Therapeutic potential of mesenchymal stem cell-derived exosomes for allergic airway inflammation.

Due to their immunomodulatory capacities, mesenchymal stem cells (MSCs) have been extensively used as therapeutic approaches in cell-based therapy for various inflammatory diseases. Several lines of studies have shown that the most beneficial effects of MSCs are associated with MSC-derived exosomes. Exosomes are nanoscale extracellular vesicles that contain important biomolecules such as RNA, microRNAs (miRNAs), DNA, growth factors, enzymes, chemokines, and cytokines that regulate immune cell functions and parenchymal cell survival. Recently, exosomes, especially MSC-derived exosomes, have been shown to have protective effects in allergic airway inflammation. This review focused on the immune-regulatory potential of MSC-derived exosomes as nanoscale delivery systems in the treatment of allergic airway inflammation.

Investigation of IL-6 serum level in COVID-19 patients with positive COVID-19 IgG/IgM antibody titers to check inflammation and disease progression.

OBJECTIVE: The SARS-CoV-2, the cause of coronavirus disease 2019 (COVID-19), leads to severe pathogenicity and high mortality among different communities around the world. Therefore, it is important to understand the mechanisms of virus pathogenesis and the immune system's response to prevent the further spread of this virus. This study was aimed to evaluate the relationship between the serum level of interleukin 6 and positive IgG and IgM antibody levels in patients with COVID-19 to investigate inflammation and disease progression. METHODS & MATERIALS: In this study, 10 ml of EDTA blood samples were taken from 414 COVID-19 patients. Then, the plasma was separated and the levels of IgM and IgG antibodies and interleukin 6 cytokine were evaluated by ELISA and chemiluminescence methods, respectively. All data were analyzed by SPSS 22 and GraphPad prism 9 software at the significance level of P < 0.05. RESULTS: The results of this study showed that there was no significant difference in the expression of IgM and IgG antibodies between men and women. Also, a significant increase in the mean expression of IL-6 was observed only in the high concentration range (100-〉1000 pg/ml) in men compared to women (P < 0.001). In addition, in the female population, all three concentration ranges (negative, medium, and high) of IL-6 have the highest correlation with high titers (>10 U/ml) of IgM and IgG antibodies. While, in men, all three concentration ranges of IL-6 had the highest correlation with > 10 U/ml IgM antibody titers, but in the case of IgG, the highest correlation between different concentrations of IL-6 was observed with the negative or moderate titers of this antibody and there was an inverse relationship with the high titers of IgG (>10 U/ml). CONCLUSION: As a result, the relationship between different serum levels of cytokine IL-6 with different titers of IgM and IgG antibodies was observed in both male and female populations. In general, it can be concluded that the correlation between different concentrations of IL-6 with different IgM titers was similar in both men and women, but in the case of different IgG titers, this correlation was higher in women than men.

A modified schedule of multiple aeroallergen ultra-rush immunotherapy in perennial allergic rhinitis: safety, efficacy, and T lymphocyte cell population studies.

BACKGROUND: This study assessed whether a modified immunotherapy schedule for allergic rhinitis could be safe and efficient. Ultra-rush immunotherapy (URIT) rapidly desensitizes patients to aeroallergens. OBJECTIVE: We aimed to develop a modified URIT protocol in 3 days to achieve the target dose while observing whether it could improve this situation and decrease the time to achieve the maintenance dose. METHODS: The URIT was exercised in 21 patients with perennial allergic rhinitis. Premeditations were given to the patients 3 days prior to the immunotherapy and during the 3 days injections immunotherapy: pred nisolone, ranitidine, and Airokast/montelukast. Finally, the T cell population frequencies of patients prior to and after immunotherapy, including T helper 1, T helper 2, cytotoxic T lymphocytes, and regulatory T cells, were studied using flow cytometry. During the URIT protocol, 21 patients received 291 injections. RESULT: Six patients (28.6%) showed systemic reactions in our study. All systemic reactions occurred on the third day by the 1:1 dilution of the maintenance dose. These systemic reactions occurred in three patients after 13 injections, and the three remaining patients showed systemic reactions following the last injection. No systemic reaction was observed on the first and second day of the therapy, and the risk of systemic reaction with every injection was about 2%. Among the T cell populations, CD3+ and CD8+ cells decreased significantly. CONCLUSION: The findings emphasized that URIT, alongside premedication with a high dose of antihistamine, helped to achieve the maintenance dose and control clinical manifestations.

Interactions of mesenchymal stromal/stem cells and immune cells following MSC-based therapeutic approaches in rheumatoid arthritis.

Rheumatoid arthritis (RA) is considered to be a degenerative and progressive autoimmune disorder. Although several medicinal regimens are used to treat RA, potential adverse events such as metabolic disorders and increased risk of infection, as well as drug resistance in some patients, make it essential to find an effective and safe therapeutic approach. Mesenchymal stromal/stem cells (MSCs) are a group of non-hematopoietic stromal cells with immunomodulatory and inhibitory potential. These cells exert their regulatory properties through direct cell-to-cell interactions and paracrine effects on various immune and non-immune cells. As conventional therapeutic approaches for RA are limited due to their side effects, and some patients became refractory to the treatment, MSCs are considered as a promising alternative treatment for RA. In this review, we introduced various experimental and clinical studies conducted to evaluate the therapeutic effects of MSCs on animal models of arthritis and RA patients. Then, possible modulatory and suppressive effects of MSCs on different innate and adaptive immune cells, including dendritic cells, neutrophils, macrophages, natural killer cells, B lymphocytes, and various subtypes of T cells, were categorized and summarized. Finally, limitations and future considerations for the efficient application of MSCs as a therapeutic approach in RA patients were presented.

The impact of propolis on clinical manifestations and specific IgE levels against salsola in perennial-allergic rhinitis patients.

Objectives: Propolis has an anti-inflammatory effect induced by inhibiting cyclooxygenase, subsequent inhibition of prostaglandin and nitric oxide synthesis, reduction of inflammatory cytokines, and eventually immunosuppressive activity [1-3]. This study aims to evaluate the impact of propolis on clinical features and specific IgE levels against salsola in perennial allergic rhinitis patients. Methods: Thirty patients diagnosed with perennial allergic rhinitis with salsola-positive skin prick test were enrolled in this randomized controlled clinical trial and divided into two groups. The intervention group received the propolis (200 mg per day), and the control group received a placebo for four months, besides intranasal corticosteroids. At baseline and the end of the intervention, the level of Salsola-specific IgE was measured by the RAST method. To assess the propolis effect on the quality of life and disease severity, miniRQLQ and SNOT22 questionnaires were completed by patients before and after the intervention. Results: According to Table 1, Serum IgE level showed decreasing changes (-0.057) despite increasing changes in the control group (1.039). However, these differences were not statistically significant (P = 0.967). Based on the miniRQLQ questionnaire, quality of life improved in both groups without any significant difference (P = 0.930). According to the SNOT-22 questionnaire, both groups' nasal and sinus problems decreased significantly. However, the intervention type did not affect this decrease and was observed over time in both groups (P> 0.05). Conclusion: Propolis supplementation did not significantly affect various laboratory parameters, clinical symptoms, and quality of life of patients with allergic rhinitis.

Prognostic Value of Serum MICA Levels as a Marker of Severity in COVID-19 Patients.

The COVID-19 global pandemic and high mortality rates necessitate the development of diagnostic and prognostic tools, as well as expanding testing capacity. Existing methods for detecting and characterizing SARS-CoV-2 infection are typically based on viral genome detection or measuring COVID-19-specific antibody levels. Despite their value, these methods are unable to predict disease outcomes in patients. Given the critical role of innate immune cells, particularly natural killer (NK) cells, in antiviral defense, this study sought to determine the prognostic value of serum secretory MHC class I polypeptide-related sequence A (sMICA) levels as an essential ligand for the NKG2D receptor, the master regulator of NK cell development and responsiveness. Serum MICA levels were measured by ELISA assay. Sera (n = 60) from SARS-CoV-2 positive patients were collected, and disease severity was determined using clinical criteria. The patient group included 30 patients with mild disease and 30 severely ill patients, as well as 30 healthy controls. Our findings revealed that serum MICA levels were significantly higher in patients than in controls, especially in cases with severe complications (P < .0001). Higher serum MICA levels may be associated with respiratory failure in COVID-19 and may serve as a marker of clinical severity in patients infected with SARS-CoV-2, particularly when clinical manifestations are insufficient to make a confident prediction.

Higher MICA levels may be associated with respiratory failure in COVID-19 infection.SMICA levels change with age, particularly for patients with severe COVID-19 disease.NKG2D ligands may have prognostic and therapeutic value for COVID-19 patients.

A significant association between CXCL10 -1447 A > G and IL18 -607 C > A gene polymorphism with human T-cell lymphotropic virus type 1 associated myelopathy/tropical spastic paraparesis (HAM-TSP), a case-control report from city of Mashhad, Iran.

Human T-cell lymphotropic virus type 1 (HTLV-1) is the first isolated retrovirus from humans, and 2-3% of infected individuals suffer from HTLV-1 associated myelopathy tropical spastic paraparesis (HAM-TSP). Previous studies indicated that the risk of HAM-TSP could be correlated with the individuals' genetic alterations. Mashhad is one of the areas infected with HTLV-1 in Iran. This study designed to examine the association between several important gene polymorphisms and HAM-TSP. Genotypes of 232 samples from controls, HTLV-1 carriers, and HAM-TSP patients were examined for FAS-670 (A > G), CXCL10-1447 (A > G), Foxp3-3279 (C > A), IL-18 -137 (C > G), and IL-18 -607 (C > A) gene polymorphisms by different polymerase chain reaction (PCR) techniques. A non-significant association was observed between FAS-670 A > G, Foxp3-3279 C > A, and IL-18 -137 C > G gene polymorphisms and HAM-TSP. Nevertheless, a significant (P < 0.001) association between CXCL10-1447 A > G and IL-18 -607 C > A gene polymorphisms with HAM-TSP was observed in our study population. As previous studies revealed that the CXCL10 level in the cerebrospinal fluid of HAM-TSP patients was associated with the disease progression, and as we noticed, a direct association was observed between CXCL10-1447 A > G polymorphism and HAM-TSP. These polymorphisms might be recommended as a valuable prediction criterion for the severity of the disease. The contradiction between our findings and other studies regarding IL-18 -607 C > A gene polymorphism might be associated with various factors such as genotypes frequency in diverse races and population heterogeneity in the city of Mashhad.

Significant association between Taq1 gene polymorphism in vitamin D receptor and chronic spontaneous urticaria in the Northeast of Iran.

OBJECTIVE: Chronic spontaneous urticaria (CSU) is defined as urticaria with an unknown etiology which persists for more than 6 weeks. CSU is an uncomfortable cutaneous condition that occurs due to an immune-mediated inflammatory reaction. Many studies have demonstrated that vitamin D deficiency and single-nucleotide polymorphisms in the vitamin D receptor (VDR) impact the immune response. In the current study, the frequency of the Taq1 polymorphism in the VDR gene were compared between patients with CSU and individuals without CSU. METHODS: In a case-control study, a group of CSU patients (n = 100) was compared with a group of healthy age- and gender-matched individuals as a control group (n =100) who visited our center between 2015 and 2017. After DNA extraction from EDTA-containing blood, polymerase chain reaction (PCR-RFLP) was used to determine the presence of the Taq1 polymorphism. Serum vitamin D levels were measured using ELISA method (Abcam, Cambridge, USA). RESULTS: Genotyping for Taq1 polymorphism showed that TT, Tt and tt genes frequency in the CSU group were 36%, 54%, and 10% respectively. The TT, Tt and tt genotypes had a distribution of 50%, 47% and 3% respectively in the control group. The mean serum vitamin D level in the CSU group was 19.88 ± 8.14 ng/ml, which was not significantly correlated with the Taq1 polymorphism (P = 0.841). There was a significant relationship between Taq1 gene polymorphism (tt genotype) and CSU (P = 0.038). Tt genotype increased the risk of CSU (odds ratio = 1.596), and inheritance of tt genotype increased the risk even further (odds ratio = 4.630). CONCLUSION: The frequency of Taq1 genotype polymorphism in the VDR gene was significantly higher in patients with CSU compared to the control group. The tt genotype polymorphism may be a risk factor for CSU.

Intravenous injection of autologous bone marrow-derived mesenchymal stem cells on the gene expression and plasma level of CCL5 in refractory rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is the most prevalent autoimmune disease, in which CCL2 and CCL5 are critically involved. The objective was to evaluate the therapeutic effects of bone marrow-derived mesenchymal stem cells (MSCs) on the foregoing chemokines in RA patients. MATERIALS AND METHODS: Thirteen RA patients were evaluated in terms of clinical manifestations, paraclinical factors, gene expression, and plasma levels of CCL2 and CCL5 prior to treatment and 1 and 6 months after intervention. Real-time-polymerase chain reaction and enzyme-linked immunosorbent assay were employed to assess the gene expression and plasma levels of CCL2 and CCL5 at different time points after MSC therapy. Statistical analysis was performed by SPSS 16 and Prism 7. RESULTS: The CCL2 gene expression had statistically significantly increased (P = 0.034), and its plasma level had insignificantly reduced after 1 month. Furthermore, the gene expression and plasma level of CCL5 had statistically significantly decreased (P = 0.032, P < 0.001). The CCL5 gene expression had statistically significantly increased after 6 months (P = 0.001) and its plasma level had insignificantly reduced. CONCLUSION: The most significant inhibitory effects of MSC therapy on the gene expression and plasma level of CCL5 were observed at the end of 1 month. The differences between the gene expression and protein levels during the treatment might be related to microRNA effects or the insufficient number of MSC injection.

The role of BAFF and APRIL in rheumatoid arthritis.

Development and activation of B cells quickly became clear after identifying new ligands and receptors in the tumor necrosis factor superfamily. B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are the members of membrane proteins Type 2 family released by proteolytic cleavage of furin to form active, soluble homotrimers. Except for B cells, ligands are expressed by all such immune cells like T cells, dendritic cells, monocytes, and macrophages. BAFF and APRIL have two common receptors, namely TNFR homolog transmembrane activator and Ca2+ modulator and CAML interactor (TACI) and B cell-maturation antigen. BAFF alone can also be coupled with a third receptor called BAFFR (also called BR3 or BLyS Receptor). These receptors are often expressed by immune cells in the B-cell lineage. The binding of BAFF or APRIL to their receptors supports B cells differentiation and proliferation, immunoglobulin production and the upregulation of B cell-effector molecules expression. It is possible that the overexpression of BAFF and APRIL contributes to the pathogenesis of autoimmune diseases. In BAFF transgenic mice, there is a pseudo-autoimmune manifestation, which is associated with an increase in B-lymphocytes, hyperglobulinemia, anti-single stranded DNA, and anti-double-stranded DNA antibodies, and immune complexes in their peripheral blood. Furthermore, overexpressing BAFF augments the number of peripheral B220+ B cells with a normal proliferation rate, high levels of Bcl2, and prolonged survival and hyperactivity. Therefore, in this review article, we studied BAFF and APRIL as important mediators in B-cell and discussed their role in rheumatoid arthritis.

Gene expression pattern of CCL2, CCL3, and CXCL8 in patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is one of the most important psychiatric disorders in the world. There is evidence suggesting the role of inflammatory mediators such as chemokines in the etiology of BD. The objective of the current study was to evaluate the gene expression of CCL2, CCL3, and CXCL8 in patients with BD and compare them to healthy controls. MATERIALS AND METHODS: A total of 48 patients with confirmed BD and 48 healthy controls enrolled in this study. All patients were recruited from April to August 2016 at Ibn-Sina Psychiatric Hospital, Mashhad University of Medical Sciences, Mashhad, Iran. RNA was extracted from the whole blood samples and then cDNA was synthesized. Gene expression of CCL2, CCL3, and CXCL8 was measured using SYBR® Green real-time polymerase chain reaction. The difference of delta-CT values between patients and healthy controls was compared with the independent samples t-tests. RESULTS: CCL2 and CXCL8 genes expressed at higher levels in patients with BD as compared to healthy controls, but not significant. On the contrary, we found lower expression levels for CCL3 gene in our patients compared to healthy controls, but the difference was not statistically significant. CONCLUSION: Our findings do not show an association between the gene expression of CCL2, CCL3 and CXCL8 and BD. Increasing the sample size and evaluation on the gene expression of other chemokines in depression and mania phases of BD might be helpful to get a better conclusion.

A significant decrease in the gene expression of interleukin-17 following the administration of synbiotic in patients with allergic rhinitis who underwent immunotherapy: A placebo-controlled clinical trial.

BACKGROUND: Allergic Rhinitis (AR) is the most common allergic disease worldwide. The present study, evaluated effects of synbiotic on gene expression of interferon-gamma (IFN-γ), interleukin-4 (IL-4), interleukin-10 (IL-10), interleukin-17 (IL-17), transforming growth factor beta (TGF-ß), and forkhead box P3 (FoxP3) in AR patients who received concomitant immunotherapy in a placebo-controlled clinical trial. MATERIALS AND METHODS: Twenty AR patients were randomized in synbiotic and placebo groups and received cluster immunotherapy for 2 months. RNA was extracted from peripheral PBMCs, then the cDNA synthesized. Subsequently, SYBR Green real-time Reverse transcription polymerase chain reaction technique was employed for studying the expression of mentioned genes. In addition, SNOT-22 and mini-Rhinoconjunctivitis Quality of Life Questionnaire questionnaires were completed by patients. Data were analyzed before and also 2 and 6 months after intervention. RESULTS: Clinical symptoms and quality of life were improved with immunotherapy, but there was no significant difference between the placebo and synbiotic groups. Gene expression of IFN-γ, TGF-ß, and FoxP3 was increased whereas the gene expression of IL-4 and IL-10 decreased, but not significant. Interestingly, the gene expression of IL-17 in the synbiotic group was significantly decreased versus placebo after 2 months (P = 0.001) and also at the end of intervention (P = 0.0001) comparing with the time zero. CONCLUSION: Significant reduction in the IL-17 gene expression following administration of synbiotic versus placebo shows the importance of synbiotic in control of the immunopathogenesis of AR. Further studies with more samples are recommended. In addition, evaluating the effects of synbiotic in patients who do not undergo immunotherapy is suggested to get a better conclusion.

Production and characterization of monoclonal antibodies against aflatoxin B1.

In this article, we embarked on production of mouse monoclonal antibodies against aflatoxin B1 which is the most commonly occurring fungal toxin in food and feed products. After immunization and fusion with myloma cells, two stable clones (A218 and B319) were selected. Isotyping showed that these monoclonal antibodies (mAbs) were IgG2b with kappa light chains. The affinity of A218 and B319 clons were 5×10(11) M(-1) and 6×10(9) M(-1), respectively. Competitive indirect ELISA results indicated these mAbs had complete (100%) cross-reaction with four major types of aflatoxins: B1, B2, G1, and G2. These mAbs could be used for immunoassay measurement of aflatoxins with high affinity and low detection limits.

The Effects of Mesenchymal Stem Cells on the Gene Expression of TGF-beta and IFN-gamma in Patients with Rheumatoid Arthritis.

The therapeutic and immunomodulatory potential of mesenchymal stem cells (MSCs) in rheumatoid arthritis (RA) has attracted considerable scientific attention in recent decades. This study aimed to evaluate the expression of genes encoding interleukin (IL)4 and IL10, as well as interferon-gamma (IFNG) and transforming growth factor beta (TGFB1) in refractory RA patients following intravenous injection of autologous bone marrow-derived MSCs (BM-MSCs). This study was registered in Iranian Registry of Clinical Trials (IRCT) (2015102824760N1) and ClinicalTrials.gov (identifier: NCT03333681). Blood samples were taken from 13 patients before and 1 and 6 months after the MSC injection to evaluate the clinical manifestations, paraclinical factors, and expression of IL4, IL10, IFNG, and TGFB1 genes employing the SYBR Green real-time reverse-transcriptase polymerase chain reaction (RT-PCR) technique. There was a significant increase in the expression of TGFB1 at 1 and 6 months after the MSC injection compared to that in the baseline, while the expression of IL4 and IL10 did not change significantly. On the other hand, the expression of IFNG increased significantly after 1 month but decreased significantly at 6 months compared to 1 month after the intervention. Nevertheless, it showed no significant decrease compared to the baseline. A significant decrease was observed for the expression of IFNG 6 months after the injection compared to that after 1 month, which was in concordance with the rise in the expression of the TGFB1 gene. A significant change in the gene expression of TGFB1 and IFNG in our study was consistent with the amelioration of clinical manifestations, suggesting a mechanism of action for MSCs in the treatment of RA.

The potential role of miRNA in regulating macrophage polarization.

Macrophage polarization is a dynamic process determining the outcome of various physiological and pathological situations through inducing pro-inflammatory responses or resolving inflammation via exerting anti-inflammatory effects. The miRNAs are epigenetic regulators of different biologic pathways that target transcription factors and signaling molecules to promote macrophage phenotype transition and regulate immune responses. Modulating the macrophage activation, differentiation, and polarization by miRNAs is crucial for immune responses in response to microenvironmental signals and under various physiological and pathological conditions. In term of clinical significance, regulating macrophage polarization via miRNAs could be utilized for inflammation control. Also, understanding the role of miRNAs in macrophage polarization can provide insights into diagnostic strategies associated with dysregulated miRNAs and for developing macrophage-centered therapeutic methods. In this case, targeting miRNAs to further regulate of macrophage polarization may become an efficient strategy for treating immune-associated disorders. The current review investigated and categorized various miRNAs directly or indirectly involved in macrophage polarization by targeting different transcription factors and signaling pathways. In addition, prospects for regulating macrophage polarization via miRNA as a therapeutic choice that could be implicated in various pathological conditions, including cancer or inflammation-mediated injuries, were discussed.

A Significant Increase in the Gene Expression of GATA-3 Following the Treatment of Osteoarthritis Patients with Crocin.

Osteoarthritis (OA) is known to be the most prevalent form of joint disease. We conducted this clinical trial to investigate the effects of KrocinaTM, a natural product containing crocin, on the gene expression of unique transcription factors of various T cell subsets in patients with OA. We collected 40 peripheral blood samples of OA patients receiving Krocina™ and equal number of those who took a placebo (IRCT2015021910507N2, NCT03375814). RNA extraction was performed from the cultured peripheral blood mononuclear cells of the OA patients who received Krocina™ and placebo and SYBR Green Real-time PCR technique was applied to assess the relative gene expression of T-bet, GATA3, ROR-γt, and FOXP3 as the unique transcription factors of various T cell subsets. The relative gene expression of T-bet and ROR-γt insignificantly decreased in the Krocina™ receiving group as compared to the placebo group. In addition, the relative gene expressions of GATA-3 and FOXP3 after the treatment with KrocinaTM showed a significant and insignificant increase, respectively. Moreover, an insignificant decrease was observed in the gene expression of GATA-3 and FOXP3 in the placebo group. A significant and insignificant decrease in the gene expression of T-bet and ROR- γt was detected in the OA patients who received a placebo. GATA-3 is known as a unique transcription factor for the differentiation of T-cells to the Th2 subset. The significant increase in the gene expression of GATA-3 in the patients with OA treated with crocin may suggest the beneficial effect of crocin on shifting towards the Th2 subset and enhancing an anti-inflammatory condition.

A Significant Reduction in the Plasma Levels and Gene Expression of CCL2 in Patients with Osteoarthritis following Intervention with Krocina™.

Background: inflammatory chemokines such as CCL2 and CCL5 are involved in the progress of osteoarthritis. Crocin with antioxidant and anti-inflammatory properties can reduce the symptoms of osteoarthritis (OA). This study was performed investigate the effect of Krocina™, on the gene expressions and plasma levels of CCL2 and CCL5 in OA patients. Methods: The study included 35 patients that were randomized in the Krocina™ and placebo groups. The intervention was Krocina™ 15mg daily for four months. Clinical and paraclinical parameters were measured. CCL2 and CCL5 genes expression and plasma levels were determined using the SYBR Green Real-Time RT-PCR and Enzyme-linked Immunosorbent Assay (ELISA) techniques. Results: The C-reactive protein (CRP) value in the Krocina™ group and the visual analogue scale (VAS) value in the Krocina™ and placebo groups decreased significantly after the intervention. The gene expression of CCL2 in the Krocina™ and placebo groups decreased significantly. On the contrary, the gene expression of CCL5 in the Krocina™ and placebo groups increased significantly. Moreover, the plasma levels of CCL2 in the Krocina™ and placebo groups decreased meaningfully. There was no difference regarding the plasma levels of CCL5 within the Krocina™ and placebo groups before and after the intervention in either of the groups. Conclusion: Administration of Krocina™ reduced the clinical signs of inflammation and CRP and VAS value. Also, Krocina™ significantly decreased the plasma levels and gene expression of CCL2 in osteoarthritis patients.

A review of PD-1/PD-L1 siRNA delivery systems in immune T cells and cancer cells.

OBJECTIVES: Programmed cell death 1 (PD-1) is a member of the CD28/CTLA-4 family of inhibitory immunological checkpoint receptors that's also widely produced by exhausted T lymphocytes in an immunosuppressive tumor microenvironment. PD-1 binds to programmed death ligand (PD-L1) and suppresses anti-cancer activity of T lymphocytes. We examined the current literature on how siRNA delivery systems can be used to target PD-1 and PD-L1, as well as the anti-cancer mechanisms and challenges associated with siRNA molecules. We look at studies that use program death 1 siRNA or program death 1 ligand siRNA to treat cancer. Several databases have been used for this purpose, including NCBI, Scopus, and Google Scholar. KEY FINDINGS: This study looked at several methods for delivering siRNA to immune cells and cancer cells. According to these findings, suppressing PD-1 in T cells increases T lymphocyte activity. PD-L1 suppression in DCs improves antigen presentation and co-stimulatory signals on their surface, resulting in T cell activation. Chemotherapy resistance and cancer cell suppression of T cells are reduced when PD-L1/2 is suppressed in cancer cells. CONCLUSION: The findings of this study indicated that several strategies for siRNA transfection to immune and cancer cells have been evaluated in recent decades, some of which effectively transfect siRNA to target cells, and defined PD-1 siRNA as a promising strategy for cancer treatment.

Curcumin as an effective suppressor of miRNA expression in patients with knee osteoarthritis.

Objective: Osteoarthritis is the most common disease in the group of joint diseases, and its incidence is directly related to aging. Given the anti-inflammatory effects of curcumin as an active ingredient of turmeric, we aimed to investigate the effects of this compound in a new curcumin nanomicelle formula named SinaCurcumin® on the expression of microRNAs (miRNAs) involved in immune responses of patients with osteoarthritis. Materials and Methods: We divided 30 patients with osteoarthritis into two groups namely, nano curcumin-receiving (15 patients) and placebo-receiving (15 patients) and we studied them for 3 months. The Iranian Registry of Clinical Trials (IRCT) approved our study with the IRCT registry No. IRCT20151028024760N4. We evaluated the rates of the expression of microRNAs 146, 155, 16, and 138 employing SYBR Green Real-Time PCR method. Results: The expression of miRNAs 155, 138, and 16 revealed a significant reduction in the curcumin-receiving group (p=0.002, p=0.024 and p=0.0001 respectively). Conclusion: Our research data indicated that the consumption of curcumin in patients with osteoarthritis could affect the immune system partially via altering the expression of microRNAs and cytokines.

Significant Effect of Crocin on the Gene Expression of MicroRNA-21 and MicroRNA-155 in Patients with Osteoarthritis.

Osteoarthritis (OA) is the most common form of arthritis associated with gradual joint destruction. The current treatment aims to alleviate pain and inflammation and improve the quality of life. Crocin is an active ingredient in saffron, with anti-inflammatory properties. MicroRNAs are small, non-coding RNAs that regulate gene expression. We aimed to evaluate the effect of crocin on the gene expression of microRNA-146a, microRNA-155, microRNA-223, and microRNA-21 in OA patients and compare it with a placebo. This study was approved and registered in the Iranian Registry of Clinical Trials (2015021910507N2) and ClinicalTrials.gov identifier: NCT03375814. Forty OA patients were randomly divided into two equal groups, receiving either crocin or placebo. Peripheral blood samples were collected before and four months after the intervention. The pain was assessed using the visual analog scale, and laboratory tests included C-reactive protein and erythrocyte sedimentation rate. The expression levels of microRNA-146a, microRNA-155, microRNA-223, and microRNA-21 genes were evaluated by SYBR Green real-time PCR. The results showed that the gene expression levels of microRNA-21 and microRNA-155 in patients receiving crocin were significantly decreased and increased, respectively. No significant changes were observed in microRNA-146a and microRNA-223 gene expression levels. In conclusion, crocin's anti-inflammatory role might be partly attributed to its effects on the gene expression of microRNA-21 and microRNA-155.