis: odds ratio (cross-sectional and case-control studies), incidence rate ratio, or hazard ratio (cohort studies). Meta-analysis of those 3 studies on PM2.5 indicated that exposure to PM2.5 was associated with MS relapse and incidence ([95% confidence interval; CI] 1.178 [1.102, 1.279]), p > 0.05. Also, assessment of risk ratio for all studies showed a correlation between PMs (PM10 and PM2.5) and MS incidence and relapse ([95% CI] 1.28, [1.13-1.43]) p < 0.05. Collectively, we found that PM exposure (PM10 and PM2.5) in MS patients associates with the occurrence and relapse of disease.

Apamin as a BBB Shuttle and Its Effects on T Cell Population During the Experimental Autoimmune Encephalomyelitis-Induced Model of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system presented by autoimmune manifestations. This study aimed at investigating the effects of apamin administration on the activated T cell population in an experimental autoimmune encephalomyelitis (EAE) MS model. Thirty mice underwent EAE induction and were then randomly divided into 5 groups. Three groups received 10, 50, and 100 µg/kg apamin; the fourth group received 1 mg/kg dexamethasone; and the fifth group received the equivalent amount of PBS (phosphate-buffered saline) intraperitoneally. Peripheral CD4 + cell and memory T cell distribution was measured with a flow cytometer every week. Also, CD4 + and CD8 + cell infiltration to the brain was assessed with immunohistochemistry. It was observed that the group receiving 50 µg/kg apamin had a lower EAE score in comparison with the groups receiving 100 µg/kg apamin (p 0.014). Also, peripheral blood memory cells with CD44 + , CD62L - , and CD4 + markers were decreased in apamin-administered groups. Regarding the infiltrated CD8 + cells, a significant decrease (p 0.002) was observed in the group receiving 50 µg/kg apamin compared with the control group. These results indicate that 50-µg/kg doses of apamin had an effective treatment over 14 days; it reduced both the severity of symptoms and the infiltration of CD8 + cells into the CNS. Moreover, it increased myelin density and decreased the circulation of CD62L - , CD44L - , and CD44 + memory T cells. So, it appears that apamin plays a critical role in regulating immunity and reducing the complications of autoimmune MS.

The Role of Distinct Subsets of Macrophages in the Pathogenesis of MS and the Impact of Different Therapeutic Agents on These Populations.

Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS). Besides the vital role of T cells, other immune cells, including B cells, innate immune cells, and macrophages (MФs), also play a critical role in MS pathogenesis. Tissue-resident MФs in the brain's parenchyma, known as microglia and monocyte-derived MФs, enter into the CNS following alterations in CNS homeostasis that induce inflammatory responses in MS. Although the neuroprotective and anti-inflammatory actions of monocyte-derived MФs and resident MФs are required to maintain CNS tolerance, they can release inflammatory cytokines and reactivate primed T cells during neuroinflammation. In the CNS of MS patients, elevated myeloid cells and activated MФs have been found and associated with demyelination and axonal loss. Thus, according to the role of MФs in neuroinflammation, they have attracted attention as a therapeutic target. Also, due to their different origin, location, and turnover, other strategies may require to target the various myeloid cell populations. Here we review the role of distinct subsets of MФs in the pathogenesis of MS and different therapeutic agents that target these cells.

Significant immunomodulatory and hepatoprotective impacts of Silymarin in MS patients: A double-blind placebo-controlled clinicaltrial.

Interferon beta (IFN-ß) has successfully been experimented with to treat multiple sclerosis (MS). However, patients sometimes do not respond effectively to treatment, and |adverse effects, including liver toxicity, accompany this therapy. |Accordingly, we decided to treat MS patients simultaneously with Silymarin (SM) as an immunomodulatory and hepatoprotective agent and IFN-ß in a clinical trial study. Complete blood count (CBC), liver enzyme levels, and the serum concentration of inflammatory and anti-inflammatory cytokines were measured. Also, the frequency of immune cells was determined by flow cytometry. Liver enzyme levels were significantly lower in the intervention group (p < 0.05). The percentage of Th17 cells in the intervention group was significantly reduced compared to the placebo group (P < 0.001). Also, the frequency of Treg cells after treatment with SM plus IFN-ß was significantly increased compared to the placebo group (p < 0.05). Furthermore, the IL-17 and IFNγ cytokine levels were significantly reduced in the intervention group (p < 0.05). Moreover, the levels of anti-inflammatory cytokines IL-10 and TGFß were significantly increased in the intervention group (P < 0.05).Overall, the results provide novel and supplementary information on SM's notable immunoregulatory effects on inflammatory response and liver function in MS patients. Clinical Trial Identifier Number: IRCTID: IRCT20171220037977N1.