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.

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 immunomodulatory properties of curcumin in patients with osteoarthritis; a successful clinical trial in Iran.

Osteoarthritis (OA) routinely is known as a multifactorial degenerative joint disease. This trial aimed to assess the curcumin (an active element of turmeric) effects on the immune responses in OA patients. Thirty patients were selected according to the American College of Rheumatology (ACR) criteria and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and equally divided into the two groups; intervention (received Sinacurcumin® 80 mg daily) and placebo, followed for 3 months. In the intervention group, our data showed a noticeably decrease in Visual Analog Score (VAS), C-reactive protein (CRP), CD4+ and CD8+ T cells, Th17 cells and B cells frequency. Additionally, Treg cells indicated a significant increase and Treg/Th17 cells ratio showed a meaningfully shifted toward Treg lymphocytes. In conclusion, our data indicated that clinical manifestation was ameliorated considerably following the administration of curcumin. Moreover, our data demonstrated the immunomodulatory effects of curcumin in OA patients.

MicroRNAs as the Important Regulators of T Helper 17 Cells: A Narrative Review.

T helper (Th)-17 cells are a distinct and important subset of Th cells and their functions are due to the ability of production and secretion of key cytokines in the immune system such as interleukin (IL)-17, IL-22, IL-21, and tumor necrosis factor-α (TNF-α). According to these cytokines, these cells have vital roles in the pathogenesis of the disease such as rheumatoid arthritis (RA) and osteoarthritis (OA). Nowadays, microRNAs (miRNAs) are defined as essential regulators of cell function by targeting transcription factors and other elements that act in cells to control gene expression. The purpose of this study was to detect and investigate articles evaluating the function of miRNA in Th-17 cell performance. The language was restricted to English and the search was done in PubMed, Web of Science and Embase. In this review, we first explain the role of effective factors in the function of Th17 lymphocytes, and then, we summarize the performance of several miRNAs involved in the activation and appropriate functions of Th17 cells in the immune system.

Association between interleukin-1 receptor associated kinase 1 rs3027898 A/C gene polymorphism and rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease predominantly involving the synovial joints and affects up to 1% of adults worldwide. The aim of the present study was to determine whether the interleukin-1 receptor (IL1R)-associated kinase (IRAK1) rs3027898 gene polymorphism confers susceptibility to RA in a sample of patients from Iran. This gene encodes IRAK1, one of two putative serine/threonine kinases that associates with IL1R upon stimulation. IRAK1 is partially responsible for IL-1-induced upregulation of the transcription factor, nuclear factor-κB. The present case-control study was performed on 120 patients with RA and 120 healthy individuals. Genomic DNA was extracted from whole blood, and the gene polymorphism was evaluated using a tetra-primer amplification refractory mutation system-polymerase chain reaction method. The results demonstrated that there was no association between IRAK1 rs3027898 CA genotype and the risk of RA in women (odds ratio=0.72, 95% confidence interval=0.41-1.49; P=0.446). Further studies with larger sample sizes and different ethnicities are required to validate the present findings.

Lectin, galactoside-binding, soluble, 3 rs4652 A/C gene variation and the risk for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a complex genetic disease. The lectin, galactoside-binding, soluble, 3 (LGALS3) gene, encodes a member of the galectin family of carbohydrate binding proteins, and is one of the best examples of a non-human leukocyte antigen gene associated with a risk for RA in various populations. In the current study, the association between LGALS3 rs4652 gene polymorphism and RA was examined. This case-control study was performed on the 120 patients with RA and 120 healthy subjects. Genomic DNA was extracted from whole blood, and gene polymorphism was tested using a tetra-primer amplification refractory mutation system-polymerase chain reaction. The results demonstrated that LGALS3 rs4652 AC genotype increased the risk of RA (OR=11.622, 95% CI=4.473-28.656; P=0.001) when compared with the AA genotype. However, the CC genotype and the C allele were not associated with RA. These findings indicated an association between LGALS3 rs4652 variation and the risk of RA in a sample of Iranian individuals. Further studies with larger sample sizes and populations of different ethnicities are required to validate our findings.

CD226 rs763361 (Gly307Ser) polymorphism is associated with susceptibility to rheumatoid arthritis in Zahedan, southeast Iran.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease with many genetic factors predisposing to disease susceptibility. The aim of the present study was to investigate the impact of CD226 rs727088 and rs763361 polymorphisms and susceptibility to RA in a sample of the Iranian population. METHODS: This case-control study was carried out on 100 patients with RA and 104 healthy subjects. The polymorphisms were determined using tetra amplification refractory mutation system-polymerase chain reaction assay. RESULTS: The rs763361 (Gly307Ser) polymorphism increased the risk of RA in codominant, dominant and recessive-tested inheritance models (odds ratio [OR] = 3.18, 95% confidence intervals [95% CI] = 1.44-7.02, P = 0.004, CC vs. TT, and OR = 1.98, 95% CI = 1.10-3.57, P = 0.023, CC vs. CT-TT, and OR = 2.61, 95% CI = 1.26-5.37, P = 0.010, CC + CT vs. TT, respectively). In addition, the rs763361 T allele increased the risk of RA (OR = 2.06, 95% CI = 1.38-3.08, P<0.001). However, no significant difference was observed among the groups regarding CD226 rs727088 polymorphism (χ2 = 3.20, P = 0.202). CONCLUSIONS: Our finding showed that CD226 rs763361, but not rs727088, gene polymorphism increased the risk of RA in a sample of the Iranian population.

Association of pre-miRNA-146a rs2910164 and pre­miRNA-499 rs3746444 polymorphisms and susceptibility to rheumatoid arthritis.

Single nucleotide polymorphisms in pre­microRNA (miRNA) may alter miRNA expression levels or processing and contribute to susceptibility in a wide range of diseases. The present study aimed to evaluate the possible association between rs2910164 and rs3746444 of the pre-miRNA (hsa-mir-146a and hsa-mir-499) polymorphisms and susceptibility to rheumatoid arthritis (RA) in an Iranian population. This case-control study was performed on 104 patients with RA and 110 healthy individuals. Tetra amplification refractory mutation system-polymerase chain reaction was used to genotype the hsa-mir-499 rs3746444 and hsa-mir-146a rs2910164 polymorphisms. The hsa-mir-499 rs3746444 polymorphism was a risk factor for predisposition to RA in codominant [TT vs. TC: odds ratio (OR), 2.11; 95% confidence interval (CI), 1.08-4.11; p=0.029; TT vs. CC: OR, 3.88; 95% CI, 1.68-8.98; p=0.002], dominant (TT vs. TC-CC: OR, 2.64; 95% CI, 1.48-4.72; p=0.001) and recessive (TC-CC vs. CC: OR, 3.05; 95% CI, 1.36-6.83; p=0.007) tested inheritance models. In addition, the rs3746444 C allele was a risk factor for RA (OR, 2.49; 95% CI, 1.63-3.81; p<0.0001). No significant difference was found between the groups concerning the rs2910164 polymorphism (χ2=0.348, p=0.841). Our findings demonstrated that the hsa-mir-499 rs3746444, but not mir-146a rs2910164, polymorphism is associated with an increased RA risk in a sample of the Iranian population. Larger studies with different ethnicities are required to validate our findings.

Association of IRGM polymorphisms and susceptibility to pulmonary tuberculosis in Zahedan, Southeast Iran.

Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. IRGM1 is an important protein in the innate immune response against intracellular pathogens by regulating autophagy. Polymorphisms in the IRGM genes are known to influence expression levels and may be associated with outcome of infections. This case-control study was done on 150 patients with PTB and 150 healthy subjects to determine whether the IRGM polymorphisms at positions -1208 A/G (rs4958842), -1161 C/T (rs4958843), and -947 C/T (rs4958846) were associated with PTB. The polymorphisms were determined using tetra-amplification refractory mutation system-PCR (T-ARMS-PCR). The results showed that the IRGM -1161 C/T and -947 C/T polymorphisms were associated with decreased susceptibility to PTB (OR = 0.06, 95% CI = 0.03-0.13, P < 0.001 and OR = 0.27; 95% CI = 0.013-0.55, P < 0.001, resp.). No significant difference was found among the groups regarding -1208 A/G polymorphism. In conclusion we found that the IRGM -1161 C/T and -947 C/T polymorphisms but not -1208 A/G polymorphism provide relative protection against PTB in a sample of Iranian population.

Comparative effectiveness of hand and ultrasonic instrumentations in root surface planing in vitro.

BACKGROUND/AIMS: A variety of techniques are employed for planing and scaling of the superficial root surfaces, of which hand and ultrasonic instrumentations have been preferentially used in routine periodontics clinics. This study was undertaken to compare the effectiveness of ultrasonic scalers and hand curettes in facilitating fibroblast attachment to the scaled root surfaces. MATERIALS AND METHODS: Sixteen patients with periodontally involved teeth and nine subjects without periodontal diseases (control subjects) were selected. Two single-rooted teeth were extracted from each subject. Mesial and distal surfaces of teeth were selected in treated and untreated groups, respectively. The mesial surface of each tooth was randomly chosen to be treated either by hand curettes or ultrasonic instrumentation. The degree of cell attachment on the root surfaces of treated and untreated groups from control subjects and patients was then determined by the use of a gingival fibroblast line established and employed at early passages. The attachment and proliferation of gingival fibroblasts on the root surfaces were evaluated using neutral red assay and scanning electron microscopy (SEM). RESULTS: Fibroblast survival and proliferation on the surfaces of untreated periodontally involved roots were found to be significantly lower compared with control untreated surfaces (p<0.0001) or treated surfaces from patients (p<0.0001). No significant difference, however, was observed between root surfaces treated either by hand curettes or ultrasonic scalers. CONCLUSION: These results indicate the beneficial effectiveness of both techniques in root treatment and planing.