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The Ras (rat sarcoma virus) is a GTP-binding protein that is considered one of the important members of the Ras-GTPase superfamily. The Ras involves several pathways in the cell that include proliferation, migration, survival, differentiation, and fibrosis. Abnormalities in the expression level and activation of the Ras family signaling pathway and its downstream kinases such as Raf/MEK/ERK1-2 contribute to the pathogenic mechanisms of rheumatic diseases including immune system dysregulation, inflammation, and fibrosis in systemic sclerosis (SSc); destruction and inflammation of synovial tissue in rheumatoid arthritis (RA); and autoantibody production and immune complexes formation in systemic lupus erythematosus (SLE); and enhance osteoblast differentiation and ossification during skeletal formation in ankylosing spondylitis (AS). In this review, the basic biology, signaling of Ras, and abnormalities in this pathway in rheumatic diseases including SSc, RA, AS, and SLE will be discussed. [ABSTRACT FROM AUTHOR]

Fibroblast-like synoviocytes (FLSs), the main pathological cells in rheumatoid arthritis (RA), display tumor-like phenotype, including hyper-proliferation, apoptosis resistance, and aggressive phenotype. Excessive proliferation and insufficient apoptosis of RA-FLSs can lead to hyperplastic synovial pannus tissue, excess production of inflammatory mediators, and destruction of joints. In this article, we investigate the effect of PRIMA-1MET on the apoptosis induction and inhibition of pro-inflammatory cytokines in RA-FLSs. Synovial tissue samples were obtained from 10 patients with RA. The FLSs were treated with different concentrations of PRIMA-1MET. The rate of apoptosis and cell survival was assessed by flow cytometry and MTT assay and Real-time quantitative PCR was performed to evaluate the transcription of p53, IL-6, IL-1β, TNF-α, Noxa, p21, PUMA, Bax, Survivin, and XIAP in treated RA-FLSs. The protein level of p53, IκBα, and phospho-IκBα were measured using Western blotting. The results showed that PRIMA-1MET induced apoptosis in RA-FLSs and increased significantly the expression of Noxa, and decreased significantly IL-6, IL-1β, p53, and phospho-IκBα expression. PRIMA-1MET can induce apoptosis in RA-FLSs through induction of Noxa expression while p53 was downregulated. Furthermore, PRIMA-1MET treatment results in the suppression of pro-inflammatory cytokine production and NF-κB inhibition. Given the role of p53 and NF-κB in RA-FLSs, PRIMA-1MET can be considered as a new therapeutic strategy for rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Background: Ankylosing spondylitis (AS) is an inflammatory autoimmune disease that mostly affects different joints of the body. Macrophages are the predominant cells that mediate disease progression by secreting several pro-inflammatory mediators. Different receptors are involved in macrophages' function including the adenosine receptors (AR). Our main objective in this study was to assess the effect of applying A2A adenosine receptor agonist (CGS-21,680) on the gene expression of inflammatory mediators including bone morphogenetic proteins (BMP)-2, 4 and matrix metalloproteinases (MMP)-3, 8, 9, and 13 on the macrophages from AS patients compared to healthy macrophages.Methods: Monocytes were isolated from the whole blood of 28 individuals (AS patients and healthy controls in a 1:1 ratio). Macrophages were differentiated using macrophage colony-stimulating factor (M-CSF), and flow cytometry was performed to confirm surface markers. CGS-21,680 was used to treat cells that had been differentiated. Using SYBR green real-time PCR, relative gene expression was determined.Results: Activating A2AAR diminished MMP8 expression in healthy macrophages while it cannot reduce MMP8 expression in patients' macrophages. The effect of A2AAR activation on the expression of BMP2 and MMP9 reached statistical significance neither in healthy macrophages nor in the patients' group. We also discovered a significant positive connection between MMP8 expression and patient scores on the Bath ankylosing spondylitis functional index (BASFI).Conclusion: Due to the disability of A2AAR activation in the reduction of MMP8 expression in patients' macrophages and the correlation of MMP8 expression with BASFI index in patients, these results represent defects and dysregulations in the related signaling pathway in patients' macrophages. [ABSTRACT FROM AUTHOR]

Objective: We sought to test the hypothesis that Polygenic Risk Scores (PRSs) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain.Methods: PRSs were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15 585 AS cases and 20 452 controls. The discriminatory values of PRSs in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), HLA-B27 and sacroiliac MRI.Results: In people of European descent, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for HLA-B27 testing alone (AUC=0.869), MRI (AUC=0.885) or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain under 45 years of age, compared with HLA-B27 testing alone, PRS provides higher positive values for 35% of patients and negative predictive values for 67.5% of patients. For PRS, in people of European descent, the maximum positive predictive value was 78.2% and negative predictive value was 100%, whereas for HLA-B27, these values were 51.9% and 97.9%, respectively.Conclusions: PRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI or HLA-B27 status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are considered as a subset of mononuclear phagocytes that composed of multiple subsets with distinct phenotypic features. DCs play crucial roles in the initiation and modulation of immune responses to both allo- and auto-antigens during pathogenic settings, encompassing infectious diseases, cancer, autoimmunity, transplantation, as well as vaccination. DCs play a role in preventing autoimmunity via inducing tolerance to self-antigens. This review focus on the most common subsets of DCs in human. Owing to the low frequencies of DC cells in blood and tissues and also the lack of specific DC markers, studies of DCs have been greatly hindered. Human DCs arise by a dedicated pathway of lympho-myeloid hematopoiesis and give rise into specialized subtypes under the influence of transcription factors that are specific for each linage. In humans, the classification of DCs has been generally separated into the blood and cutaneous subsets, mainly because these parts are more comfortable to examine in humans. [ABSTRACT FROM AUTHOR]

Asenapine (ASE) has been used for treatment of bipolar disorder. There is also evidence that it may be useful in the treatment of neurodegenerative disorders. In this regard, the effi cacy of ASE in an experimental model of seizure and memory impairment caused by seizures in rats has been investigated in the present study. Seizures in male Wistar rats (200-250 g) were induced by pentylenetetrazole (PTZ, 60 mg/kg, intraperitoneally (i.p.)), and the anticonvulsant effect of ASE (0.5 and 1 mg/kg, i.p.) was evaluated. The effect on memory was assessed using passive avoidance (PA) test in a shuttle box apparatus. After behavioral tests, the animals underwent deep anesthesia and were euthanized painlessly. Serum was isolated for oxidative stress assays (nitric oxide (NO), and glutathione (GSH)). Intraperitoneal injection of ASE decreased the mean number of myoclonic jerks and duration of generalized tonic clonic seizures (GTCS) and increased the mean latency of myoclonic jerk and GTCS compared to the PTZ group. Moreover, in the PA test, ASE caused a signifi cant increase in retention latency (RL) and total time spent in the light compartment (TLC) compared to the PTZ group. Biochemical tests showed that ASE was able to signifi cantly increase GSH serum levels and signifi - cantly reduce NO serum levels compared to the PTZ group. Overall, this study suggests the potential neuroprotective effects of ASE in a model of memory impairment caused by seizures via the mechanism of inhibition of the oxidative stress pathway. [ABSTRACT FROM AUTHOR]

Objectives Infection control is one of the most important aspects of dentistry. Since intraoral radiographic films are directly in contact with the oral environment, microbial contamination may transmit infectious diseases. The purpose of this study was to investigate the frequency of microbial contamination of intraoral radiographic films and compare the probable microbial contamination of two intraoral radiographic film brands available in the Iranian market. Methods in this in vitro, experimental study, 900 radiographic films of two commercial brands, i.e. Intra X-ray and Carestream films were placed in aerobic, anaerobic, and fungal culture media immediately after removal from the packaging in sterile conditions. The samples were transferred to the respective culture media after incubation. The cultured bacteria were Gram-stained, and microscopically observed. The percentage of the contaminated intraoral radiographic films and the type of microbial contamination were reported. Data were analyzed using the Chi-square test. Results Of all, 32.6% of the Carestream films and 44.6% of Intra X-ray films were infected by aerobic microorganisms, mostly Bacillus. In the anaerobic culture, the turbidity of the medium indicated the possible presence of microorganisms. In the fungal culture, no fungal hyphae were observed microscopically. Conclusion The results of this study showed that intraoral films cannot be considered sterile. Intra X-ray radiographic films were significantly more contaminated than Care stream radiographic films. [ABSTRACT FROM AUTHOR]