CircRNA-associated ceRNA regulatory networks as emerging mechanisms governing the development and biophysiopathology of epilepsy.

The etiology of epilepsy is ascribed to the synchronized aberrant neuronal activity within the brain. Circular RNAs (circRNAs), a class of non-coding RNAs characterized by their circular structures and covalent linkage, exert a substantial influence on this phenomenon. CircRNAs possess stereotyped replication, transience, repetitiveness, and paroxysm. Additionally, MicroRNA (miRNA) plays a crucial role in the regulation of diverse pathological processes, including epilepsy. CircRNA is of particular significance due to its ability to function as a competing endogenous RNA, thereby sequestering or inhibiting miRNA activity through binding to target mRNA. Our review primarily concentrates on elucidating the pathological and functional roles, as well as the underlying mechanisms, of circRNA-miRNA-mRNA networks in epilepsy. Additionally, it explores the potential utility of these networks for early detection and therapeutic intervention.

Hijacking and rewiring of host CircRNA/miRNA/mRNA competitive endogenous RNA (ceRNA) regulatory networks by oncoviruses during development of viral cancers.

A significant portion of human cancers are caused by oncoviruses (12%-25%). Oncoviruses employ various strategies to promote their replication and induce tumourigenesis in host cells, one of which involves modifying the gene expression patterns of the host cells, leading to the rewiring of genes and resulting in significant changes in cellular processes and signalling pathways. In recent studies, a specific mode of gene regulation known as circular RNA (circRNA)-mediated competing endogenous RNA (ceRNA) networks has emerged as a key player in this context. CircRNAs, a class of non-coding RNA molecules, can interact with other RNA molecules, such as mRNAs and microRNAs (miRNAs), through a process known as ceRNA crosstalk. This interaction occurs when circRNAs, acting as sponges, sequester miRNAs, thereby preventing them from binding to their target mRNAs and modulating their expression. By rewiring the host cell genome, oncoviruses have the ability to manipulate the expression and activity of circRNAs, thereby influencing the ceRNA networks that can profoundly impact cellular processes such as cell proliferation, differentiation, apoptosis, and immune responses. This review focuses on a comprehensive evaluation of the latest findings on the involvement of virus-induced reprogramming of host circRNA-mediated ceRNA networks in the development and pathophysiology of human viral cancers, including cervical cancer, gastric cancer, nasopharyngeal carcinoma, Kaposi's sarcoma, hepatocellular carcinoma, and diffuse large B cell lymphoma. Understanding these mechanisms can improve our knowledge of how oncoviruses contribute to human tumourigenesis and identify potential targets for developing optimised therapies and diagnostic tools for viral cancers.

Evaluation of the Expression of Infection-Related Long Noncoding RNAs among COVID-19 Patients: A Case-Control Study.

Background and Aims: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a worldwide pandemic, activates signaling cascades and leads to innate immune responses and secretion of multiple chemokines and cytokines. Long noncoding RNAs (lncRNAs) have a crucial role in inflammatory pathways. Through our search on the PubMed database, we discovered that existing research has primarily focused on examining the regulatory impacts of five lncRNAs in the context of viral infections. However, their role in regulating other conditions, including SARS-CoV-2, has not been explored. Therefore, this study aimed to investigate the expression pattern of lncRNAs in the peripheral blood mononuclear cells (PBMC) and their potential roles in SARS-CoV-2 infection. Potentially significant competing endogenous RNA (ceRNA) networks of these five lncRNAs were found using online in-silico techniques. Methods: Ethylenediaminetetraacetic acid (EDTA) blood samples of the control group consisted of 45 healthy people, and a total of 53 COVID-19-infected patients in case group, with a written informed consent, was collected. PBMCs were extracted, and then, the RNA extraction and complementary DNA (cDNA) synthesis was performed. The expression of five lncRNAs (lnc ISR, lnc ATV, lnc PAAN, lnc SG20, and lnc HEAL) was assessed by real-time PCR. In order to evaluate the biomarker roles of genes, receiver operating characteristic (ROC) curve was drawn. Results: Twenty-four (53.3%) and 29 (54.7%) of healthy and COVID-19-infected participants were male, respectively. The most prevalent symptoms were as follows: cough, general weakness, contusion, headache, and sore throat. The results showed that three lncRNAs, including lnc ISR, lnc ATV, and lnc HEAL, were expressed dramatically higher in the case group compared to healthy controls. According to ROC curve analysis, lnc ATV has a higher AUC and is a better biomarker to differentiate COVID-19 patients from the healthy controls. Then, using bioinformatics methods, the ceRNA network of these lncRNAs enabled the identification of mRNAs and miRNAs with crucial functions in COVID-19. Conclusion: The considerable higher expression of ISR, ATV, and HEAL lncRNAs and the significant area under curve (AUC) in ROC curve demonstrate that these RNAs probably have a potential role in controlling the host innate immune responses and regulate the viral replication of SARS-CoV-2. However, these assumptions need further in vitro and in vivo investigations to be confirmed.

tRNA-derived fragments: Key determinants of cancer metastasis with emerging therapeutic and diagnostic potentials.

Metastasis is a significant clinical challenge responsible for cancer mortality and non-response to treatment. However, the molecular mechanisms driving metastasis remain unclear, limiting the development of efficient diagnostic and therapeutic approaches. Recent breakthroughs in cancer biology have discovered a group of small non-coding RNAs called tRNA-derived fragments (tRFs), which play a critical role in the metastatic behavior of various tumors. tRFs are produced from cleavage modifications of tRNAs and have different functional classes based on the pattern of these modifications. They perform post-transcriptional regulation through microRNA-like functions, displacing RNA-binding proteins, and play a role in translational regulation by inducing ribosome synthesis, translation initiation, and epigenetic regulation. Tumor cells manipulate tRFs to develop and survive the tumor mass, primarily by inducing metastasis. Multiple studies have demonstrated the potential of tRFs as therapeutic, diagnostic, and prognostic targets for tumor metastasis. This review discusses the production and function of tRFs in cells, their aberrant molecular contributions to the metastatic environment, and their potential as promising targets for anti-metastasis treatment strategies.

Key Non-coding Variants in Three Neuroapoptosis and Neuroinflammation-Related LncRNAs Are Protectively Associated with Susceptibility to Parkinson's Disease and Some of Its Clinical Features.

Research findings show that genetic susceptibility to sporadic Parkinson's disease (PD), a common neurodegenerative disorder, is determined through gene variation of loci involved in its development and pathogenesis. A growing body of strong evidence has revealed that dysfunction of long non-coding RNAs (lncRNAs) plays key roles in the pathogenesis and progression of PD through impairing neuronal signaling pathways, but little is known about the relationship between their variants and PD susceptibility. In this research, we intended to study the relationship between functional SNPs rs12826786C>T, rs3200401C>T, and rs6931097G>A in the key lncRNAs stimulating neuroapoptosis and neuroinflammation in PD, including HOTAIR, MALAT1, and lincRNA-P21, respectively, with susceptibility to PD as well as its clinical symptoms.The population of this study consisted of 240 individuals, including 120 controls and 120 cases, and the sample taken from them was peripheral blood. Genotyping of the target SNPs was done using PCR-RFLP. We found that the healthy individuals carry more T allele of MALAT1-rs3200401C>T compared to the patients (P= 0.019). Furthermore, it was observed that in the dominant genetic model, subjects with genotypes carrying the T allele have a lower risk of PD (OR= 0.530; CI= 0.296-0.950; P= 0.033). Regarding the lincRNA-P21-rs6931097G>A, we observed a significant protective relationship between its GA (OR= 0.144; CI= 0.030-0.680; P= 0.014) and AA (OR= 0.195; CI= 00.047-0.799; P= 0.023) genotypes with the manifestation of tremor and bradykinesia symptoms, respectively. Furthermore, the findings indicated that the minor TT genotype of HOTAIR-rs12826786C>T was significantly associated with a reduced risk of bradykinesia symptoms (OR= 0.147; CI= 0.039-0.555; P= 0.005). Collectively, these findings suggest that MALAT1-rs3200401C>T may be an important lncRNA SNP against the development of PD, while the other two SNPs show protective effects on the clinical manifestations of PD in a way that lincRNA-P21-rs6931097G>A has a protective effect against the occurrence of tremor and bradykinesia symptoms in PD patients, and HOTAIR -rs12826786C>T indicates a protective effect against the display of bradykinesia feature. Therefore, they can have valuable potential as biomarkers for clinical evaluations of this disease.

Peripheral blood mononuclear cells expression of miR-200c, miR-125b, miR-27b, miR-203, and miR-155 in patients with significant or insignificant coronary artery stenosis.

Coronary artery disease (CAD) is one of the principal causes of death worldwide. Among several predisposing factors, inflammation and inflammatory genes play a significant role in disease pathogenesis. Inflammatory microRNAs, small noncoding RNAs involved in regulating inflammation, are promising candidates for understanding pathogenesis of CAD and developing diagnostic biomarkers. The aim of the study was to evaluate the alteration of miR-200c, miR-125b, miR-27b, miR-203 and, miR-155 in patients suffering from coronary artery stenosis and insignificant coronary artery stenosis compared to healthy subjects. In this study we compared expressions of five inflammatory miRNAs in peripheral blood mononuclear cells (PBMCs) of 72 patients suffering significant coronary artery stenosis (CAD), 74 individuals without coronary artery disease and 30 individuals with insignificant coronary artery stenosis (ICAD). After blood collection, PBMCs were isolated and RNA was extracted. Gene expression levels were assessed by SYBR green based real-time PCR. Statistical analysis was performed using R program. Expression levels of miR-200c, miR-203, and miR-155 were lower in subjects with ICAD than that in CAD patients and subjects of the control group. MiR-125b was downregulated in CAD and ICAD groups compared to the control group. PBMC miR-27b was upregulated in the CAD group as compared to the ICAD and control groups. Receiver operating characteristic curve analysis verified potential of three miRNAs in separating subjects with ICAD from CAD patients and healthy individuals. In conclusion, this original investigation suggested that altered expression of these five miRNAs may serve as a novel diagnostic biomarker discriminating clinical presentations of coronary artery diseases.

Decreased frequency of regulatory T cells and level of helios gene expression in secondary progressive multiple sclerosis patients: Evidence about the development of multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an aggressive disease characterized by central nervous system (CNS) inflammatory and demyelinating lesions. Tolerance failure is implicated in the development of several autoimmune disorders, including MS. Due to their involvement in maintaining environmental tolerance, regulatory T cells (Tregs) are regarded as efficient immune cells. We examined the frequency of Tregs in this study using CD4/CD25/forkhead box protein P3 (FOXP3)/Helios markers. METHODS: Fifty participants, including 25 patients with secondary progressive MS (SPMS) and 25 healthy controls (HCs), were enrolled in this study, and their demographic characteristics were recorded. Peripheral blood samples ranging from 5 to 6 mL were obtained, and the Ficoll technique was used to extract peripheral blood mononuclear cells (PBMCs). Then, the percentage of CD4+CD25+FOXP3+Helios+ regulatory T lymphocytes was examined by flow cytometry in the study groups. Real-time polymerase chain reaction (PCR) was also used to assess the Helios gene expression level. RESULTS: This study showed that the percentage of Tregs with CD4 and CD25 markers did not reveal a significant difference compared with HCs despite the decrease in SPMS patients (P = 0.6). However, lymphocytes with CD4/CD25/FOXP3/Helios markers were significantly reduced in the patients (P = 0.01). Additionally, SPMS patients had statistically significantly lower Helios gene expression levels (P = 0.002). CONCLUSION: In SPMS patients, a decrease in the frequency of the CD4+CD25+FOXP3+Helios+ Treg population can result in an imbalanced immune system. In other words, one of the immunological mechanisms involved in this disease may be a deficiency in Tregs. Helios gene expression was also decreased in these patients, which may exacerbate functional defects in Tregs.

The use of nanoparticles in the treatment of infectious diseases and cancer, dental applications and tissue regeneration: a review.

The emergence of nanotechnology as a field of study can be traced back to the 1980s, at which point the means to artificially produce, control, and observe matter on a nanometer level was made viable. Recent advancements in technology have enabled us to extend our reach to the nanoscale, which has presented an unparalleled opportunity to directly target biomolecular interactions. As a result of these developments, there is a drive to arise intelligent nanostructures capable of overcoming the obstacles that have impeded the progress of conventional pharmacological methodologies. After four decades, the gradual amalgamation of bio- and nanotechnologies is initiating a revolution in the realm of disease detection, treatment, and monitoring, as well as unsolved medical predicaments. Although a significant portion of research in the field is still confined to laboratories, the initial application of nanotechnology as treatments, vaccines, pharmaceuticals, and diagnostic equipment has now obtained endorsement for commercialization and clinical practice. The current issue presents an overview of the latest progress in nanomedical strategies towards alleviating antibiotic resistance, diagnosing and treating cancer, addressing neurodegenerative disorders, and an array of applications, encompassing dentistry and tuberculosis treatment. The current investigation also scrutinizes the deployment of sophisticated smart nanostructured materials in fields of application such as regenerative medicine, as well as the management of targeted and sustained release of pharmaceuticals and therapeutic interventions. The aforementioned concept exhibits the potential for revolutionary advancements within the field of immunotherapy, as it introduces the utilization of implanted vaccine technology to consistently regulate and augment immune functions. Concurrently with the endeavor to attain the advantages of nanomedical intervention, it is essential to enhance the unceasing emphasis on nanotoxicological research and the regulation of nanomedications' safety. This initiative is crucial in achieving the advancement in medicine that currently lies within our reach.

Purinergic receptors are a key bottleneck in tumor metabolic reprogramming: The prime suspect in cancer therapeutic resistance.

ATP and other nucleoside phosphates have specific receptors named purinergic receptors. Purinergic receptors and ectonucleotidases regulate various signaling pathways that play a role in physiological and pathological processes. Extracellular ATP in the tumor microenvironment (TME) has a higher level than in normal tissues and plays a role in cancer cell growth, survival, angiogenesis, metastasis, and drug resistance. In this review, we investigated the role of purinergic receptors in the development of resistance to therapy through changes in tumor cell metabolism. When a cell transforms to neoplasia, its metabolic processes change. The metabolic reprogramming modified metabolic feature of the TME, that can cause impeding immune surveillance and promote cancer growth. The purinergic receptors contribute to therapy resistance by modifying cancer cells' glucose, lipid, and amino acid metabolism. Limiting the energy supply of cancer cells is one approach to overcoming resistance. Glycolysis inhibitors which reduce intracellular ATP levels may make cancer cells more susceptible to anti-cancer therapies. The loss of the P2X7R through glucose intolerance and decreased fatty acid metabolism reduces therapeutic resistance. Potential metabolic blockers that can be employed in combination with other therapies will aid in the discovery of new anti-cancer immunotherapy to overcome therapy resistance. Therefore, therapeutic interventions that are considered to inhibit cancer cell metabolism and purinergic receptors simultaneously can potentially reduce resistance to treatment.

tRNA-derived fragments in gastric cancer: Biomarkers and functions.

tRNA-derived fragments (tRFs), non-coding RNAs that regulate protein expression after transcription, have recently been identified as potential biomarkers. We identified differentially expressed tRFs in gastric cancer (GC) and the biological properties of tRFs in predicting the malignancy status of GCs as possible biomarkers. Until 15 February 2022, two independent reviewers did a thorough search in electronic databases of Scopus, EMBASE and PubMed. The QUADAS scale was used for quality assessment of the included studies. Ten articles investigating the clinical significance of tRFs, including 928 patients, were analysed. In 10 GC studies, seven tRFs were considerably upregulated and five tRFs were significantly downregulated when compared to controls. Risk of bias was rated low for index test, and flow as well as timing domains in relation to the review question. The applicability of the index test, flow and timing and patient selection for 10 studies was deemed low. In this study, we review the advances in the study of tRFs in GC and describe their functions in gene expression regulation, such as suppression of translation, cell differentiation, proliferation and the related signal transduction pathways associated with them. Our findings may offer researchers new ideas for cancer treatment as well as potential biomarkers for further research in GC.

One-year prevalence and the association between SARS-CoV-2 cycle threshold, comorbidity and outcomes in population of Babol, North of Iran (2020-2021).

Background: The present study aimed to investigate the one-year prevalence of SARS-CoV-2, common comorbidities and demographic information among negative- and positive rRT-PCR in health care workers (HCW), hospitalized and outpatients. Also, the association between SARS-CoV-2 cycle threshold (Ct) and the outcomes of patients were analyzed in Babol, northern Iran. Methods: This large retrospective cross-sectional study was performed between March 2020 and March 2021. The records of 19232 hospitalized, outpatients and HCW suspected to COVID-19 were collected from teaching hospitals in the North of Iran. Results: Out of the 19232 suspected to COVID-19 patients, 7251 (37.7%) had a positive rRT-PCR result; 652 (9%), 4599 (63.4%) and 2000 (27.6%) of those were categorized as HCW, hospitalized and outpatients, respectively. Moreover, between the hospitalized and the outpatient group, 10.2 and 0.8% cases died, whereas no death cases were reported in the HCW. Furthermore, it seems that death rate was significantly different between the three groups of Ct value, the highest mortality in those with Ct between 21 and 30 (group B=7.6%) and the lowest in the group with the highest Ct (between 31 and 40 = 5.5%) (p<0.001). Conclusion: In summary, 37.7% of cases were positive for SARS-CoV-2; of which, 63.4, 27.6 and 9% were hospitalized, outpatients and HCW, respectively. With regard to the mortality rate in hospitalized patients and the significant association with Ct under 20 and 30, it seems that the early detection and the initial quantification of SARS-CoV-2 in the first week of the conflict and therapeutic considerations to reduce the relative load can reduce the mortality rate.

A Large Retrospective Study of Epidemiological Characteristics of COVID-19 Patients in the North of Iran: Association between SARS-CoV-2 RT-PCR Ct Values with Demographic Data.

Objectives: To avoid worsening from mild, moderate, and severe diseases and to reduce mortality, it is necessary to identify the subpopulation that is more vulnerable to the development of COVID-19 unfavorable consequences. This study aims to investigate the demographic information, prevalence rates of common comorbidities among negative and positive real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) patients, and the association between SARS-CoV-2 cycle threshold (Ct) at hospital admission, demographic data, and outcomes of the patients in a large population in Northern Iran. Methods: This large retrospective cross-sectional study was performed from 7 March to 20 December 2020. Demographic data, including gender, age, underlying diseases, clinical outcomes, and Ct values, were obtained from 8,318 cases suspected of COVID-19, who were admitted to four teaching hospitals affiliated to Babol University of Medical Sciences (MUBABOL), in the north of Iran. Results: Since 7 March 2020, the data were collected from 8,318 cases suspected of COVID-19 (48.5% female and 51.5% male) with a mean age of 53 ± 25.3 years. Among 8,318 suspected COVID-19 patients, 3,250 (39.1%) had a positive rRT-PCR result; 1,632 (50.2%) patients were male and 335 (10.3%) patients died during their hospital stay. The distribution of positive rRT-PCR revealed that most patients (464 (75.7%)) had a Ct between 21 and 30 (Group B). Conclusion: Elderly patients, lower Ct, patients having at least one comorbidity, and male cases were significantly associated with increased risk for COVID-19-related mortality. Moreover, mortality was significantly higher in patients with diabetes, kidney disease, and respiratory disease.

Individual genetic variability mainly of Proinflammatory cytokines, cytokine receptors, and toll-like receptors dictates pathophysiology of COVID-19 disease.

Innate and acquired immunity responses are crucial for viral infection elimination. However, genetic variations in coding genes may exacerbate the inflammation or initiate devastating cytokine storms which poses severe respiratory conditions in coronavirus disease-19 (COVID-19). Host genetic variations in particular those related to the immune responses determine the patients' susceptibility and COVID-19 severity and pathophysiology. Gene polymorphisms such as single nucleotide polymorphisms (SNPs) of interferons, TNF, IL1, IL4, IL6, IL7, IL10, and IL17 predispose patients to the severe form of COVID-19 or severe acute respiratory syndrome coronavirus-2 (SARS-COV-2). These variations mainly alter the gene expression and cause a severe response by B cells, T cells, monocytes, neutrophils, and natural killer cells participating in a cytokine storm. Moreover, cytokines and chemokines SNPs are associated with the severity of COVID-19 and clinical outcomes depending on the corresponding effect. Additionally, genetic variations in genes encoding toll-like receptors (TLRs) mainly TLR3, TLR7, and TLR9 have been related to the COVID-19 severe respiratory symptoms. The specific relation of these mutations with the novel variants of concern (VOCs) infection remains to be elucidated. Genetic variations mainly within genes encoding proinflammatory cytokines, cytokine receptors, and TLRs predispose patients to COVID-19 disease severity. Understanding host immune gene variations associated with the SARS-COV-2 infection opens insights to control the pathophysiology of emerging viral infections.

Genetic variations in ATM and H2AX loci contribute to risk of hematological abnormalities in individuals exposed to BTEX chemicals.

BACKGROUND: Loci controlling DNA double-strand breaks (DSBs) repair play an important role in defending against the harmful health effects of benzene, toluene, ethylbenzene, and xylene (BTEX), but their gene variants may alter their repair capacity. The aim of the current study was to determine the relationship of functional polymorphisms ATM-rs228589 A>T, WRN-rs1800392 G>T and H2AX-rs7759 A>G in DBS repair loci with the abnormal hematological indices in workers who exposed to BTEXs. METHODS: We included 141 cases with one or more abnormal hematological parameters, who had been occupationally exposed to BTEX chemicals and 152 controls with a similar exposure condition but without any abnormal hematological parameters. Atmospheric concentrations of BTEXs were measured and whole blood samples were taken from the participants to determine hematologic parameters and SNP genotyping. RESULTS: Results showed that T allele of ATM-rs228589 and G allele of H2AX-rs7759 had a higher frequency in cases than controls (p = 0.012 and p = 0.001, respectively). Also, AT and TT genotypes of ATM-rs228589 and AG and GG genotypes of H2AX-rs7759 were higher in cases compared to controls. The AT and TT genotypes of ATM-rs228589 have significant associations with a risk of hematological abnormalities in the codominant (AT vs. AA, p = 0.018), dominant (AT + TT vs. AA, p = 0.010) and overdominant (AT vs. AA + TT, p = 0.037) models. The GG and AG genotypes of H2AX-rs7759 were in relation with increased risk of abnormal hematological indices under codominant (GA vs. AA, p = 0.009 & GG vs. AA, p = 0.005), dominant (AG + GG vs. AA, p = 0.001), and recessive (GG vs. AA + AG, p = 0.025) models. CONCLUSIONS: These observations may help to understand the mechanisms of BTEX hematotoxicity and identify useful biomarkers of risk assessment for workers exposed to BTEX.

Potential roles of hsa_circ_000839 and hsa_circ_0005986 in breast cancer.

BACKGROUND: Breast cancer (BC) is one of the leading causes of death among women around the world. Circular RNAs (circRNAs) are a newly discovered group of non-coding RNAs that their roles are being investigated in BC and other cancer types. In this study, we evaluated the association of hsa_circ_0005986 and hsa_circ_000839 in tumor and adjacent normal tissues of BC patients with their clinicopathological characteristics. MATERIALS AND METHODS: Total RNA was extracted from tumors and adjacent non-tumor tissues by the Trizol isolation reagent, and cDNA was synthesized using First Strand cDNA Synthesis Kit (Thermo Scientific). The expression level of hsa_circ_0005986 and hsa_circ_000839 was quantified using RT-qPCR. Online in silico tools were used for identifying potentially important competing endogenous RNA (ceRNA) networks of these two circRNAs. RESULTS: The expression level of hsa_circ_0005986 and hsa_circ_000839 was lower in the tumor as compared to adjacent tissues. The expression level of hsa_circ_0005986 in the patients who had used hair dye in the last 5 years was significantly lower. Moreover, a statistically significant negative correlation between body mass index (BMI) and hsa_circ_000839 expression was observed. In silico analysis of the ceRNA network of these circRNAs revealed mRNAs and miRNAs with crucial roles in BC. CONCLUSION: Downregulation of hsa_circ_000839 and hsa_circ_0005986 in BC tumors suggests a tumor-suppressive role for these circRNAs in BC, meriting the need for more experimentations to delineate the exact mechanism of their involvement in BC pathogenesis.

Clinical values of expression signature of circCDR1AS and circHIAT1 in prostate cancer: Two circRNAs with regulatory function in androgen receptor (AR) and PI3K/AKT signaling pathways.

BACKGROUND: Prostate cancer (PCa) is a genetically heterogeneous disease with highly molecular aberrations. It has been revealed that a newly discovered class of non-coding RNAs called circular RNAs (circRNAs) play key roles in dictating tumor behaviors and phenotypes of the prostate tumors. In the current study, our aim was to determine the expression profiles of circHIAT1 and circCDR1AS in PCa compared with benign prostatic hyperplasia (BPH) tissues, as well as their clinicopathological relevance. METHODS: The 50 prostate tissues including 25 PCa tissues and 25 BPH samples were collected for analyzing the expression levels of target circRNAs by quantitative real-time PCR (qRT-PCR). RESULTS: The results revealed that expression of circCDR1AS was significantly elevated in PCa compared with the BPH (p < 0.05). We also observed that PCa patients over the age of 60 had a higher expression of the circCDR1AS than patients under the age of 60 (p = 0.017). Moreover, a lower expression level of circHIAT1 was found in the PCa than BPH tissues (p < 0.05), and finally, the findings indicated that the area under the curve (AUC) of circCDR1AS was 0.848, with 92% sensitivity and 76% specificity, as well as an AUC of 0.828, with the 80% sensitivity and 76% specificity for circHIAT1. CONCLUSION: These observations suggest that the abnormal expression of circCDR1AS and circHIAT1 can be regarded as two different types of molecular pathology with potential biomarker values for PCa, although further studies are needed.

Epi-miRNAs: Regulators of the Histone Modification Machinery in Human Cancer.

Cancer is a leading cause of death and disability worldwide. Epigenetic deregulation is one of the most critical mechanisms in carcinogenesis and can be classified into effects on DNA methylation and histone modification. MicroRNAs are small noncoding RNAs involved in fine-tuning their target genes after transcription. Various microRNAs control the expression of histone modifiers and are involved in a variety of cancers. Therefore, overexpression or downregulation of microRNAs can alter cell fate and cause malignancies. In this review, we discuss the role of microRNAs in regulating the histone modification machinery in various cancers, with a focus on the histone-modifying enzymes such as acetylases, deacetylases, methyltransferases, demethylases, kinases, phosphatases, desumoylases, ubiquitinases, and deubiquitinases. Understanding of microRNA-related aberrations underlying histone modifiers in pathogenesis of different cancers can help identify novel therapeutic targets or early detection approaches that allow better management of patients or monitoring of treatment response.

Altered Expression of hsa_circ_0001445 and hsa_circ_0020397 in Breast Cancer Representing Associations with BMI and Reproductive Factors.

BACKGROUND: Circular RNAs (circRNAs), one of the recent subclasses of non-coding RNAs (ncRNAs), show pivotal functions in regulation of gene expression and have significant roles in malignancies including breast cancer (BC). This study was aimed to assess the hsa_circ_0001445 and hsa_circ_0020397 expression and role in BC, as well as the potential circRNA/miRNA/mRNA crosstalk in these contexts. METHODS: The expression of hsa_circ_0001445 and hsa_circ_0020397 in 50 breast tumors and 50 normal tissues adjacent to the tumors was investigated using quantitative real-time polymerase chain reaction (qRT-PCR). Finally, bioinformatics analyses were used to uncover hsa_circ_0001445, hsa_circ_0020397-miRNA-mRNA potential regulatory networks. RESULTS: The hsa_circ_0001445 expression was considerably downregulated in malignant tissues compared to their normal counterparts (P=0.020), while the hsa_circ_0020397 showed an upregulated pattern (P<0.001). Additionally, it was observed that the higher expression of hsa_circ_0001445 was associated with hair dye avoidance (P=0.034) and normal body mass index (BMI) (P=0.016) while hsa_circ_0020397 over-expression had an important association with a lack of vitamin D consumption (P=0.039). On the other hand, lower expression of hsa_circ_0001445 was significantly associated with age at menarche ˂14 years (P=0.027). Our study also revealed that the two circRNAs have potential ability to regulate key mRNAs and miRNAs in competing endogenous RNA (ceRNA) networks. CONCLUSION: It is suggested that hsa_circ_0001445 and hsa_circ_0020397 with two opposite roles may be involved in BC development through sponging some miRNAs regulating ceRNA networks. However, their molecular interactions should be validated by further functional studies.

Dysregulated Expression of miR-146a and Its Associated Immune Effectors in Peripheral Blood Mononuclear Cells of Esophageal Carcinoma Patients.

Esophageal cancer is one of the least studied aggressive tumors, with the squamous cell carcinoma (ESCC) being the most frequent histological type around the world. Growing evidence has shown that the abnormal expression of microRNAs (miRNAs) in peripheral blood mononuclear cells (PBMCs) is closely related to the pathogenesis of cancers. MiR-146a is a crucial regulator of inflammatory cascades. There is currently no data available regarding the possible role of miR-146a in PBMCs of ESCC patients. We evaluated the expression of miR-146a, as well as its target genes (IRAK1 and TRAF6) and its associated immune effectors (NF-κB1, IL1B, and IL6) in PBMCs of 40 ESCC patients and 50 control subjects. The geometric mean expression of five transcripts was used for normalizing expressions. The PBMC level of miR-146a, as measured by RT-qPCR, was upregulated, whereas levels of its target genes, IRAK1 and TRAF6, were downregulated in ESCC patients. NF-κB1 and IL6 was downregulated in PBMCs of ESCC patients. There was no difference in terms of the IL1B level between patients and the control group. Logistic regression and receiver operating characteristic curve analysis suggested that a model with PBMC levels of either NF-κB1+ IL6 or NF-κB1+ miR-146a as predictors may discriminate ESCC patients from subjects of the control group. Our findings, in the context of the current literature, may suggest a possible downregulatory mechanism of immune responses in PBMCs of ESCC patients.

Circular RNA-associated ceRNA network involved in HIF-1 signalling in triple-negative breast cancer: circ_0047303 as a potential key regulator.

The aggressive and highly metastatic nature of triple-negative breast cancer (TNBC) causes patients to suffer from the poor outcome. HIF-1 signalling pathway is a prominent pathway that contributes to angiogenesis and metastasis progression in tumours. On the contrary, the undeniable importance of circular RNAs (circRNAs) as multifunctional non-coding RNAs (ncRNAs) has been identified in breast cancer. These ncRNAs owing to their high stability and specificity have been becoming a hotspot in cancer researches. circRNAs act as competing endogenous RNAs (ceRNAs) and compete with mRNAs for shared miRNAs, thus modulate gene expression. Since the most dysregulated biological functions in TNBC are associated with cellular invasion, understanding the molecular pathogenesis of these processes is a crucial step towards the development of new treatment approaches. The purpose of this study is to undermine the circRNA-associated ceRNA network involved in HIF-1 signalling in TNBC using an integrative bioinformatics approach. In the next step, the novel circ_0047303-mediated ceRNA regulatory axes have been extracted and validated across TNBC samples. We show that circ_0047303 has the highest degree in the circRNA-associated ceRNA network and shows a significant up-expression in TNBC. Moreover, our results suggest that circ_0047303 could mediate the upregulation of key angiogenesis-related genes, including HIF-1, EIF4E2 and VEGFA in TNBC through sponging the tumour-suppressive miRNAs. The circ_0047303 could be a promising molecular biomarker and/or therapeutic target for TNBC.