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Multiple myeloma is one of the most hard-to-treat cancers among blood malignancies due to the high rate of drug resistance and relapse. The researchers are trying to find more effective drugs for treatment of the disease. Hence, the use of drugs targeting signaling pathways has become a powerful weapon. Overactivation of phosphatidylinositol 3-kinase signaling pathways is frequently observed in multiple myeloma cancer cells, which increases survival, proliferation, and even drug resistance in such cells. In recent years, drugs that inhibit the mediators involved in this biological pathway have shown promising results in the treatment of multiple myeloma. In the present study, we aimed to introduce phosphatidylinositol 3-kinase signaling inhibitors which include small molecules, herbal compounds, and microRNAs.

The NF-κB family includes some transcription factors which have important functions in the regulation of immune responses, therefore participating in the pathophysiology of inflammatory conditions such as peripheral neuropathies. We have quantified expression of a number of NF-κB-related transcripts in patients with Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP) versus healthy subjects. These transcripts have been previously shown to be functionally related with this family of transcription factors. Expressions of ATG5, DICER-AS1, PACER, DILC, NKILA and ADINR have been increased in both CIDP and GBS patients compared with controls. However, expression of ATG5 was not different between female CIDP cases and female controls. Moreover, expression of PACER was not different between male GBS cases and male controls. Expression levels of CHAST and CEBPA were not different between patients and controls. Expression of none of the assessed genes was different between GBS and CIDP cases. Significant correlations have been revealed between expression amounts of NF-κB-related transcripts both among CIDP/ GBS patients and among controls except for NKILA/ATG5, ADINR/ATG5 and PACER/ATG5 and DICER-AS1/ATG5 pairs among controls whose expression levels have not been correlated. In the patient group, CEBPA/PACER, CHAST/PACER and CHAST/DICER-AS1 pairs had the most robust correlations (r = 0.94). Among controls, NKILA/ADINR pair had the most strong correlation (r = 0.78). ADINR and DICER-AS1 levels could differentiate CIDP cases from controls with 100% sensitivity and specificity. In differentiation of GBS cases from controls, these two transcripts had the AUC values of 0.99 and 1. Combination transcript levels of NF-κB-related transcripts similarly detects CIDP and GBS cases from healthy controls with 100% sensitivity and specificity. Therefore, NF-κB-related transcripts are possibly involved in the pathophysiology of inflammatory peripheral nerve disorders and can be used as diagnostic markers for these conditions.

Migraine is a complex disabling condition which is associated with dysregulation of several pathways particularly those being associated with immune responses. In order to assess contribution of protein inhibitor of activated STAT (PIAS) in the pathogenesis of migraine, we quantified expression levels of PIAS1–PIAS4 genes in the circulation of patients with migraine compared with controls. Expression of PIAS1 was substantially lower in total migraineurs compared with controls (ratio of mean expressions (RME) = 0.18, SE = 0.29, P value

Oxytocin is a neuropeptide released by the central nervous system. A number of studies have demonstrated the role of this neuropeptide in the pathogenesis of breast cancer. In the present project, we have identified mRNA coding genes and long non-coding RNAs (lncRNAs) that are associated with this pathway through an in-silico strategy, and measured their expression in a cohort of Iranian females affected with this type of malignancy. Expression levels of OXTR, FOS, ITPR1, RCAN1, CAMK2D, CACNA2D and lnc_ZFP161 were significantly down-regulated in breast cancer tissues compared with nearby non-cancerous tissues. On the other hand, expression of lnc_MTX2 was higher in breast cancer tissues compared with controls. Expression of lnc_TNS1 and lnc_FOXF1 were not different between these two kinds of samples. Expression of CACNA2D was associated with mitotic rate and PR status (P values = 3.02E−02 and 2.53E−02, respectively). Expression of other oxytocin-related genes was not associated with clinicopathological parameters. FOS and ITPR1 had the highest AUC value among the oxytocin-related genes. Combination of expression profiles of all oxytocin-related genes increased the AUC value to 0.75. However, the combinatorial sensitivity and specificity values were lower than some individual genes. In the breast cancer tissues, the most robust correlations have been detected between lnc_ZFP161/ lnc_FOXF1, CAMK2D/ lnc_ZFP161 and CAMK2D / lnc_FOXF1 (r = 0.86, 0.71 and 0.64 respectively). In the non-cancerous tissues, the strongest correlation was detected between lnc_FOXF1/lnc_MTX2 and lnc_ZFP161/CAMK2D respectively (r = 0.78 and 0.65). Taken together, oxytocin-associated genes have been dysregulated in breast cancer tissues. Moreover, the correlation ratio between these genes is connected with the existence of cancer.

Epilepsy is a frequent chronic disorder of the brain characterized by intermittent epileptic seizures caused by hypersynchronous discharge of neurons in the brain. Studies have reported the role of cytokines in the pathogenesis of epilepsy, and a number of investigations have shown decreased levels of omega-3 fatty acids in epileptic patients. We investigated differences in serum levels of two cytokines, transforming growth factor (TGF)-β and interferon (IFN)-γ, in 40 epileptic cases prior to and after treatment with omega-3 fatty acids. IFN-γ levels were significantly increased after the 16-week treatment period (P

Guillain-Barré syndrome (GBS) is an acute inflammatory polyradiculoneuropathy syndrome. Several genetic and environmental risk factors have been recognized for GBS. AS GBS is an immune-related disorder, abnormal functions of T cells, production of autoantibodies, and dysregulation of gene expression have been detected in GBS patients. Based on the critical role of human leukocyte antigen (HLA) in the regulation of immune responses, HLA alleles are among the mostly investigated loci in GBS. A number of polymorphisms within different genes, especially those linked with the regulation of immune responses, have been associated with GBS in different populations. Moreover, several studies have demonstrated abnormal expression of cytokine-coding genes in this disorder. Investigations in the animal model of GBS have also verified the aberrant regulation of Th1/Th2/Th17/Treg cytokines. In the current review, we describe the information about the role of these factors in GBS.

NF-κB signaling pathway has important roles in the regulation of growth and development of nervous system. This pathway has also been shown to participate in the pathogenesis of schizophrenia. Meanwhile, activity of NF-κB signaling pathway is regulated by several factors including non-coding RNAs (lncRNAs). In the current study, we evaluated expression of nine NF-κB-related lncRNAs namely DILC, ANRIL, PACER, CHAST, ADINR, DICER1-AS1, HNF1A-AS1, H19 and NKILA as well as two mRNA coding genes namely ATG5 and CEBPA in the peripheral blood of patients with schizophrenia compared with matched healthy subjects. Expressions of these genes were assessed by real time PCR technique. Expression of PACER was lower in patients with schizophrenia compared with controls (Posterior beta = − 0.684, P value = 0.049). On the other hand, expressions of CHAST, CEBPA, H19, HNF1A-AS1 and DICER1-AS1 were higher in patients compared with controls (Posterior beta = 0.39, P value = 0.005; Posterior beta = 0.844, P value CHAST, CEBPA, DICER1-AS1, H19 and HNF1A-AS1 in distinguishing between patients with schizophrenia and controls through depicting ROC curves. Based on the area under curve (AUC) values, CEBPA had the best diagnostic power (AUC = 0.948, P H19 (AUC = 0.815, P

Celiac disease (CD) is a common autoimmune disease that is manifested by inflammation of the small intestine and varying extra intestinal symptoms, also considered to be associated with human HLA-DQ genes. In this study, 40 patients of CD and 40 healthy control samples were genotyped for HLA-DQB1 and 14 patients of CD and 14 healthy control samples were genotyped for HLA-DQA1genes using the SSP-PCR technique and a commercial kit.The DQA1*05 allele had the highest frequency among the patient group (42.86%). The frequency of this allele was 28.57% in healthy controls, and there was no statistically significant difference in this case (p= 0.771).The DQB1*02 allele was the most common in patients (33.75%) followed by the DQB1*03 allele (31.25%).The difference in frequency of the HLA-DQB1*02 allele in the patient and control groups was statistically significant (P= 0.0002, OR = 4.72). The remarkable differences in the distribution of HLA-DQ2 in Iranian patients compared to controls and relative risks signified the role of these alleles in the development of CD in Iranian patients and confirmed the likelihood of using HLA-DQ typing in the substantiation of the disease.

Long non-coding RNAs (lncRNAs) have crucial roles in lncRNAs in periodontal development and disorders of this tissue. A number of lncRNAs especially those regulating immune responses contribute in the pathophysiology of periodontitis. In the current case-control study, we assessed expression levels of two immune response-related lncRNAs namely the antisense non-coding RNA in the INK4 locus (ANRIL) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in gingival tissues and blood samples of patients with periodontitis and healthy subjects. Expression of ANRIL was significantly lower in peripheral blood of patients compared with controls (Posterior Beta RE = -1.734, P value = 0.035). However, when diving study participants based on their gender, no significant difference was found between patients and sex-matched controls. Expression of this lncRNA was not different between periodontitis tissues and normal tissues. Expression of MALAT1 was not different between samples obtained from cases and controls. Tissue or blood expressions of ANRIL or MALAT1 were not correlated with age of either patients or controls. There were significant correlations between expression levels of ANRIL and MALAT1 in gingival tissues both in cases (r = 0.62, P, Highlights • Expression of ANRIL was significantly lower in peripheral blood of patients with periodontitis compared with controls. • Expression of ANRIL was not different between periodontitis tissues and normal tissues. • Expression of MALAT1 was not different between samples obtained from cases and controls. • Tissue or blood expressions of ANRIL or MALAT1 were not correlated with age.

The Brain cytoplasmic 200 RNA (BC200 RNA) is neuron-specific lncRNA with putative roles in normal aging and in the pathogenesis of Alzheimer's disease. Its role in the neuron plasticity has also been documented. In the current study, we genotyped a single nucleotide polymorphism (SNP) within this lncRNA (rs4404327) in a population of Iranian patients with diverse neuropsychiatric conditions including substance addiction (n = 315), attention deficit hyperactive disorder (ADHD) (n = 53), bipolar 1 (BP1) (n = 131), bipolar 2 (BP2) (n = 68), major depressive disorder (MDD) (n = 56) and schizophrenia (SCZ) (n = 177) as well as age-/ sex-matched healthy controls. This SNP was associated with ADHD in co-dominant model (C/T vs. C/C) (OR (95% CI) = 3.7 (1.96-10), P value = 0.000193), dominant model (C/T + T/T vs. C/C) (OR (95% CI) = 4.43(2.02-9.72), P value = 1.37E-04) and multiplicative model (C vs. T) (OR (95% CI) = 3.20(1.64-6.25), P value = 4.316269E-04). Moreover, this SNP was associated with risk of BP1 in dominant model (OR (95% CI) = 1.67(1.08-2.62), P value = 0.02) and multiplicative model (OR (95% CI) = 1.51 (1.04-2.21), P value = 0.028). After correction for multiple comparisons (6 cohorts × 4 models), associations remained significant in ADHD but not in BP1. No other significant association was detected. The current project showed association between a certain SNP within BC200 RNA and ADHD. Further studies are required to assess these associations in larger cohorts of patients and find the underlying mechanism for this observation.

Periodontitis is a complex disorder that affects a large number of human beings from different ethnic groups. This condition has been associated with dysregulation of a number of genes, among them are long noncoding RNAs (lncRNAs). In the current study, we assessed the expression of four lncRNAs (BDNF-AS, MIAT, MIR137HG, and PNKY) as well as BDNF in the peripheral blood and gingival tissues obtained from patients with periodontitis and healthy subjects. The expression of BDNF was significantly lower in blood samples of male patients with periodontitis compared with male controls (posterior β of RE = -4.754, p = .048). However, there was no significant difference in the expression of BDNF in tissue samples from the cases and controls. The expression of BDNF-AS was significantly lower in the tissue samples of patients compared with control tissue samples (posterior β of RE = -2.151, p = .019). Such an expression difference was detected between male subgroups as well (posterior β of RE = -3.679, p = .009). However, expression of this lncRNA was not different in blood samples obtained from patients compared with healthy subjects. The expression of PNKY was significantly higher in tissue samples obtained from female patients compared with sex-matched controls (posterior β of RE = 6.23, p = .037). Blood levels of this lncRNA were not different between cases and controls. There was no significant difference either in the tissue expression or in blood expression of MIR137HG or MIAT between cases and controls. The current study indicates the putative role of BDNF, BDNF-AS, and PNKY in the pathophysiology of periodontitis and potentiates these genes as candidates for functional studies.

Multiple sclerosis (MS) is among the most common diseases affecting brain and spinal cord. MS progression is characterized by breakdown of blood brain barrier which leads to increased vascular permeability and angiogenesis. Consequently, vascular endothelial growth factor A (VEGF) and its receptors are considered to be important components of MS progression. VEGFA and fms-related tyrosine kinase 1 (FLT1) play important roles in various aspects of MS. In this study, we investigated the relationship between these genes and MS. For this purpose, the expression levels of VEGFA and FLT1 were measured in the blood of 50 relapsing-remitting MS (RR-MS) patients and 50 healthy individuals using TaqMan quantitative real-time PCR. A significant upregulation of VEGFA expression was observed among MS patients compared with controls (p = 0.04). However, the difference in FLT1 gene expression between study groups was insignificant (p = 0.947). In addition, there was a significant positive correlation between VEGFA and FLT1 genes expressions (r = 0.769, p

Long non-coding RNAs (lncRNAs) have been demonstrated to be involved in the pathogenesis of neuropsychiatric disorders such as epilepsy. In the current study, we evaluated expression of eight lncRNAs in 80 epileptic patients (40 refractory and 40 non-refractory ones) and 40 normal individual using quantitative real-time PCR. Bayesian regression model showed significant higher expression of UCA1 in both refractory and non-refractory groups compared with controls (posterior beta of relative expression (RE) = 2.03, P value = 0.003, and posterior beta of RE = 4.05, P value

Periodontal diseases are common conditions in almost all age groups and a public health problem. Numerous risk factors have been demonstrated for this condition. The main mechanism of tissue destruction in the periodontitis is the functional interactions between microbial pathogens and host immune responses, thus cytokines have crucial roles in the pathogenesis periodontitis. Our previous study has demonstrated the susceptibility role of HLA-DRB1*04 allele in development of this disease. So, the individuals who were positive for HLA-DRB1*04 allele were excluded. We aimed to appraise the function of cytokines in the pathogenesis of periodontitis via assessment of tissue and blood levels of a number of cytokine coding genes, namely IL-1B, CXCL8, IL-17, IFNG, TGFB and TNFA1. Expressions of IFNG, IL-17, TGFB and TNFA1 were significantly higher in the peripheral blood of individuals with periodontitis compared with unaffected persons (Posterior beta = 1.91, P value = 0.043; Posterior beta = 1.84, P value = 0.033; Posterior beta = 0.713, P value = 0.009 and Posterior beta = 2.85, P value = 0.001, respectively). Moreover, expression of IL-17 was higher in females compared with males (Posterior beta = 1.47, P value = 0.036). As the interaction effect between gender and group was remarkable for IL-17 expression, we further conducted subgroup analysis within gender group. Expression of IL-17 was higher in male patients compared with unaffected males (Posterior beta = 1.9, P value = 0.048). We did not detect any significant difference in the expression of these cytokines in tissues obtained from affected individuals and unaffected controls. Therefore, our results imply dysregulation of cytokine coding genes in patients with periodontitis and warrant further mechanistical studies.

Circular RNAs (circRNAs) are non-coding RNAs with closed ends which makes them resistant to degrading enzyme RNAse R. These RNA molecules show cell, tissue or organ specific expression. Regulatory functions have been reported for a number of circRNAs. Particularly, they have been found to affect cell cycle and control cell proliferation. CircRNAs are involved in physiological processes like natural organ development. Their dysregulation in high-throughput technologies have been shown in a growing number of diseases especially many types of cancers such as renal cell carcinoma (RCC). Differentially expressed circRNAs in RCC tissues compared to normal tissues may affect carcinogenesis process. Overexpressed circRNAs promote tumorigenic functions of RCC cell lines while down-regulated transcripts repress them. Both dysregulated circRNAs are correlated with clinicopathological features, prognosis and survival in RCC patients which along with their acceptable diagnostic values suggest them as potential biomarkers in diagnosis or prediction of prognosis of RCC patients. In this review, we have assessed tumorigenic or tumor-suppressing effects of circRNAs and also their diagnostic and prognostic potentials in RCC.

Parkinson’s disease (PD) has been shown to affect approximately 1% of the persons aged more than 65 years. This multifactorial disorder has been associated with abnormal function of NF-κB signals. In this research, we have evaluated expressions of NF-κB-related long non-coding RNAs in the circulation of PD patients compared with healthy controls. Expression of PACER was lower in total PD patients compared with healthy persons (Ratio of mean expressions (RME)=0.32, P valueDILC was higher in total PD patients (RME=4.07, P valueCEBPA was significantly over-expressed in total PD patients (RME=14.76, P valueHNFA1-AS was down-regulated in all comparisons (RME=0.10, P value=2E-06, RME=0.08, P valueNKILA and ADINR were robustly correlated with each other (r=0.75, P value=2.40E-10). In addition, expression levels of DICER1-AS were significantly correlated with those of ADINR, PACER and H19 in these patients (r=0.73, P value=1.76E-9; r=0.72, P value=5.15E-09 and r=0.72, P value=3.09E-09, respectively). Correlation analyses among healthy controls revealed robust correlations between CHAST and CEBPA (r=0.84, P value=3.09E-09), NKILA and ADINR (r=0.80, P value=4.24E-12) as well as between DILC and CHAST (r=0.76, P value=1.70E-10). CEBPA had the best parameters among all assessed genes (AUC=0.96, Sensitivity=0.90 and specificity=0.97). DILC and ATG5 were the most appropriate markers after CEBPA with AUC values of 0.82 and 0.80, respectively. Most notably, combination of all genes improved AUC, sensitivity and specificity parameters to 1, 0.97 and 0.99, respectively. Cumulatively, the current study provides evidence for participation of NF-κB-related lncRNAs in the pathoetiology of PD.

Migraine is a complex neurological condition affecting a large proportion of persons. Dysregulation of several immune-related transcripts has been noted in migraineurs suggesting an immune-based background for this condition. We measured expression levels suppressor of cytokine signaling (SOCS) genes in the venous blood of migraineurs compared with controls. SOCS1 was down-regulated in patients without aura compared with controls [Ratio of mean expression (RME) = 0.08, P value < 0.001]. This pattern was also detected among female subgroups (RME = 0.06, P value = 0.010), but not among male subgroups (RME = 0.22, P value = 0.114). Expression of SOCS1 was significantly higher in patients with aura compared with those without aura (RME = 5.89, P value = 0.037). Meanwhile, expression of SOCS2 was lower in migraineurs with aura compared with controls (RME = 0.03, P value < 0.001). In addition, this gene was under-expressed in patients without aura compared with controls and in both sex-based subgroups of this group of patients (RME = 0.01, P value < 0.001 for all comparisons). However, its expression was higher in male patients with aura compared with those without aura (P value < 0.001). For SOCS3, we detected a lower level of expression in patients without aura compared with controls (RME = 0.07, P value < 0.001). However, the expression of SOCS3 was higher in patients with aura compared with those without aura (RME = 7.46, P value = 0.001). SOCS5 was down-regulated in patients without aura compared with controls (RME = 0.10, P value < 0.001). Expression of this gene was also lower in patients with aura compared with controls (RME = 0.03, P value < 0.001), and in male patients of this group compared with controls (RME = 0.03, P value = 0.004). On the other hand, expression of SOCS5 was higher in male patients with aura compared with sex-matched patients without aura (RME = 6.67, P value = 0.001). SOCS2 levels could appropriately differentiate migraineurs from healthy subjects. The current study suggests the role of SOCS genes in the pathoetiology of migraine.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immunological disorder. Although the precise pathoetiology of CIDP has not been clarified yet, it is believed that both B and T cells of immune system contribute in this disorder. Based on the importance of human leukocyte antigen (HLA) cluster in the regulation of immune responses, this family of proteins is putative determinants of risk of CIDP. We conducted the current investigation to appraise association between HLA alleles/genotypes/haplotypes and risk of CIDP in Iranian patients. HLA-DQB1*02 allele was significantly more prevalent among cases compared with controls (OR [95% CI] = 4.82 [2.06, 11.3], P value = 0.000215, adjusted P value = 0.0124). A*01-B*52-C*12-DRB1*15-DQB1*02 and A*23-B*35-C*04-DRB1*11-DQB1*03 haplotypes with frequency of 0.03 were the most frequent HLA haplotypes. These haplotypes were not detected among healthy controls. The present study introduces HLA-DQB1*02 allele as a risk allele for CIDP among Iranian patients and further supports the importance of HLA region in this immunological condition.

Background Periodontitis is a chronic inflammatory disorder with a complex etiology. Long non-coding RNAs (lncRNAs) have been shown to affect pathoetiology of periodontitis. We aimed at identification of expression of five lncRNAs, namely Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 in the circulation and gingival tissues of these patients compared with healthy controls. Methods In a pilot case–control study, we compared expressions of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 lncRNAs between blood and tissue samples of patients with periodontitis and healthy controls using real time quantitative PCR technique. The present work was performed on samples got from 26 patients with periodontitis and 28 controls. Female/male ratio was 16/10 and 12/16 in cases and controls, respectively. Results There was no significant difference in the expressions of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 genes between affected and unaffected tissues. However, expressions of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 genes were significantly lower in the blood samples of patients when compared with control samples (Ratio of mean expression = 0.16, 0.14, 0.13, 0.10 and 0.14, respectively). Subsequently, we compared expressions of these lncRNAs between patients and controls in a sex-based manner. Expressions of Linc00667, FENDRR and DIRC3 genes were significantly lower in female patients compared with female controls (RME = 0.09, 0.07 and 0.10, respectively). Yet, there was no significant difference in expression of any of mentioned lncRNAs among male subgroups. Consistent with the similar levels of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 in tissue samples of patients and controls, none of them could separate these two sets of samples. However, AUC values for of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 expression levels in blood samples were 0.66, 0.72, 0.70, 0.72, 0.70 and 0.68, respectively with FENDRR having the best sensitivity value. Conclusion Taken together, lncRNAs might be involved in the pathologic events in the circulation of patients with periodontitis.

Signal Transducer and Activator of Transcription (STAT) pathway is functionally located downstream of Janus kinases proteins and can integrate signals from diverse pathways, thus regulating several aspects of immune responses. Although contribution of STAT proteins in the pathogenesis of several inflammatory conditions has been confirmed, their role in the development of periodontitis has been less appraised. Thus, we assessed levels of STAT transcripts in the periodontal tissues and circulation of affected individuals compared with the corresponding controls. Expression of STAT1 was remarkably lower in tissues samples of patients compared with control tissues (Ratio of mean expression (RME) = 0.15, SE = 0.99, P value = 0.01). Expression of STAT3 was lower in total periodontitis tissues compared with total control tissues (RME = 0.20, SE = 0.95, P value = 0.02). Expression of STAT6 was higher in total periodontitis tissues compared with total control tissues (RME = 0.5.38, SE = 0.74, P value < 0.001). Expressions of other STAT genes were statistically similar in tissues obtained from cases and controls. Moreover, blood levels of all STAT genes were statistically similar between patients and controls. Correlation analysis demonstrated significant correlations between tissues levels of individual STAT genes as well as between their blood levels. However, tissue and blood levels of each STAT gene were not correlated. The current investigation potentiates the role of certain STAT genes in the development of this immune-related condition and warrants functional assays to clarify the mechanism.

Highly up-regulated in liver cancer (HULC) is a cancer-associated long non-coding RNA (lncRNA) which may regulate expression of other genes by working as a competing RNA for microRNAs. In the current study, we assessed transcript levels of this lncRNA in peripheral blood of multiple sclerosis (MS) patients and healthy persons to evaluate its possible role in the pathogenesis of this inflammatory disease and its diagnostic power. The results of Multilevel Bayesian showed no significant difference between cases and controls (P = 0.002, 95% confidence interval (CI) = [3.08, 13.3]). However, based on the results of Quantile regression, there was a significant difference in HULC expression between cases and controls after controlling the effects of sex and age (P = 0.002, 95% CI = [3.08, 13.3]) which shows different trends in males and females. HULC expression was inversely correlated with age of male subjects but not female subjects. HULC transcript levels had 91.1% accuracy in diagnosis of MS disease (Specificity: 80%, Sensitivity: 86.6%). The diagnostic power of HULC was higher in male subjects aged less than 50 years (AUC = 0.923, Specificity: 80%, Sensitivity: 100%). The present study shows the possibility of application of transcript levels of HULC as diagnostic marker in MS disease. However, future studies with larger sample sizes are necessary to validate our results.

The protein inhibitors of activated STAT (PIAS) are involved in regulation of many transcription factors and signaling pathways that contribute to the pathogenesis of bipolar disease (BD). In the current study, we evaluated the expression of four PIAS genes (PIAS1-4) in peripheral blood of BD patients and healthy subjects to explore their contribution in the pathogenesis of BD and their suitability as peripheral biomarkers for this disorder. All PIAS genes were significantly upregulated in total BD patients compared with total controls. The sex-based analysis confirmed upregulation of PIAS1-4 genes in male BD patients compared with male controls (P < 0.001). However, PIAS1 was significantly downregulated in female patients compared with female controls (P = 0.02). Expression levels of other PIAS genes were not significantly different between female patients and female controls. There were no significant correlations between expression levels of PIAS genes and any of the clinical data of study participants after adjustment of the effects of the sex. On the basis of the area under the curve (AUC) values in receiver operating characteristic curves, PIAS4 had the best performance in the differentiation of disease status between study participants (AUC = 0.81). PIAS3 and PIAS4 genes had the best sensitivity and specificity values, respectively. Combination of expression levels of four genes resulted in the improvement of diagnostic power (AUC = 0.82). The current data implies the role of PIAS genes in the pathogenesis of BD and denotes their suitability as peripheral markers for this disorder.

Multiple sclerosis (MS) is a devastating autoimmune disease of the central nervous system associated with demyelination and axonal injury. This study was designed to find potential lncRNAs and their targets that are associated with the molecular basis of MS pathogenesis. In this study, peripheral blood samples were obtained from 50 relapsing-remitting MS (RR-MS) patients and 50 healthy controls. lncRNAs and their target were selected for validation using TaqMan Real-Time PCR. Interactions were studied based on approaches that used to investigation biological functions and signaling pathways affected by differentially expressed messenger RNAs (mRNAs). The results of this study indicate an increase in the expression of HUR1 (p = 0.0001), CPSF7 (p = 0.02), and reduction of CSTF2 expression (p = 0.04). Also, an increase in the expression of OIP5-AS1 (p = 0.01) was observed in men less than 30 years old. We performed a comparative analysis of the long noncoding RNAs (lncRNAs), and then we ranked them as candidate biomarkers according to a decreasing area under the receiver operating characteristic (ROC) curve (AUC) and plotted the results. Dysregulation of lncRNA expression has been linked to diseases. Further studies on the HUR1 gene can be used as diagnostic tools for the identification of high-risk individuals in families with a history of disease before, during, and even after treatment. Our data uncovered the expression profiles of lncRNAs and mRNAs in MS patients, which will help delineate the molecular mechanisms in MS pathogenesis. However, further studies need to determine the precise role of these genes in the pathological process in MS.

Autism spectrum disorders (ASD) are complex neurodevelopmental impairments in which dysregulation of long noncoding RNAs (lncRNAs) has been indicated. LncRNAs tend to play role in constituting comprehensive networks of ribonucleoprotein complexes including argonautes. Here, we aimed to study the expressions of MALAT1, a highly conserved lncRNA, and AGO2 gene, encoding the catalytic component of the RNA-induced silencing complex (RISC), in ASD patients. In this case-control study, peripheral whole blood samples were gathered from 30 ASD patients and 41 healthy controls and expression level of genes were matured by quantitative TaqMan real-time PCR. we found an increase in MALAT1 expression, which was statistically insignificant. Moreover, the AGO2 expression revealed a decrease that did not reach a level of significance. There was a significant and direct correlation between expression levels of MALAT1 and AGO2 (r = 0.427, P

Long non-coding RNAs (lncRNAs) play critical roles in regulation of immunological pathways. Consequently, their expression profile represents new biomarkers for susceptibility and progression of immunological disorders. However, their role in chronic inflammatory diseases such as multiple sclerosis (MS) remained unknown. Here, we assessed the expression of lncRNAs MALAT1 and HOTAIRM1 as well as their target genes in peripheral blood of MS patients to show their possible roles in disease initiation and progression. In this study, 50 patients with relapsing-remitting MS and 50 healthy matched controls were enrolled. Comparative Ct method via TaqMan assay was used to quantify transcript levels of MALAT1, HOTAIRM1, AGO2, CSTF2, CPSF7, and WDR33. Our analysis depicted significant differences in lncRNAs and their target genes expression levels. AGO2 expression was significantly elevated in MS patients (P

Objectives Protein inhibitors of activated STAT (PIAS) are transcription co-regulator of the Janus kinase/signal transducer and activator of transcription signaling pathway as well as nuclear factor-κB family of transcription factors. Both of them are involved in cytokine release during inflammatory response. Patients and methods Considering the role of cytokine imbalance in the pathogenesis of multiple sclerosis (MS), we compared blood expressions of PIAS1-4 genes in 48 interferon β (IFNβ)-treated MS patients with those of healthy subjects by means of real time PCR. Results Although the expression levels of these genes were not significantly different between MS patients and healthy subjects, significant inverse correlations have been found between PIAS1 expression and age at disease onset. PIAS2 and PIAS3 expressions were inversely correlated with Expanded Disability Status Scale (EDSS) in patients. Moreover, PIAS3 expression was correlated with disease duration in patients and with age in controls. In addition, PIAS4 expression was inversely correlated with EDSS and age at disease onset while it was positively correlated with disease duration. Conclusion The present study provides evidences for altered expression of PIAS genes in IFNβ-treated MS patients compared with healthy subjects. However, future studies are needed for elaboration of their exact function in this disorder.

The β-site APP-cleaving enzyme 1 (BACE1) is the principal enzyme in the cleavage of amyloid precursor protein. It participates in the pathogenesis of neurologic disorders such as Alzheimer's disease and multiple sclerosis (MS). More recently, the naturally occurring antisense for this transcript (BACE1-AS) has been shown to stabilize the expression and function of BACE1. In the present study, we assessed expression of BACE1 and BACE1-AS in peripheral blood of 50 MS patients who were responsive to IFNβ-1a treatment and 50 healthy subjects by means of real time PCR. We found neither significant difference in their expression levels between MS patients and healthy subjects nor any correlations between their expression levels and patients' characteristics. However, we detected a significant correlation between transcript levels of BACE1 and BACE1-AS both in patients and healthy subjects which is in line with the proposed role for BACE1-AS in stabilization of BACE1. The similar expression patterns of BACE1 and BACE1-AS in MS patients and healthy subjects might be due to the effect of IFNβ-1a treatment on their expression. So, future studies are needed to elaborate the underlying mechanism of this observation.

Protein inhibitors of activated STAT (PIAS) are involved in the regulation of the JAK/STAT signaling pathway and have interactions with NF-κB, p73 and p53. These proteins regulate immune responses; therefore dysregulation in their expression leads to several immune-mediated disorders. In the present study, we examined expression of PIAS1-4 in peripheral blood of patients with acute/chronic inflammatory demyelinating polyradiculoneuropathy (AIDP/CIDP) compared with healthy subjects. We demonstrated down-regulation of all PIAS genes in both AIDP and CIDP cases compared with controls. Similarly, comparisons in gender-based groups revealed down-regulation of these gene0s in patients of each gender compared with gender-matched controls. There was no significant difference in expression of PIAS genes between AIDP and CIDP cases. Based on the area under the receiver operating characteristic curves, PIAS1-4 genes could distinguish between inflammatory demyelinating polyradiculoneuropathy and healthy status with accuracy values of 0.87, 0.87, 0.79 and 0.80, respectively. In differentiation between AIDP cases and healthy controls, these values were 0.92, 0.92, 0.83 and 0.86, respectively. Finally, PIAS1-4 genes could discriminate CIDP from healthy status with accuracy values of 0.82, 0.83, 0.75 and 0.75, respectively. The current study underscores the role of PIAS genes in the pathogenesis of inflammatory demyelinating polyradiculoneuropathy and their potential usage as biomarkers.

Inflammatory demyelinating polyradiculoneuropathies are a group of peripheral nerve system disorders in which immune reactions are dysregulated. Cytokines have noticeable roles in the regulation of these responses. We compared transcript levels of nine cytokine coding genes namely IL-1B, IL-2, IL-4, IL-6, IL-8, IL-17A, IFN-G, TGF-B and TNF-A in the peripheral blood of patients with acute and chronic kinds of this condition (AIDP and CIDP) and healthy persons. Expression of IL-17A was significantly lower in female AIDP cases compared with female controls (Expression Ratio = 0.02, P value = 0.02). Expression of this cytokine was higher in female CIDP cases compared with female AIDP cases (Expression ratio = 65.69, P value = 0.02). Moreover, expression of IL-6 tended to be diminished in female AIDP cases compared with normal females (Expression Ratio = 0.06, P value = 0.05). Expression of TGF-B was lower in female AIDP cases compared with female controls (Expression Ratio = 0.06, P value = 0.01). Transcript amounts of IL-1B were lower in whole CIDP cases compared with whole controls and in female AIDP cases compared with female controls (Expression Ratios = 0.09 and 0.00; P values = 0.04 and 0.01, respectively). Expression of this gene was considerably increased in female CIDP cases compared with female AIDP cases (Expression Ratio = 764.10, P value = 0.02). Finally, expression of this gene was lower in total cases compared with total controls (Expression ratio = 0.19, P value = 0.03). Diagnostic power of IL-4 was estimated to be 0.7 in differentiating between CIDP cases and controls. IL-1B had the diagnostic power of 0.72 in distinguishing between ADP cases and controls. Finally, TNF-A had the diagnostic power of 0.71 in differentiating between AIDP cases and CIDP cases. The current results suggest the possible role of these cytokines in the pathogenesis of inflammatory demyelinating polyradiculoneuropathies.

Background Coronavirus disease 2019 (COVID-19) has been shown to cause serious health problems among them is the Acute Respiratory Distress syndrome (ARDS). Vitamin D receptor (VDR) signaling possibly partakes in the pathophysiology of this devastating complication. Methods In the current project, we have appraised expression levels of VDR, CYP27B1 and a number of associated lncRNAs in the circulation of COVID-19 patients versus healthy subjects using real-time PCR method. Results Expression of SNHG6 was considerably lower in COVID-19 patients compared with control subjects (Ratio of mean expression (RME) = 0.22, P value = 7.04E-05) and in both female and male COVID-19 patients compared with sex-matched unaffected individuals (RME = 0.32, P value = 0.04 and RME = 0.16, P value = 0.000679683, respectively). However, its expression was similar among ICU-hospitalized and non-ICU patients. Similarly, expression of SNHG16 was lower in in COVID-19 patients compared with controls (RME = 0.20, P value = 5.94E-05) and in both female and male patients compared with sex-matched controls (RME = 0.32, P value = 0.04 and RME = 0.14, P value = 0.000496435, respectively) with no significant difference among ICU-hospitalized and non-ICU hospitalized patients. Expression of VDR was lower in COVID-19 patients compared with controls (RME = 0.42, P value = 0.04) and in male patients compared with male controls (RME = 0.27, P value = 0.02). Yet, expression of VDR was statistically similar between female subgroups and between ICU-hospitalized and non-ICU hospitalized patients. Expression levels CYP27B, Linc00511 and Linc00346 were similar among COVID-19 patients and healthy subjects or between their subgroups. Significant correlations have been detected between expression levels of VDR, CYP27B and SNHG6, SNHG16, Linc00511 and Linc00346 lncRNAs both among COVID-19 patients and among healthy controls with the most significant ones being SNHG6 and SNHG16 (r = 0.74, P value = 3.26e-17 and r = 0.81, P = 1.54e-22, respectively). Conclusion Combination of transcript levels of VDR, CYP27B and SNHG6, SNHG16, Linc00511 and Linc00346 could differentiate patients from controls with AUC = 0.76, sensitivity = 0.62 and specificity = 0.81. The current data potentiate SNHG6, SNHG16 and VDR as possible contributors in COVID-19 infection but not in the severity of ARDS.

Long non-coding RNAs (lncRNAs) have been shown to alter immune responses, thus contributing to the pathobiology of autoimmune conditions. We investigated the expression levels of ANRIL, PICART1, MALAT1, CCAT1, CCAT2, and CCHE1 lncRNAs in acute and chronic inflammatory demyelinating polyneuropathy (AIDP and CIDP). ANRIL, PICART1, MALAT1, CCAT1, CCAT2, and CCHE1 lncRNAs were significantly downregulated in individuals with both AIDP and CIDP compared with unaffected individuals. Gender-based comparisons also verified such downregulations in both male and female subjects compared with sex-matched unaffected controls for all lncRNAs. There was no significant difference in the expression of any of the lncRNAs between cases with AIDP and cases with CIDP. While the expression levels of ANRIL and PICART1 were significantly correlated in healthy subjects (r = 0.86, p = 8.5E-16), similar analysis in cases with AIDP and CIDP revealed no significant correlation. The most robust correlation among patients was detected between ANRIL and MALAT1 lncRNAs (r = 0.59, p = 3.52E-6). ANRIL, MALAT1, and PICART1 had the diagnostic power of 0.96, 0.94, and 0.92 in distinguishing between cases with CIDP and controls, respectively. A combination of all lncRNAs resulted in 0.95 diagnostic power with a sensitivity of 0.85 and specificity of 0.96 for this purpose. Diagnostic power values of these lncRNAs in differentiation between cases with AIDP and controls were 0.98, 0.95, and 0.93, respectively. The combinatorial diagnostic power reached 0.98 for differentiation between cases with AIDP and controls. The six-lncRNA panel could differentiate combined cases with AIDP and CIDP from controls with area under the curve (AUC), sensitivity, and specificity values of 0.97, 0.90, and 0.96, respectively. Collectively, the lncRNA panel is suggested as a sensitive and specific diagnostic panel for acquired immune-mediated polyneuropathies.

Immune-related genes have essential roles in the pathobiology of periodontitis. In the current projects, we aimed at appraisal of the expression amounts of three immune-related genes including two mRNA coding genes (NR3C1 and CSTF2) and a long non-coding RNA (CCAT2) in tissue sections and blood of patients with this condition versus healthy controls. Our previous study has shown the susceptibility role of HLA-DRB1*04 allele in development of this disease. So the subjects who were positive for HLA-DRB1*04 allele were excluded. Expression amounts of CCAT2, NR3C1 and CSTF2 genes have been statistically similar between periodontitis patients and controls in both blood samples and tissue samples. Expression levels of CCAT2, NR3C1 and CSTF2 genes have been significantly correlated in blood samples as well as in tissue samples. However, there was no significant correlation between tissue and blood levels of each gene. Expression levels of CCAT2, NR3C1 and CSTF2 genes in blood or tissue sections could not appropriately distinguish patients with periodontitis from healthy subjects. The best AUC values have been displayed for CCAT2 and CSTF2 genes in blood samples (AUC = 0.71). Our study indicates that CCAT2, NR3C1 and CSTF2 genes are not important factors in the development of periodontitis and cannot be used as biomarkers for this condition.

Migraine is a prevalent disorder in humans and represents one of the top 10 causes of years lived with disability. Several genetic and environmental factors are involved in the pathobiology of migraine. A number of studies have underscored the role of dysregulated immune reactions. We compared the expression levels IL-2, IL-4, CXCL8, IL-17, IFN-γ, TGF-β and TNF-α cytokines in blood specimens of patients with migraine and those of healthy persons to identify any possible dysregulation in their expression and to propose mechanisms for this disorder. Expression of INF-γ was suggestively higher in migraine cases than in healthy individuals (posterior beta = 0.35, adjusted P value = 0.017). In addition, expression of this cytokine was lower in female subjects than in male subjects (posterior beta = −0.712, adjusted P value = 0.012). Expression of IL-4, TGF-β and TNF-α was also higher in cases compared with controls (posterior beta = 1.34, adjusted P value = 0.04; posterior beta = 0.849, adjusted P value = 0.036; posterior beta = 0.451, adjusted P value = 0.042, respectively). On the other hand, CXCL8 expression was lower in migraine cases than in controls (posterior beta = −0.78, adjusted P value = 0.039). Expression levels of IL-1B, IL-17 and IL-2 were not meaningfully different between cases and controls. The current study highlights the dysregulation of cytokine-coding genes in the blood of patients with migraine.

Periodontitis is a bacteria-related chronic immune-associated condition that destructs bone and connective tissues around teeth. With a high incidence rate, it is regarded as a condition that impose substantial health burden. About half of the variance in the severity of periodontitis is attributed to genetic factors. Long non-coding RNAs (lncRNAs) have crucial roles in the development of several disorders such as periodontitis. A number of studies have reported dysregulation of lncRNAs such as UCA1, ANRIL, FGD5-AS1, NEAT1, FAS-AS1, Linc-RAM and NKILA in gingival tissues or blood samples of patients with periodontitis in comparison with healthy subjects. Moreover, several single nucleotide polymorphisms within lncRNAs have been associated with the susceptibility to this disorder. In the current review, we discuss the most recent articles about the role of lncRNAs in the pathogenesis of periodontitis.

Long non-coding RNAs (lncRNAs) have regulatory roles in several aspects of cellular physiology. Recent studies have also revealed their role in neuronal differentiation and the pathophysiology of neurologic disorders such as epilepsy. We have recently reported altered expression of a number of lncRNAs in the peripheral blood of epileptic patients in association with their response to antiepileptic drugs. One the most significantly altered lncRNAs in epileptic patients is the antisense non-coding RNA in the INK4 locus (ANRIL), whose expression has been found to be higher in both refractory and non-refractory groups compared with controls. In the current study, we aimed to identify the methylation status of this lncRNA to suggest a potential mechanism for deregulated ANRIL expression. Thus, we assessed the methylation status of the ANRIL promoter in 40 patients with refractory epilepsy, 40 patients with non-refractory epilepsy and 40 normal controls using the high-resolution melting (HRM) method. The HRM results showed hypomethylation of the ANRIL promoter region in both refractory epilepsy and non-refractory epilepsy patients compared with normal controls. This methylation pattern was consistent with the recently reported upregulation of this lncRNA in patients with epilepsy. Thus, we suggest altered methylation of the ANRIL promoter as a potential cause of its aberrant expression in peripheral blood of epileptic patients.

A number of recent studies have shown dysregulation of some long non-coding RNAs (lncRNAs) in affected tissues or peripheral blood of patients with periodontitis. In the current study, we investigated the role of TNF and HNRNPL related immunoregulatory (THRIL) and p50-associated COX-2 extragenic RNA (PACER) lncRNAs in periodontitis. We assessed expression of these lncRNAs in 30 affected tissue, 30 control tissue samples, 23 blood samples from patients and 18 blood samples from healthy controls. Expression of PACER was higher in total blood samples of patients compared with controls (Posterior beta of RE = 5.143, P value = 0.001). However, when assessing its expression in a gender-based manner, the difference in the expression of this lncRNA was significant only among male subgroups (Posterior beta of RE = 7.16, P value < 0.0001). Moreover, expression of PACER was significantly higher in female subjects compared with male subjects (Posterior beta of RE = 3.098, P value < 0.0001). There was no significant difference in tissue expression of PACER between study subgroups. Expression of THRIL was not significantly different between blood/tissue samples of cases and controls. However, expression of this lncRNA was higher in blood of female subjects compared with male subjects (Posterior beta of RE = 4.353, P value = 0.002). Tissue expression of THRIL was correlated with blood levels of this lncRNA (r = 0.33, P < 0.0001) and with the tissue levels of PACER (r = 0.3, P < 0.0001). Moreover, blood levels of these lncRNAs were correlated with each other (r = 0.34, P < 0.0001). However, there was no significant correlation between blood and tissue levels of PACER. Expression of these lncRNAs were not correlated with age either in males or in females. Taken together, we demonstrated a sex-based up-regulation of PACER in blood samples of patients with periodontitis which implies possible participation of this lncRNA in the pathobiology of periodontitis., Cell biology; Molecular biology; Biocomputational method; Inflammation; Gene expression; Biomolecules; Genetic disorders; Immune disorder; THRIL, PACER, lncRNA, Periodontitis.

Fanconi anemia includes a number of clinically and genetically diverse disorders all of them being associated with genomic instability. Some previous studies reported higher frequencies of certain HLA alleles in patients with Fanconi anemia. In the current study, we genotyped HLA-A/B/DRB1 alleles in 40 Iranian patients with Fanconi anemia. We also genotyped these alleles in the same number of Iranian sex-matched healthy individuals. The frequency of DRB1*11 was significantly higher in patients compared with controls (OR (95% CI) = 2.143 [1.05, 4.46], P value = 0.036). On the other hand, the frequencies of DRB1*13 and B*13 were lower in patients compared with controls (OR (95% CI) = 0.134 [0.02, 0.55], P value = 0.003 and OR (95% CI) = 0.13 [0.01, 0.89], P value = 0.035, respectively). Assessment of genetic divergence using Fstat test showed complete divergence in HLA-A, -B, -DRB1 alleles and haplotypes between patients and controls. The current study provides evidences for different distribution of HLA alleles between patients with Fanconi anemia and healthy subjects.

Recent studies have shown contribution of long non-coding RNAs (lncRNAs) in the pathogenesis of a number of psychiatric disorders. In the current study, we investigated the association between a single nucleotide polymorphism in the lncRNA HOX transcript antisense intergenic RNA (HOTAIR) and risk of diverse neuropsychiatric conditions in Iranian population. The selected polymorphism (rs1899663) is an intronic variant of this lncRNA which has been associated with several cancers in different populations. This SNP was genotyped in 323 individuals with methamphetamine addiction, 55 children with attention-deficit hyperactive disorder (ADHD), 138 patients with bipolar disorder 1 (BPD1), 86 patients with BPD2, 53 patients with major depressive disorder (MDD), and 194 patients with schizophrenia (SCZ). There was no significant association between rs1899663 genotypes and risk of methamphetamine addiction or SCZ in any assessed inheritance model. There was a significant association between rs1899663 SNP and risk of BPD1 in allelic, co-dominant, and dominant models (P values of 0.003, 0.009, and 0.003, respectively). The T allele of this SNP conferred risk of BPD1 (OR (95% CI) = 1.70 (1.20–2.41)). This SNP was associated with risk of BPD2 in allelic and dominant models (P values of 0.02 and 0.04). The T allele of this SNP was revealed to be the risk allele for BPD2 as well (OR (95% CI) = 1.61 (1.09–2.40)). Besides, the mentioned SNP was associated with susceptibility to MDD in allelic and dominant models (P values of 0.01 and 0.03). Finally, the rs1899663 was associated with risk of ADHD in allelic, co-dominant, and dominant models (P values of 3.6E-4, 0.002, and 1.2E-4, respectively). The current investigation highlights the role of rs1899663 in conferring risk of BPD1, BPD2, MDD, and ADHD and suggests a similar underlying genetic background for these conditions.

Arezou Sayad,1 Mohammad Taghi Akbari,2 Rezvan Noroozi,3 Mir Davood Omrani,1,4 Hidetoshi Inoko,5 Mohammad Taheri,6 Soudeh Ghafouri-Fard1 1Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 2Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; 3Photochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 4Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 5Department of Molecular Life Science, Tokai University, Hiratsuka, Japan; 6Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran Background: Autism spectrum disorders (ASD) are a group of heterogeneous neurodevelopmental disorders known by impaired social interaction and activities and abnormal repetitive behavior. As a multifactorial disorder, several genetic and immunological factors have been shown to be implicated in its pathogenesis. Methods: Among them are certain human leukocyte antigen (HLA) alleles. In the current study, we genotyped HLA-A, -B & DRB alleles in 103 Iranian ASD patients and 180 age, gender, and ethnic-matched healthy controls. Results: After Boferroni correction no allele or haplotype was associated with genetic susceptibility to ASD in Iranian population. Conclusion: Future studies are needed to assess contribution of immunological factors such as HLA alleles in ASD pathogenesis. Keywords: autism, HLA typing, immune response

Fateme Asadzadeh Manjili,1 Seyed Mehdi Kalantar,2 Shahram Arsang-Jang,3 Soudeh Ghafouri-Fard,4 Mohammad Taheri,4,5 Arezou Sayad4 1Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; 2Reproductive and Genetic Unit, Recurrent Abortion Research Center, Yazd Reproductive Science Institute, Yazd University of Medical Sciences, Yazd, Iran; 3Clinical Research Development Center (CRDU), Qom University of Medical Sciences, Qom, Iran; 4Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 5Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Introduction: Low level of vitamin D is a potential risk factor for developing schizophrenia. Through interaction with its receptor (VDR) and the related enzymes (CYP27B1, CYP24A1), vitamin D modulates neurodevelopment, neuroprotection, and immunomodulation. Its deficiency leads to aberrant neurodevelopment in schizophrenic patients. Methods: In this case–control study, relative expression of VDR, CYP27B1, and CYP24A1 in schizophrenic patients was compared with healthy individuals. Total RNA was extracted from whole blood of 50 patients with schizophrenia and 50 healthy controls. Real-time PCR was used to determine relative gene expression levels of VDR, CYP27B1, and CYP24A1. Results: Significant upregulations were observed in VDR (P=0.004, 95% CI=0.77, 0.86), CYP27B1 (P=0.002, 95% CI=1.22, 4.98), and CYP24A1 (P≤0.0001, 95% CI=-2.721, 1.061) expressions in peripheral blood of schizophrenic patients compared with controls. Moreover, the gender-based analysis revealed upregulation of all genes in all the categories of male and female except for VDR gene in male group (P=0.234, 95% CI=-0.79, 3.35) and CYP27B1 gene in the female group (P=0.09, 95% CI=-0.21, 6.55). The age-based analysis demonstrated overexpression of VDR and CYP27B1 genes in all categories. Finally, there were significant correlations between expression levels of all genes (P

Multiple sclerosis (MS) is a chronic autoimmune disorder in which dysregulation or aberrant expressions of several immune-related genes have been noted. More recently, the participation of long non-coding RNAs (lncRNAs) in regulation of immune responses has been highlighted. In the present study, we evaluated expression levels of three lncRNAs named Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), P21 associated ncRNA DNA damage activated (PANDA) and Taurine-up-regulated gene 1 (TUG1) in peripheral blood of 50 relapsing-remitting MS patients and 50 matched healthy subjects. All three lncRNAs have been significantly over-expressed in MS patients compared with healthy subjects. In addition, significant correlations were found between expression levels of these three lncRNAs in the patients group. NEAT1 expression was inversely correlated with age at onset and disease duration in female patients. Moreover, TUG1 expression was inversely correlated with disease duration in female patients. The present study provides further evidences for the role of lncRNAs in pathogenesis of MS.

Epilepsy is a chronic disorder in which immune dysregulation is shown to be involved. Imbalances in the cytokine levels both in serum and brain tissue have been demonstrated in epileptic patients. In the present study, we assessed mRNA expression of TNF-α, TGF-β, IFN-γ, CXCL8, IL-1β, IL-2, 1L-4, IL-6, IL-17 and CXCL8 in blood samples of 40 epileptic patients compared with age- and sex-matched healthy controls by means of quantitative real time PCR. The relative levels of CXCL8 transcripts were significantly higher in total epileptic patients compared with healthy subjects (P = .023). Relative mRNA expression of IFN-γ was significantly higher in female patients compared with female healthy subject (P = .048). In addition, significant correlations have been found between the mRNA levels of mentioned cytokines. Such imbalance between expression of pro-inflammatory and anti-inflammatory cytokines might be implicated in the pathogenesis of epilepsy.

Hereditary spastic paraplegia (HSP) includes a number of inherited disorders which are characterized by stiffness in the lower extremities and progressive gait disturbance. Mutations in terms of spastic gait genes (SPGs) are responsible for occurrence of different types of HPS with autosomal recessive, X-linked recessive, and autosomal dominant modes of inheritance. In the current case report, we identified a mutation in SPG11 gene in a female patient with progressive stiffness of lower extremities and atrophy of corpus callosum and the “lynx ear” sign in brain MRI. Whole exome sequencing (WES) revealed a homozygote frameshift deletion variant in SPG11 gene (NM001160227: exon 28: c.4746delT, p.N1583Tfs*23). This variant is a null variant classified as a pathogenic variant (PVS1) according to ACMG standards and guidelines. The frequency of this variant in 1000G, ExAC, and Iranome databases was 0. This study shows the role of WES in the identification of disease-causing mutations in a disease such as HSP which can be caused by diverse mutations in several genes.

Beta-secretase 1 (BACE1) gene encodes a transmembrane protease from the peptidase A1 family of aspartic proteases whose role in the pathogenesis of Alzheimer's disease has been assessed. The enzymatic activity of BACE1 on several proteins implicated in epileptogenesis implies its role in the pathogenesis of epilepsy. In the present study, we assessed expression of BACE1 and its naturally occurring antisense (BACE1-AS) in peripheral blood of 40 epileptic patients and 40 age- and sex-matched healthy subjects. We did not detect either any difference in the expression of these genes between cases and controls or significant correlation between their expressions and participants' age. However, we demonstrated a significant correlation between expression levels of BACE1 and BACE1-AS which supports the previously suggested feed-forward mechanism of regulation between these two transcripts. Future studies in larger sample sizes are needed to elaborate the function of BACE1 in epilepsy.

Multiple sclerosis (MS) is a complex inflammatory, autoimmune disease of the central nervous system (CNS). The disease pathogenesis is not well defined yet. Cytokines have an important role in inflammation as characteristic feature of the disease. Janus kinase/signal transducers and activators of transcriptions (JAK/STAT) family promote cytokine-mediated cell activation. Failure in the JAK/STAT signaling pathway is associated with the pathological outcome in MS. In this study, we compared the expression levels of STAT5a and STAT6 genes in the blood of 50 relapsing-remitting MS (RR-MS) patients and 50 healthy controls by Taqman Quantitative Real-Time PCR in patients and healthy control group. We found that STAT5a expression was significantly down-regulated (p = .049), whereas STAT6 gene expression was significantly up-regulated (p = .046) in MS patients compared with controls. Moreover, there was significant correlation between the STAT6 gene expression and Kurtzke Expanded Disability Status Scale (EDSS) criterion. However, no significant correlation was demonstrated between the expression of STAT5a gene and clinical findings. Furthermore, there was not significant correlation between expression levels of STAT5a and STAT6 genes. Our findings suggest that STAT5a and STAT6 dysregulation may have a critical role in modification of immune responses leading to imbalance between Th2- and Th1-related cytokines. However, the mechanisms underlying it still remain to be elucidated. Future studies are needed to explore the role of STAT5a and STAT6 as prognostic biomarkers in research, design of experimental therapies or clinical settings of the MS.

Background Multiple sclerosis (MS) is a complex immune-related disorder of the central nervous system (CNS) in which dysregulation of different classes of T cells are involved. Variants in Ecotropic Viral Integration Site 5 (EVI5) gene has been shown to be significantly associated with MS in different populations. Objectives However, there is no data regarding relative expression of this gene in peripheral blood of MS patients compared with healthy controls. Methods In the present study we assessed expression of EVI5 in 50 Iranian MS patients compared with healthy subjects by means of quantitative real time RT-PCR. Results Statistical analyses showed no significant difference in EVI5 relative expression neither between total MS patients and healthy controls nor between age- and sex-based subgroups of patients and controls except for a trend toward significance in patients aged between 30 and 40 years compared with healthy subjects in both sexes (P= 0.068 and 0.075 for males and females respectively). No significant correlation was found between the expression level of this gene and disease duration, age at onset or Expanded Disability Status Scale (EDSS). Conclusion Future studies are needed to explore the role of EVI5 in the pathogenesis of MS.

Multiple sclerosis (MS) is a chronic inflammatory disorder with several genetic and environmental factors being implicated in its pathogenesis. Protein prenylation as one of the important posttranslational modifications of proteins has crucial role in immune system regulation. In the current case–control study, we compared expression of five genes coding for the different subunits of proteins implicated in protein prenylation in 50 Iranian MS patients with those of healthy subjects. No significant difference has been found in FNTA and PGGT1B expressions between cases and controls. Spearman correlation analysis between FNTA relative expression and disease duration showed significant correlation in male patients (r = − 0.671, P = 0.024) but not female patients (r = 0.253, P = 0.12). FNTB expression was significantly higher in MS patients compared with healthy subjects. Spearman correlation analysis between FNTB relative expression and disease duration showed significant correlation in male patients (r = −0.876, P = 0.004) but not female patients (r = 0.296, P = 0.06). RABGGTA was significantly upregulated in total MS patients, total male patients, female patients aged between 30 and 40 and male patients aged >40 compared with corresponding control groups. RABGGTB was significantly downregulated in total MS patients, total female patients, and female patients aged > 40 compared with corresponding control groups. Totally, we demonstrated dysregulation of protein prenylation pathway in MS patients compared with healthy subjects. Future studies are needed to find the clinical implication of this pathway in MS patients.

Objective Several previous linkage and association studies and an expression analysis have suggested the gamma-aminobutyric acid type A receptor beta3 subunit (GABRB3) gene as an important candidate gene for autism. In addition, polymorphisms in the promoter region of GABRB3 might modulate the expression of this gene. In order to investigate the underlying mechanism of the role of GABRB3 in autism susceptibility, we designed a case-control study to analyze the association of the rs4906902 single nucleotide polymorphism (SNP) in the promoter region of the GABRB3 gene with autism spectrum disorder (ASD) in Iranian patients. Materials & methods The rs4906902 polymorphism was genotyped using the polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) technique. The frequency of the risk allele and its association with disease was examined in 518 patients and 472 control individuals. Result The results demonstrated that the genotype frequencies were in Hardy-Weinberg equilibrium in both the case and the control groups. The results shown that neither allelic frequencies nor genotypic distribution of the rs4906902 was significantly different between autism patients and healthy controls. In conclusion It seems that the GABRB3 gene may influence the Autism susceptibility via a different SNPs in this gene. Also, another independent mechanisms like epigenetic effects should not be ignored when we want to explore the link between GABRB3 and ASD.

Background Multiple sclerosis (MS) as an auto-immune disease is an inflammatory, demyelinating disease of the central nervous system. Certain genes have shown to be involved in the initiation of MS but the specific role of some of them, e.g. IFNAR1 has not been identified in certain populations yet. Objective The IFNAR1 as a type I membrane protein shapes one of the two chains of a receptor for interferons alpha and beta. Methods To find out how IFNAR1 functions in the Iranian population, the researchers compared the expression level of this gene in relapsing-remitting MS (RR-MS) samples with normal individuals. RNA from the whole blood of 50 RR-MS patients and 50 normal controls were extracted. All patients were HLA-DRB1*15 negative and were responders to interferon-beta with a normal vitamin D level. The level of IFNAR1 gene expression was measured using quantitative RT-PCR. Results According to the results the RR-MS patients manifested a statistically higher expression level of IFNAR1 than their normal counterparts (p= 0.012). Age-wise, females between the ages, 30 to 40 had a significant increase (p= 0.046) but males under 30 showed a statistically meaningful decrease in the expression level (p= 0.04). In terms of sex, only the female patients manifested a statistically significant increase in IFNAR1 (p= 0.004). Conclusions The overall results show an increase in IFNAR1 level in MS patients treated with IFN-B.

This study aimed to examine the expression of TYK2, CBLB and LMP7 genes at both mRNA and protein levels in relapsing-remitting MS (RRMS) patients in compare with healthy controls. Seventy-eight RRMS patients treated with IFNβ-1a and 79 age- and ethnic-matched healthy subjects were studied. The mRNA expression levels of TYK2, CBLB and LMP7 in PBMCs were quantified by real-time PCR and plasma concentrations of three molecules were measured by ELISA. Results were compared between patients and controls, IFNβ-responders and non-responders. Forty-nine of 78 patients were classified as IFNβ-responders and 29 cases were non-responders. Significantly down-regulated expression of TYK2, CBLB and LMP7 genes was found in the patients group versus controls (P0.001). Decreased plasma levels of three molecules were observed in patients compared to controls (P0.001). IFNβ-responders had significantly higher expressions for CBLB (P=0.001) and LMP7 (P=0.02) than non-responders. Also, we observed increased expressions of LMP7 (P=0.39) and CBLB (P=0.02) genes in patients under 30y and increased expression of TYK2 in patients40years (P=0.002). Our results suggest that expression analysis of TYK2, CBLB and LMP7 genes could be useful for evaluation of T cells immunity and clinical response to IFNβ-therapy in RRMS patients.