A Comprehensive Overview of NF1 Mutations in Iranian Patients.

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations in the NF1 gene. This disorder shows nearly complete penetrance and high phenotypic variability. We used the whole-exome sequencing technique to identify mutations in 32 NF1 cases from 22 Iranian families. A total of 31 variants, including 30 point mutations and one large deletion, were detected. In eight cases, variants were inherited, while they were sporadic in the remaining. Seven novel variants, including c.5576 T > G, c.6658_6659insC, c.2322dupT, c.92_93insAA, c.4360C > T, c.3814C > T, and c.4565_4566delinsC, were identified. The current study is the largest in terms of the sample size of Iranian NF1 cases with identified mutations. The results can broaden the spectrum of NF1 mutations and facilitate the process of genetic counseling in the affected families.

miR-196a in the carcinogenesis and other disorders with an especial focus on its biomarker capacity.

miR-196a has important roles in the pathoetiology of different disorders ranging from non-malignant to malignant ones. This miRNA is transcribed from two genomic loci, namely HOXC and HOXB on human chromosomes 12 and 17, respectively. The current study aims to summarize the role of miR-196a in different disorders. In the most conducted studies in the framework of cancer, miR-196a has been identified as an oncogene. However, few studies are not conformed to this concept. In head and neck, lung, oral and pancreatic cancers, miR-196a is a possible diagnostic marker. In addition, it has a possible role in the pathoetiology of diabetic nephropathy, Huntington's disease, idiopathic male infertility, keloid, chronic kidney disease and spinal and bulbar muscular atrophy; and is regarded as a biomarker for focal segmental glomerulosclerosis and chronic kidney disease. We aim to recapitulate the role of miR-196a in different malignant and non-malignant disorders.

CRISPR/Cas9 gene editing: a novel strategy for fighting drug resistance in respiratory disorders.

Respiratory disorders are among the conditions that affect the respiratory system. The healthcare sector faces challenges due to the emergence of drug resistance to prescribed medications for these illnesses. However, there is a technology called CRISPR/Cas9, which uses RNA to guide DNA targeting. This technology has revolutionized our ability to manipulate and visualize the genome, leading to advancements in research and treatment development. It can effectively reverse epigenetic alterations that contribute to drug resistance. Some studies focused on health have shown that targeting genes using CRISPR/Cas9 can be challenging when it comes to reducing drug resistance in patients with respiratory disorders. Nevertheless, it is important to acknowledge the limitations of this technology, such as off-target effects, immune system reactions to Cas9, and challenges associated with delivery methods. Despite these limitations, this review aims to provide knowledge about CRISPR/Cas9 genome editing tools and explore how they can help overcome resistance in patients with respiratory disorders. Additionally, this study discusses concerns related to applications of CRISPR and provides an overview of successful clinical trial studies.

Differential expression of cancer-related lncRNAs in different subtypes of pituitary adenomas.

Recent investigations have demonstrated abnormal expression of non-coding RNAs in pituitary adenomas. Cntribution of many lncRNAs to the pathogenesis of these tumors has not been evaluated yet. HOTTIP, ANRIL, PANDAR, PCGEM1 and HOTAIR are among lncRNAs with established roles in the pathogenesis of human cancers, particularly those originated from endocrine organs. The current study aims at assessment of expression of these lncRNAs in pituitary adenomas in comparison with the adjacent non-cancerous pituitary tissues. HOTAIR expression was absent from the majority of adenoma and non-tumoral samples. Expression of HOTTIP was significantly higher in non-functioning pituitary adenoma (NFPA) samples compared with paired normal samples (expression ratio (95 % CI)= 2.1 (1.13-2.1), P value=0.03). Expression of PANDAR was higher in total adenoma samples compared with paired normal samples (expression ratio (95 % CI)= 1.91 (1.16-3.13), P value=0.02). Expression of ANRIL was higher in NFPA samples compared with paired normal samples (expression ratio (95 % CI)= 1.94 (1.05-3.6), P value=0.048) and in total adenoma samples compared with paired normal samples (expression ratio (95 % CI)= 1.82 (1.11-2.98), P value=0.025). The current study raises the possibility of contribution of lncRNAs in the pathogenesis of at least some subtypes of pituitary adenomas and warrant further functional studies in this field.

Expression analysis of necroptosis related genes and lncRNAs in patients with pituitary neuroendocrine tumors.

Necroptosis can either be the cause of tumorigenesis or it can impede its process. Recently, it has been proved that long non-coding RNAs (lncRNAs) have different crucial roles at cellular level, especially on cell death. Regarding the important role of necroptosis and lncRNAs in the pathogenesis of different cancers, especially pituitary adenomas (PAs), we assessed expression levels of two necroptosis related genes, namely TRADD and BIRC2, in addition to three related lncRNAs, namely FLVCR1-DT, MAGI2-AS3, and NEAT1 in PAs compared with adjacent normal tissues (ANTs). TRADD had no significant difference between two groups; however, BIRC2, FLVCR1-DT, MAGI2-AS3, and NEAT1 were upregulated in PAs compared to ANTs (Expression ratios [95% CI] = 2.3 [1.47-3.6], 2.13 [1.02-4.44], 3.01 [1.76-5.16] and 2.47 [1.37-4.45], respectively). When taking into account different types of PAs, significant upregulation of BIRC2, MAGI2-AS3 and NEAT1 was recorded in non-functioning PAs compared with corresponding ANTs (Expression ratios [95% CI] =1.9 [1.04-3.43], 2.69 [1.26-5.72] and 2.22 [0.98-5.01], respectively). Additionally, higher levels of BIRC2 were associated with higher flow of CSF (P value=0.048). Moreover, higher Knosp classified tumors had lower levels of BIRC2 (P value=0.001). Finally, lower levels of MAGI2-AS3 were associated with larger tumor size (P value=0.006). NEAT1 expression was correlated with FLVCR1-DT and TRADD. TRADD expression was correlated with FLVCR1-DT. Additional correlation was observed between expression of BIRC2 and MAGI2-AS3. In sum, this study provides evidence that dysregulated levels of studied genes could contribute to the pathogenesis of pituitary tumors.

HLF is a promising prognostic, immunological, and therapeutic biomarker in human tumors.

Despite past research linking HLF mutations to cancer development, no pan-cancer analyses of HLF have been published. As a result, we utilized multiple databases to illustrate the potential roles of HLF in diverse types of cancers. Several databases were used to assess HLF expression in the TCGA cancer samples. Additional assessments were undertaken to investigate the relationship between HLF and overall survival, immune cell infiltration, genetic alterations, promoter methylation, and protein-protein interaction. HLF's putative roles and the relationship between HLF expression and drug reactivity were investigated. HLF expression was shown to be lower in tumor tissues from a variety of malignancies when compared to normal tissues. There was a substantial link found between HLF expression and patient survival, genetic mutations, and immunological infiltration. HLF influenced the pathways of apoptosis, cell cycle, EMT, and PI3K/AKT signaling. Abnormal expression of HLF lowered sensitivity to numerous anti-tumor drugs and small compounds. According to our findings, reduced HLF expression drives cancer growth, and it has the potential to be identified as a vital biomarker for use in prognosis, immunotherapy, and targeted treatment of a range of malignancies.

Alteration in the expression of long non-coding RNAs in the circulation of migraineurs.

BACKGROUND: Current studies have shown emerging roles of lncRNAs in the pathobiology of neuropathic pain and migraine. METHODS: We have chosen five lncRNAs, namely, PVT1, DSCAM-AS, MEG3, LINC-ROR, and SPRY4-IT1 for assessment of their expression in the circulation of migraineurs. RESULTS: Expressions of PVT1 and MEG3 were higher in total migraineurs and both subgroups compared with controls (P < 0.0001). Meanwhile, expression of both lncRNA was higher in migraineurs with aura versus migraineurs without aura (P value < 0.0001 and = 0.01, respectively). Expression of DSCAM-AS1 was not different between any groups of patients compared with controls. Expression of LINC-ROR was elevated in total patients and patients with aura compared with controls (P value = 0.0002 and < 0.0001, respectively). It was also over-expressed in migraineurs with aura vs. migraineurs without aura (P = 0.01). Finally, expression of SPRY4-IT1 was higher in total patients and patients without aura compared with migraine-free persons (P values < 0.0001). Expressions of five mentioned lncRNAs were correlated in almost all study groups. In patients without aura, correlations were significant only for two pairs (SPRY4-IT1/PVT1 and SPRY4-IT1/DSCAM-AS1). PVT1 and MEG3 had the appropriate AUC, sensitivity and specificity values for separation of total migraineurs and both groups of patients from controls. The highest AUC value was reported for PVT1 in separation of migraineurs with aura from healthy controls (AUC = 0.98). CONCLUSION: Cumulatively, our study shows evidence for deregulation of lncRNAs in migraineurs.

Identification of miR-125a and miR-106b signature as a potential diagnostic biomarker in breast cancer tissues.

MicroRNAs (miRNAs) have essential roles in the etiology of breast cancer and are regarded as possible markers in this malignancy. In order to find new markers for breast cancer, the current study has measured expression level of four miRNAs, namely miR-125a, miR-106b, miR-96 and miR-92a-3p in the paired breast samples. Expression levels of miR-125a and miR-106b were higher in tumoral tissues compared with control tissues (Expression ratios (95% CI) = 4.01 (1.96-8.19) and 3.9 (1.95-7.81); P values = 0.0005 and 0.0003, respectively). miR-106b and miR-125a differentiated between malignant and non-malignant tissues with AUC values of 0.7 and 0.67, respectively. We detected association between expression of miR-106b and clinical stage (P = 0.03), in a way that its expression was the lowest in the advanced stages. Finally, significant relationships were found between miR-96 and miR-125a in both tumoral and non-tumoral specimens (ρ = 0.76 and 0.69, respectively). This nonparametric measure of rank correlation also showed relationship between miR-106b and miR-96 in both sets of samples (ρ = 0.63 and 0.61, respectively). Cumulatively, the assessed miRNAs, particularly miR-125a and miR-106b are putative targets for further expression and functional assays in breast cancer.

Association Between RORA Polymorphisms and Obesity.

RORα is a transcription factor encoded by RORA gene. This protein is involved in several metabolic conditions, including obesity. We assessed association between two polymorphisms within this gene (namely rs11639084 and rs4774388) and severe obesity in Iranian population. Both SNPs were associated with obesity in all models (P < 0.0001) except for over-dominant model. T allele of rs11639084 was associated with this trait with OR (95% CI) of 16.85 (13.11-21.67) and was considered as the risk allele. Allelic model best fit the data, since the AIC value for this model was the highest (AIC = 28.82). In the co-dominant model, TT genotype was associated with obesity with OR (95% CI) of 301.6 (137.4-662.1). This genotype was shown to be the risk genotype in the recessive model when compared with TC+CC (OR (95% CI) = 60.54 (30.35-120.7)). The C allele of rs4774388 was shown to be the risk allele with OR (95% CI) of 4.61 (3.72-5.71). In the recessive model, the CC genotype was associated with the mentioned trait with OR (95% CI) of 9.92 (6.62-14.8). This model best fit the data (AIC = 37.08). Cumulatively, the current study suggests contribution of RORα to the pathogenesis of obesity.

Factor VIII as a Novel Biomarker for Diagnosis, Prognosis, and Therapy Prediction in Human Cancer and Other Disorders.

Coagulation factor VIII (FVIII) is an essential cofactor in the coagulation cascade, encoded by the F8 gene on the long arm of chromosome X (Xq28). FVIII is normally circulated in complex with Von Willebrand factor (VWF) and has relevant emerging extracoagulative functions. Dysregulation of FVIII is associated with tumor progression, and could be used as a novel biomarker for tumor screening and monitoring. In breast cancer, bladder cancer, colorectal carcinoma, esophageal carcinoma, hepatocellular carcinoma and lung cancer, F8 is regarded as an oncogene. In coronary heart disease, hemophilia A and liver disease, F8 dysregulation has been recognized as a potential biomarker for disease diagnosis and prognosis. However, the basis of these differential expression levels remains to be understood. In this review, which is a mixture of literature review and bioinformatics analysis we described the biological functions and characteristics of FVIII, and also its expression level in non-malignant disorders and various cancers.

Tracing vitamins on the long non-coding lane of the transcriptome: vitamin regulation of LncRNAs.

A major revelation of genome-scale biological studies in the post-genomic era has been that two-thirds of human genes do not encode proteins. The majority of non-coding RNA transcripts in humans are long non-coding RNA (lncRNA) molecules, non-protein-coding regulatory transcripts with sizes greater than 500 nucleotides. LncRNAs are involved in nearly every aspect of cellular physiology, playing fundamental regulatory roles both in normal cells and in disease. As result, they are functionally linked to multiple human diseases, from cancer to autoimmune, inflammatory, and neurological disorders. Numerous human conditions and diseases stem from gene-environment interactions; in this regard, a wealth of reports demonstrate that the intake of specific and essential nutrients, including vitamins, shapes our transcriptome, with corresponding impacts on health. Vitamins command a vast array of biological activities, acting as coenzymes, antioxidants, hormones, and regulating cellular proliferation and coagulation. Emerging evidence suggests that vitamins and lncRNAs are interconnected through several regulatory axes. This type of interaction is expected, since lncRNA has been implicated in sensing the environment in eukaryotes, conceptually similar to riboswitches and other RNAs that act as molecular sensors in prokaryotes. In this review, we summarize the peer-reviewed literature to date that has reported specific functional linkages between vitamins and lncRNAs, with an emphasis on mammalian models and humans, while providing a brief overview of the source, metabolism, and function of the vitamins most frequently investigated within the context of lncRNA molecular mechanisms, and discussing the published research findings that document specific connections between vitamins and lncRNAs.

Role of circular RNA/miRNA axes in the pathophysiology of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a disorder resulted from interactions between genetic and environmental factors. Based on the importance of epigenetic factors in the pathoetiology of PCOS, the current review focused on identification of circular RNAs (circRNAs) that are involved in PCOS through acting as molecular sponges for microRNAs (miRNAs). The literature search led to identification of circ_0043533/miR-1179, circ_0030018/miR-136, circ_FURIN/miR-423-5p, circ-FURIN/miR-195-5p, circ_0043532/miR-182, circ_RANBP9/miR-136-5p, circRHBG/miR-515-5p, circMTO1/miR-320b, circASPH/miR-375, circPSMC3/miR-296-3p, circLDLR/miR-1294, circPUM1/miR-760, and hsa_circ_0118530/miR-136 as molecular axes contributing to the pathogenesis of PCOS. To set the stage for future research on the role of the ceRNA network in PCOS, in-silico analyses were performed using miRWalk, miRNet, and miRDIP databases. miRWalk identified 80 genes regulated by 5 miRNAs, miRNet revealed 6449 circRNAs potentially controlling 11 miRNAs, and miRDIP identified 11 miRNAs associated with 35 human pathways. These targets can be used in the treatment options, design of personalized medicine and prediction of prognosis of PCOS.

Impact of miRNAs in the pathoetiology of recurrent implantation failure.

Recurrent implantation failure (RIF) is a condition with a multifactorial basis. Recent research has focused on the role of genetic factors in the pathophysiology of RIF. Of particular note, miRNAs have been found to contribute to the pathogenesis of RIF. Several miRNA polymorphisms have been investigated in this context. Moreover, dysregulation of expression of a number of miRNAs, including miR-374a-5p, miR-145-5p, miR-30b-5p, miR-196b-5p, miR-22, miR-181 and miR-145 has been found in RIF. This review concentrates on the role of miRNAs in RIF to help in identification of the molecular basis for this condition and design of more effective methods for management of RIF, especially in a personalized manner that relies on the expression profiles of miRNAs in the peripheral blood or endometrium.

In Silico Prediction of Functional SNPs Interrupting Antioxidant Defense Genes in Relation to COVID-19 Progression.

The excessive production of reactive oxygen species and weakening of antioxidant defense system play a pivotal role in the pathogenesis of different diseases. Extensive differences observed among individuals in terms of affliction with cancer, cardiovascular disorders, diabetes, bacterial, and viral infections, as well as response to treatments can be partly due to their genomic variations. In this work, we attempted to predict the effect of SNPs of the key genes of antioxidant defense system on their structure, function, and expression in relation to COVID-19 pathogenesis using in silico tools. In addition, the effect of SNPs on the target site binding efficiency of SNPs was investigated as a factor with potential to change drug response or susceptibility to COVID-19. According to the predicted results, only six missense SNPs with minor allele frequency (MAF) ≥ 0.1 in the coding region of genes GPX7, GPX8, TXNRD2, GLRX5, and GLRX were able to strongly affect their structure and function. Our results predicted that 39 SNPs with MAF ≥ 0.1 led to the generation or destruction of miRNA-binding sites on target antioxidant genes from GPX, PRDX, GLRX, TXN, and SOD families. The results obtained from comparing the expression profiles of mild vs. severe COVID-19 patients using GEO2R demonstrated a significant change in the expression of approximately 250 miRNAs. The binding efficiency of 21 of these miRNAs was changed due to the elimination or generation of target sites in these genes. Altogether, this study reveals the fundamental role of the SNPs of antioxidant defense genes in COVID-19 progression and susceptibility of individuals to this virus. In addition, different responses of COVID-19 patients to antioxidant defense system enhancement drugs may be due to presence of these SNPs in different individuals.

Upregulation of lnc-FOXD2-AS1, CDC45, and CDK1 in patients with primary non-M3 AML is associated with a worse prognosis.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy with an unfavorable outcome. The present research aimed to identify novel biological targets for AML diagnosis and treatment. In this study, we performed an in-silico method to identify antisense RNAs (AS-RNAs) and their related co-expression genes. GSE68172 was selected from the AML database of the Gene Expression Omnibus and compared using the GEO2R tool to find DEGs. Antisense RNAs were selected from all the genes that had significant expression and a survival plot was drawn for them in the GEPIA database, FOXD2-AS1 was chosen for further investigation based on predetermined criteria (logFC ≥|1| and P < 0.05) and its noteworthy association between elevated expression level and a marked reduction in the overall survival (OS) in patients diagnosed with AML. The GEPIA database was utilized to investigate FOXD2-AS1-related co-expression and similar genes. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene ontology (GO) function analysis of the mentioned gene lists were performed using the DAVID database. The protein-protein interaction (PPI) network was then constructed using the STRING database. Hub genes were screened using Cytoscape software. Pearson correlation analysis was conducted using the GEPIA database to explore the relationship between FOXD2-AS1 and the hub genes. The transcription of the selected coding and non-coding genes, including FOXD2-AS1, CDC45, CDC20, CDK1, and CCNB1, was validated in 150 samples, including 100 primary AML non-M3 blood samples and 50 granulocyte colony stimulating factor (G-CSF)-mobilized healthy donors, using quantitative Real-Time PCR (qRT-PCR). qRT-PCR results displayed significant upregulation of lnc-FOXD2-AS1, CDC45, and CDK1 in primary AML non-M3 blood samples compared to healthy blood samples (P = 0.0032, P = 0.0078, and P = 0.0117, respectively). The expression levels of CDC20 and CCNB1 were not statistically different between the two sets of samples (P = 0.8315 and P = 0.2788, respectively). We identified that AML patients with upregulation of FOXD2-AS1, CDK1, and CDC45 had shorter overall survival (OS) and Relapse-free survival (RFS) compared those with low expression of FOXD2-AS1, CDK1, and CDC45. Furthermore, the receiver operating characteristic (ROC) curve showed the potential biomarkers of lnc -FOXD2-AS1, CDC45, and CDK1 in primary AML non-M3 blood samples. This research proposed that the dysregulation of lnc-FOXD2-AS1, CDC45, and CDK1 can contribute to both disease state and diagnosis as well as treatment. The present study proposes the future evolution of the functional role of lnc-FOXD2-AS1, CDC45, and CDK1 in AML development.

Inhibition of breast cancer cell growth and migration through siRNA-mediated modulation of circ_0009910/miR-145-5p/MUC1 axis.

Circular RNAs (circRNAs) characterize a novel kind of regulatory RNAs distinguished by great evolutionary conservation and constancy. Although their exact role in malignancies is not fully understood, they mainly work through specific axes. Circular RNA/miRNA/mRNA axes affect the pathogenesis of human cancers including breast cancer. We assessed the expression and function of circ_0009910/miR-145-5p/MUC1 axis in Breast Cancer tissues and MCF-7 cells. Expression levels of circ_0009910 and MUC1 were notably increased in breast cancer tissues compared with control tissues, parallel with the down-regulation of miR-145-5p. Clinicopathological analysis indicated that up-regulation of circ_0009910 in breast tumors is related to invasion of the tumor to lymph node (P value = 0.011). Also, the downregulation of miR-145-5p was significantly correlated with tumor invasion to lymph nodes (P value = 0.04) and HER2-negative tumors (P value = 0.037). Finally, overexpression of MUC1 was correlated with age under 45 years (P value = 0.002). More importantly, circ_0009910-siRNA decreased the proliferation and migration ability of breast cancer cells, enhanced expression of miR-145-5p, and decreased levels of MUC1. Taken together, the circ_0009910/miR-145-5p/MUC1 axis has been demonstrated to affect the pathogenesis of breast cancer and might provide a target for breast cancer treatment.

Impacts of non-coding RNAs in the pathogenesis of varicocele.

Two classes of non-coding RNAs, namely lncRNAs and miRNAs have been reported to be involved in the pathogenesis of varicocele. MIR210HG, MLLT4-AS1, gadd7, and SLC7A11-AS1 are among lncRNAs whose expression has been changed in patients with varicocele in association with the sperm quality. Animal studies have also suggested contribution of NONRATG001060, NONRATG002949, NONRATG013271, NONRATG027523 and NONRATG023747 lncRNAs in this pathology. Meanwhile, expression of some miRNAs, such as miR-210-3p, miR-21, miR-34a, miR-122a, miR-181a, miR-34c and miR-192a has been altered in this condition. Some of these transcripts have the potential to predict the sperm quality. We summarize the impacts of lncRNAs and miRNAs in the pathogenesis of varicocele.

"Hyperglycemic Memory": Observational Evidence to Experimental Inference.

Several epidemiological studies have appreciated the impact of "duration" and "level" of hyperglycemia on the initiation and development of chronic complications of diabetes. However, glycemic profiles could not fully explain the presence/absence and severity of diabetic complications. Genetic issues and concepts of "hyperglycemic memory" have been introduced as additional influential factors involved in the pathobiology of late complications of diabetes. In the extended phase of significant diabetes randomized, controlled clinical trials, including DCCT/EDIC and UKPDS, studies have concluded that the quality of glycemic or metabolic control at the early time around the diabetes onset could maintain its protective or detrimental impact throughout the following diabetes course. There is no reliable indication of the mechanism by which the transient exposure to a given glucose concentration level could evoke a consistent cellular response at target tissues at the molecular levels. Some biological phenomena, such as the production and the concentration of advanced glycation end products (AGEs), reactive oxygen species (ROS) and protein kinase C (PKC) pathway activations, epigenetic changes, and finally, the miRNAs-mediated pathways, may be accountable for the development of hyperglycemic memory. This work summarizes evidence from previous experiments that may substantiate the hyperglycemic memory soundness by its justification in molecular terms.

Integrated bioinformatics approaches and expression assays identified new markers in pituitary adenomas.

Pituitary adenomas (PA) include about one third of primary central nervous tumors in adolescent and young adult. Despite extensive research, the underlying mechanism of PA tumorigenesis is still unknown. In the present study, through bioinformatics analysis of a PA-related dataset downloaded from GEO database, we attempted to identify pair(s) of lncRNA/target mRNA whose expression changes may be involved in the tumorigenesis of PAs. For this end, we evaluated expression of a set of bioinformatically obtained genes in 46 PA tissues against adjacent non-tumor pituitary tissues. The bioinformatics step led to selection of four genes for validation through expression assays. Expression levels of HIF1A and MAPK1 were increased in NFPA tissues (P < 0.0001 and =0.0042, respectively). Expression level of BANCR was significantly decreased in tumor tissues (P < 0.0001). However, expression of STAT3 was not meaningfully different between the two tissue types (P = 0.56). Since there was no significant correlation between MAPK1 and BANCR expressions in either tumor or adjacent normal tissues, the regulatory effect of BANCR on MAPK1 was not confirmed. In conclusion, this study offers information about deregulation of bioinformatically identified genes in PA tumors and indicates that further studies in this field is needed to understand the involved molecular mechanisms.