Interleukin-17, C-reactive protein, Neutrophil-to-Lymphocyte ratio, Lymphocyte-to-Monocyte ratio, and lipid profiles in healthy menopausal women with or without hot flashes: A cross-sectional study.

INTRODUCTION: The reciprocation between systemic inflammatory markers (SIMs), dyslipidemia, and hot flashes (HFs) can play a part in the pathogenesis of endothelial dysfunction through menopause. This study intended to determine the association between some SIMs, lipids, and HFs in healthy menopausal women. MATERIALS AND METHODS: We designed a cross-sectional study in which 160 healthy menopausal women aged 40-60 were enrolled. Concerning their HFs status, they were stratified into two groups by consecutive sampling: without HFs (n = 40) and with HFs (n = 120). In addition to clinical variables and HFs experience, we measured the fasting serum levels of SIMs and lipid profiles (LPs), including Interleukin-17 (IL-17), high- sensitivity C-Reactive Protein (hs-CRP), Total Cholesterol (TC), Triglycerides (TG), Low-Density Lipoprotein Cholesterol (LDL-C), and High-Density Lipoprotein Cholesterol (HDL-C) in each group. Then, we calculated TC/HDL-C concerning the related variables and determined Neutrophil-to-Lymphocyte Ratio (NLR), and Lymphocyte-to-Monocyte Ratio (LMR), according to Complete Blood Count (CBC) quantitative parameters in each group. Furthermore, we used logistic regression analysis to assess the association between SIMs, LPs, and HFs. SETTINGS: We performed this study in a governmental teaching hospital, Guilan/Rasht, Iran, from April to September 2021. RESULTS: The two groups of menopausal women without and with HFs were not significantly different regarding the median of IL-17, hs-CRP, NLR, LMR, TG, HDL-C, and TC/HDL-C, and the mean of TC and LDL-C. Based on multiple logistic regression, TG levels appeared to be associated with the incidence of HFs (B = 0.004, P = 0.040, Odds Ratio:1.004, 95%CI:1.000-1.009). NLR seemed to have an increasing impact on the HFs severity, according to ordinal logistic regression (B = 0.779, P = 0.005, Odds Ratio = 2.180, 95%CI:1.270-3.744). Furthermore, hs-CRP negatively correlated with TG (r = -0.189, P = 0.039) and TC/HDL-C (r = -0.268, P = 0.003) in menopausal women with HFs. CONCLUSION: This study indicated an association between SIMs, lipids, and HFs. These connections may suggest HFs as links between SIMs/LPs alterations and their outcomes.

A biological and a mathematical model of SLE treated by mesenchymal stem cells covering all the stages of the disease.

In this study, we proposed a biological model explaining the progress of autoimmune activation along different stages of systemic lupus erythematosus (SLE). For any upcoming stage of SLE, any new component is introduced, when it is added to the model. Particularly, the interaction of mesenchymal stem cells, with the components of the model, is specified in a way that both the inflammatory and anti-inflammatory functions of these cells would be covered. The biological model is then recapitulated to a model with less complexity that explains the main features of the problem. Later, a 7th-order mathematical model for SLE is proposed, based on this simplified model. Finally, the range of validity of the proposed mathematical model was assessed. For this purpose, we simulated the model and analyzed the simulation results in case of some known behaviors of the disease, such as tolerance breach, the appearance of systemic inflammation, development of clinical signs, and occurrence of flares and improvements. The model was able to reproduce these events, qualitatively.

COVID-19 immunopathology with emphasis on Th17 response and cell-based immunomodulation therapy: Potential targets and challenges.

The role of the immune system against coronavirus disease 2019 (COVID-19) is unknown in many aspects, and the protective or pathologic mechanisms of the immune response are poorly understood. Pro-inflammatory cytokine release and a consequent cytokine storm can lead to acute respiratory distress syndrome (ARDS) and result in multi-organ failure. There are many T cell subsets during anti-viral immunity. The Th17-associated response, as a pro-inflammatory pathway, and its consequent outcomes in many autoimmune disorders play a fundamental role in progression of systemic hyper-inflammation during COVID-19. Therapeutic strategies based on immunomodulation therapy could be helpful for targeting hyper-inflammatory immune responses in COVID-19, especially Th17-related inflammation and hyper-cytokinemia. Cell-based immunotherapeutic approaches including mesenchymal stem cells (MSCs), tolerogenic dendritic cells (tolDCs) and regulatory T cells (Tregs) seem to be promising strategies as orchestrators of the immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, we highlight Th17-related immunopathology of SARS-CoV-2 infection and discuss cell-based immunomodulatory strategies and their mechanisms for regulation of the hyper-inflammation during COVID-19.

A survey on the seroprevalence of toxocariasis and related risk factors in Eosinophilic children of Northwest Iran.

Background: Toxocariasis is a serious zoonotic helminthic disease caused by the nematodes; Toxocara species. Aim: A cross-sectional study was conducted to determine the seroprevalence of toxocariasis and related risk factors in eosinophilic children referred to the pediatrics hospital of Qazvin province northwest Iran during 2019-2020. Methods: A total of 200 blood samples were collected from eosinophilic children referred to the Qods Pediatrics Hospital. Demographic data, clinical symptoms, and dogs- and soil-contact history were collected. The presence of anti-Toxocara IgG antibody was evaluated by T. canis IgG ELISA kit. Results: Anti-Toxocara IgG antibodies were detected in 14 (7%) of the total eosinophilic children. The seropositive rate of toxocariasis in hyper-eosinophilic children (>1000/mm3) was 15.1%, while the seropositivity was 4.1% in children with eosinophilia status (500-999/mm3). There was a significant association between the eosinophilia rate and seropositivity (P<0.05). Also, seroprevalence in asymptomatic eosinophilic children was 4.4%, while in children with clinical symptoms it was 17.1%. Accordingly, a statistically significant difference was found between clinical symptoms and Toxocara infection (P<0.05). Conclusion: The prevalence of toxocariasis in eosinophilic children is a serious health problem in the study area. Therefore, serologic evaluation for the diagnosis of Toxocara infection is recommended for eosinophilic children.

Modeling codelivery of CD73 inhibitor and dendritic cell-based vaccines in cancer immunotherapy.

Dendritic cells (DCs) are the dominant class of antigen-presenting cells in humans; therefore, a range of DC-based approaches have been established to promote an immune response against cancer cells. The efficacy of DC-based immunotherapeutic approaches is markedly affected by the immunosuppressive factors related to the tumor microenvironment, such as adenosine. In this paper, based on immunological theories and experimental data, a hybrid model is designed that offers some insights into the effects of DC-based immunotherapy combined with adenosine inhibition. The model combines an individual-based model for describing tumor-immune system interactions with a set of ordinary differential equations for adenosine modeling. Computational simulations of the proposed model clarify the conditions for the onset of a successful immune response against cancer cells. Global and local sensitivity analysis of the model highlights the importance of adenosine blockage for strengthening effector cells. The model is used to determine the most effective suppressive mechanism caused by adenosine, proper vaccination time, and the appropriate time interval between injections.

Stroke Associated with SARS-CoV-2 Infection and its Pathogenesis: A Systematic Review.

INTRODUCTION: The change of stroke incidence during the COVID-19 pandemic period and the proposed mechanisms of the relationship between SARS-CoV-2 and stroke is reviewed. METHODS: Web of Science, PMC/Medline, and Scopus databases were searched until July 2020 without time and language limitations. After quality assessment, 22 articles were included in this study. RESULTS: Based on the results, it is impossible to conclude any definite relationship between the rising or decreasing stroke frequency or the shift in the ischemic and hemorrhagic ratio and SARS-CoV-2 infection. However, it appears that SARS-CoV-2 infection has some correlation with stroke. The supposed mechanisms for the SARS-CoV-2-related hemorrhagic stroke include 1) SARS-CoV-2-related vasculopathy with the endothelial damage of small vessels, 2) viral infection-induced platelet dysfunction or thrombocytopenia, and 3) activation of the proinflammatory cascade leading to coagulopathy. The helpful strategies are receiving therapeutic anticoagulation for high D-dimer or a known thrombus due to SARS-CoV-2 infection, as well as using extracorporeal membrane oxygenation (ECMO) in some patients. Furthermore, the possible mechanisms for the SARS-CoV-2-related ischemic stroke include 1) dysregulation of angiotensin-converting enzyme 2 (a key host cellular receptor for SARSCoV-2)-related physiologic functions, 2) endothelial cell damages, 3) thrombo-inflammation, and 4) coagulopathy and coagulation abnormalities related to SARS-CoV-2 infection. CONCLUSION: A better understanding of the SARS-CoV-2 pathogenesis and its relation to neurologic abnormalities such as stroke can help to design new therapeutic approaches.

Comparing the Effects of Long-term Exposure to Extremely Low-frequency Electromagnetic Fields With Different Values on Learning, Memory, Anxiety, and ß-amyloid Deposition in Adult Rats.

Introduction: Extremely Low-Frequency Electromagnetic Fields (ELF-EMFs) have gathered significant consideration for their possible pathogenicity. However, their effects on the nervous system's functions were not fully clarified. This study aimed to assay the impact of ELF-EMFs with different intensities on memory, anxiety, antioxidant activity, ß-amyloid (Aß) deposition, and microglia population in rats. Methods: Fifty male adult rats were randomly separated into 5 groups; 4 were exposed to a flux density of 1, 100, 500, and 2000 microtesla (µT), 50 Hz frequency for one h/day for two months, and one group as a control group. The control group was without ELF-EMF stimulation. After 8 weeks, passive avoidance and Elevated Plus Maze (EPM) tests were performed to assess memory formation and anxiety-like behavior, respectively. Total free thiol groups and the index of lipid peroxidation were evaluated. Additionally, for detection of Aß deposition and stained microglia in the brain, anti-ß-amyloid and anti-Iba1 antibodies were used. Results: The step-through latency in the retention test in ELF-EMF exposure groups (100500 & 2000 µT) was significantly greater than the control group (P<0.05). Furthermore, the frequency of the entries into the open arms in ELF-EMF exposure groups (especially 2000 µT) decreased than the control group (P<0.05). No Aß depositions were detected in the hippocampus of different groups. An increase in microglia numbers in the 100, 500, and 2000 µT groups was observed compared to the control and one µT group. Conclusion: Exposure to ELF-EMF had an anxiogenic effect on rats, promoted memory, and induced oxidative stress. No Aß depositions were detected in the brain. Moreover, the positive impact of ELF-EMF was observed on the microglia population in the brain. Highlights: ELF-EMFs have gathered significant consideration for their possible pathogenicity.ELF-EMFs' effects on the nervous system's functions were not clarified yet.Positive impact of ELF-EMF was observed on the microglia population in the brain. Plain Language Summary: ELF-EMFs effects on human health are a considerable concern. Studies revealed the adverse effects of ELF-EMF in neurological disorders such as Alzheimer's Disease (AD). Anxiety could be an early manifestation of AD. There is a correlation between occupational exposure to ELF-EMF and AD. Recently the researchers interested in the study of the effects of ELF-EMFs on the human body. Some studies examined the molecular mechanisms and the influence of ELF-EMFs on the biologic mechanisms in the body. Also, Microglia act in the Central Nervous system (CNS) immune responses; over-activated microglia can be responsible for devastating and progressive neurotoxic consequences in neurodegenerative disorders. This study aimed to evaluate the memory, anxiety, antioxidant activity, ß-amyloid deposition, and frequency of the microglial cells exposed to microtesla (µT) and 2000 (µT) ELF-EMFs.

The role of Th17 cells in auto-inflammatory neurological disorders.

The role of T helper 17 (Th17) cells in auto-inflammatory neurological disorders such as Multiple Sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and schizophrenia has not been clarified completely. Th17-derived pro-inflammatory cytokines including IL-17, IL-21, IL-22, IL-23, GM-CSF, and IFN-γ have a critical role in the pathogenesis of these disorders. In this review, we demonstrate the role of Th17 cells and their related cytokines in the immunopathology of above-mentioned disorders to get a better understanding of neuroinflammatory mechanisms mediated by Th17 cells associated with events leading to neurodegeneration.

Is TGFß as an anti-inflammatory cytokine required for differentiation of inflammatory TH17 cells?

T-Helper 17 (TH17) cells are a CD4+ TH subset that plays a critical role in the pathophysiology of inflammatory disorders, especially chronic forms. It seems that the derivation of TH17 cells from their precursors take place in inflammatory microenvironment. The role of transforming growth factor (TGF)-ß as an anti-inflammatory cytokine in TH17 cell differentiation is controversial. To address some of the discrepancies that exist among different studies, this study was undertaken to more clarify the TGFß role in human TH17 cell differentiation. Here, CD4+ T-cells were isolated from peripheral blood samples and cultured in X-VIVO 15 serum-free medium. Purified cells were then treated with different combinations of polarizing cytokines (interleukin [IL]1-ß, -6, and -23, with or without TGFß), neutralizing anti-interferon (IFN)-γ and anti-IL-4 antibodies and polyclonal stimulators anti-CD3 and -CD28 antibodies, and then analyzed for IL-17, IFNγ, Foxp3, and CD25 expression by flow cytometry and for release of IL-17, -21, -22, and -10 into culture media by ELISA. The effects of selective inhibition of TGFß signaling pathway on TH17 cell polarization were also determined by using small molecules SB-431542 and A83-01. The current study found that a combination of pro-inflammatory cytokines, including IL-1ß, -6, and -23, but not TGFß, could be used as a cytokine combination to induce development of human TH17 cells. It was also shown that TGFß acted as a negative regulator in this regard and also led to reduced IL-17 and IL-22 production while inducing Foxp3 expression. Indeed, blocking of TGFß signaling pathways by selective inhibitors up-regulated TH17 cell differentiation. From the data here, we concluded that TGFß down-regulates human TH17 cell differentiation and that a presence of pro-inflammatory cytokines (along with IFNγ and IL-4 neutralizing antibodies) is sufficient for optimal differentiation of human TH17 cells.

The effect of pro-inflammatory cytokines on immunophenotype, differentiation capacity and immunomodulatory functions of human mesenchymal stem cells.

Mesenchymal stem cells (MSCs), as cells with potential clinical utilities, have demonstrated preferential incorporation into inflammation sites. Immunophenotype and immunomodulatory functions of MSCs could alter by inflamed-microenvironments due to the local pro-inflammatory cytokine milieu. A major cellular mediator with specific function in promoting inflammation and pathogenicity of autoimmunity are IL-17-producing T helper 17 (Th17) cells that polarize in inflamed sites in the presence of pro-inflammatory cytokines such as Interleukin-1ß (IL-1ß), IL-6 and IL-23. Since MSCs are promising candidate for cell-based therapeutic strategies in inflammatory and autoimmune diseases, Th17 cell polarizing factors may alter MSCs phenotype and function. In this study, human bone-marrow-derived MSCs (BM-MSC) and adipose tissue-derived MSCs (AD-MSC) were cultured with or without IL-1ß, IL-6 and IL-23 as pro-inflammatory cytokines. The surface markers and their differentiation capacity were measured in cytokine-untreated and cytokine-treated MSCs. MSCs-mediated immunomodulation was analyzed by their regulatory effects on mixed lymphocyte reaction (MLR) and the level of IL-10, TGF-ß, IL-4, IFN-γ and TNF-α production as immunomodulatory cytokines. Pro-inflammatory cytokines showed no effect on MSCs morphology, immunophenotype and co-stimulatory molecules except up-regulation of CD45. Adipogenic and osteogenic differentiation capacity increased in CD45+ MSCs. Moreover, cytokine-treated MSCs preserved the suppressive ability of allogeneic T cell proliferation and produced higher level of TGF-ß and lower level of IL-4. We concluded pro-inflammatory cytokines up-regulate the efficacy of MSCs in cell-based therapy of degenerative, inflammatory and autoimmune disorders.

Modeling of tumor growth in dendritic cell-based immunotherapy using artificial neural networks.

Exposure-response modeling and simulation is especially useful in oncology as it permits to predict and design un-experimented clinical trials as well as dose selection. Dendritic cells (DC) are the most effective immune cells in the regulation of immune system. To activate immune system, DCs may be matured by many factors like bacterial CpG-DNA, Lipopolysaccharaide (LPS) and other microbial products. In this paper, a model based on artificial neural network (ANN) is presented for analyzing the dynamics of antitumor vaccines using empirical data obtained from the experimentations of different groups of mice treated with DCs matured by bacterial CpG-DNA, LPS and whole lysate of a Gram-positive bacteria Listeria monocytogenes. Also, tumor lysate was added to DCs followed by addition of maturation factors. Simulations show that the proposed model can interpret the important features of empirical data. Owing to the nonlinearity properties, the proposed ANN model has been able not only to describe the contradictory empirical results, but also to predict new vaccination patterns for controlling the tumor growth. For example, the proposed model predicts an exponentially increasing pattern of CpG-matured DC to be effective in suppressing the tumor growth.

Reduced efficacy of multiple doses of CpG-matured dendritic cell tumor vaccine in an experimental model.

CpG motifs have been advanced as agents that stimulate the maturation of DCs for immunotherapy. The present study tested the hypothesis that multiple doses of CpG-matured DC vaccine would be efficacious for complete eradication of experimentally-induced tumor. Accordingly, WEHI164 cells were implanted subcutaneously in the flank of BALB/c mice. During DC culture, tumor lysate was added to immature DCs followed by addition of CpG or non-CpG control 4-6h later. A total of three doses of CpG or non-CpG control-matured DCs were injected around tumors. The results showed that multiple doses of CpG-matured DCs led to considerable decrease in cytotoxicity of lymphocytes and significantly increased tumor growth rate compared to a single dose. Further, mice which received three doses of the vaccine also displayed significant FoxP3 in tumor tissue. In conclusion, multiple doses of CpG-matured DCs exhibited decreased anti-tumor immunity in association with increased expression of FoxP3.