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.

Potential roles of NLRP3 inflammasome in the pathogenesis of Kawasaki disease.

There is a heterogeneous group of rare illnesses that fall into the vasculitis category and are characterized mostly by blood vessel inflammation. Ischemia and disrupted blood flow will cause harm to the organs whose blood arteries become inflamed. Kawasaki disease (KD) is the most prevalent kind of vasculitis in children aged 5 years or younger. Because KD's cardiovascular problems might persist into adulthood, it is no longer thought of as a self-limiting disease. KD is a systemic vasculitis with unknown initiating factors. Numerous factors, such as genetic predisposition and infectious pathogens, are implicated in the etiology of KD. As endothelial cell damage and inflammation can lead to coronary endothelial dysfunction in KD, some studies hypothesized the crucial role of pyroptosis in the pathogenesis of KD. Additionally, pyroptosis-related proteins like caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), proinflammatory cytokines like IL-1 and IL-18, lactic dehydrogenase, and Gasdermin D (GSDMD) have been found to be overexpressed in KD patients when compared to healthy controls. These occurrences may point to an involvement of inflammasomes and pyroptotic cell death in the etiology of KD and suggest potential treatment targets. Based on these shreds of evidence, in this review, we aim to focus on one of the well-defined inflammasomes, NLRP3, and its role in the pathophysiology of KD.

The potential roles of Th17 cells in the pathogenesis of oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a T cell-mediated chronic autoimmune disease, whose pathogenesis and etiology are not entirely understood. OLP is characterized by subepithelial lymphocyte infiltration and elevated intra-epithelial lymphocytes. The majority of lamina propria lymphocytes are CD4+ T cells. CD4+ helper T (Th) cells play a crucial role in activating CD8+ cytotoxic T cells (CTLs) through interactions and cytokine production. Th1 and Th2 cells are well-accepted to be associated with OLP pathogenesis. However, OLP treatment is challenging yet, the more information we have about the pathology of OLP, the easier it will be treated. With the discovery of Th17 cells in recent years and the demonstration of their role in autoimmune disease, many researchers started to investigate the role of Th17 in the pathogenesis of OLP. METHODS: To make up this review, studies covering the role of TH17 in different types of lichen planus were selected from major databases. RESULTS: As we review in this article, Th17 cells and their signature cytokines play an important role in OLP pathogenesis. As well, utilizing some anti-IL-17 antibodies showed promising results in improving the disease; however, more studies are still needed to better understand and treat OLP.

Expression analysis of hsa_circ_0020397, hsa_circ_0005986, hsa_circ_0003028, and hsa_circ_0006990 in renal cell carcinoma.

Renal cell carcinoma (RCC) is a prevalent heterogeneous kidney cancer. So far, different genes have been reported for RCC development. However, its particular molecular mechanism remains unclear. Circular RNAs (circRNAs), a class of non-coding RNAs, are involved in numerous biological processes in different malignancies such as RCC. This study aims to assess the expression and underlying mechanism of four circRNAs (hsa_circ_0020397, hsa_circ_0005986, hsa_circ_0003028, hsa_circ_0006990) with possible new roles in RCC. In the experimental step, we investigated the expression of these four circRNAs in our RCC samples using quantitative real-time polymerase chain reaction. In the bioinformatics step, the differential expressed mRNAs (DEmRNAs), and miRNAs (DEmiRNAs) were obtained from the GEO datasets using the GEO2R tool. A protein-protein interaction network was constructed using the STRING database, and hub genes were identified by Cytoscape. Molecular pathways associated with hub genes were detected using KEGG pathway enrichment analysis. Then, we utilized the ToppGene database to detect the relationships between DEmiRNAs and hub genes. Furthermore, interactions between circRNAs and DEmiRNAs were predicted by the StarBase and circinteractome databases. Finally, a circRNA-DEmiRNA-hub gene triple network was constructed. Our results revealed that the expression of hsa_circ_0020397, hsa_circ_0005986, and hsa_circ_0006990 was downregulated in RCC tissues. Moreover, these circRNAs had a significantly lower expression in patients with a history of kidney disease. Furthermore, hsa_circ_0003028 and hsa_circ_0006990 showed higher expression in the tumor of participants with Lymphovascular/perineural invasion and oncocytoma type, respectively. Based on bioinformatic results, 15 circRNA-DEmiRNA-hub gene ceRNA regulatory axes were predicted, which included three hub genes, five miRNAs, and four selected circRNAs. In conclusion, the current work is the first to emphasize the expression of the hsa_circ_0020397, hsa_circ_0005986, hsa_circ_0003028, and hsa_circ_0006990 in RCC patients presents a novel perspective on the molecular processes underlying the pathogenic mechanisms of RCC.

Evaluation of Circ_0000977-Mediated Regulatory Network in Breast Cancer: A Potential Discriminative Biomarker for Triple-Negative Tumors.

Previous investigations have revealed that circular RNAs (circRNAs) play pivotal roles in cancer development and progression by participating in several biological procedures, such as competing endogenous RNA (ceRNA) networks. Recently, circRNAs have been proposed as non-invasive, stable, and affordable cell-free biomarkers for cancer screening and test monitoring. Although, their clinical usefulness vastly remains to be evaluated in breast cancer (BC). Triple-negative breast cancer (TNBC), as the most challenging BC subtype, is an urgent requirement of identifying specific biomarkers and discovering the molecular mechanisms that lead to aggressive behaviors of tumor cells. The therapeutic strategies for TN patients have remained limited due to the impracticality of endocrine therapies and a remarkable portion of patients with TNBC experience recurrence, chemoresistance, and metastasis. TNBC Microarray expression profile analysis found that circ_0000977 is one of the most dysregulated circRNA in TNBC in comparison with non-TNBC. It could be a clue referring to the potential clinical utility of circ_0000977 in TNBC. The current study aims to assess the clinical implications and potential ceRNA regulatory network of circ_0000977 in TNBC. We confirmed circ_0000977 down-regulation in TNBC cell lines and tumors versus non-TNBC samples by real-time PCR. Subsequently, an assessment of the diagnostic value of circ_0000977 in plasma samples from triple-negative patients revealed a potential diagnostic cell-free biomarker in triple-negative BC. Finally, our integrative approach uncovered potential circ-0000977/miR-135b-5p/mRNAs regulatory network in TNBC. The inhibitory effect of miR-135b-5p on its downstream mRNAs was assessed by knocking down it in MDA-MB-231 cells. Functional and correlation analyses revealed APC and GATA3 could be regulated by circ_0000977/miR-135b-5p ceRNA axis, which presents valuable insight into circ-0000977-mediated gene silencing involved in the ceRNA network of TNBC. This study uncovered the potential clinical implication of circ_0000977 for the diagnosis and treatment of TNBC patients.

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.

Investigation of BRCAness associated miRNA-gene axes in breast cancer: cell-free miR-182-5p as a potential expression signature of BRCAness.

The concept of the 'BRCAness' phenotype implies the properties that some sporadic breast cancers (BC) share with BRCA1/2-mutation carriers with hereditary BC. Breast tumors with BRCAness have deficiencies in homologous recombination repair (HRR), like BRCA1/2-mutation carriers, and consequently could benefit from poly-(ADP)-ribose polymerase (PARP) inhibitors and DNA-damaging chemotherapy. Triple-negative breast cancers (TNBC) show a higher frequency of BRCAness than the other BC subtypes. Therefore, looking for BRCAness-related biomarkers could improve personalized management of TNBC patients. microRNAs (miRNAs) play a pivotal role in onco-transcriptomic profiles of tumor cells besides their suitable features as molecular biomarkers. The current study aims to evaluate the expression level of some critical miRNAs-mRNA axes in HRR pathway in tumors and plasma samples from BC patients. The expression levels of three multi-target miRNAs, including miR-182-5p, miR-146a-5p, and miR-498, as well as six downstream HRR-related protein-coding genes, have been investigated in the breast tumors and paired adjacent normal tissues by Real-time PCR. In the next step, based on the results derived from the previous step, we examined the level of cell-free miR-182-5p in the blood plasma samples from the patients. Our results highlight the difference between TNBC and non-TNBC tumor subgroups regarding the dysregulation of the key miRNA/mRNA axes involved in the HRR pathway. Also, for the first time, we show that the level of cell-free miR-182-5p in plasma samples from BC patients could be a clue for screening BC patients eligible for receiving PARP inhibitors through a personalized manner. Altogether, some sporadic BC patients, especially sporadic TNBC, have epigenetically dysregulated HRR pathway that could be identified and benefit from BRCAness-specific therapeutic agents.

Anticancer traits of chimeric antigen receptors (CARs)-Natural Killer (NK) cells as novel approaches for melanoma treatment.

Owing to non-responsiveness of a high number of patients to the common melanoma therapies, seeking novel approaches seem as an unmet requirement. Chimeric antigen receptor (CAR) T cells were initially employed against recurrent or refractory B cell malignancies. However, advanced stages or pretreated patients have insufficient T cells (lymphopenia) amount for collection and clinical application. Additionally, this process is time-consuming and logistically cumbersome. Another limitation of this approach is toxicity and cytokine release syndrome (CRS) progress and neurotoxicity syndrome (NS). Natural killer (NK) cells are a versatile component of the innate immunity and have several advantages over T cells in the application for therapies such as availability, unique biological features, safety profile, cost effectiveness and higher tissue residence. Additionally, CAR NK cells do not develop Graft-versus-host disease (GvHD) and are independent of host HLA genotype. Notably, the NK cells number and activity is affected in the tumor microenvironment (TME), paving the way for developing novel approaches by enhancing their maturation and functionality. The CAR NK cells short lifespan is a double edge sword declining toxicity and reducing their persistence. Bispecific and Trispecific Killer Cell Engagers (BiKE and Trike, respectively) are emerging and promising immunotherapies for efficient antibody dependent cell cytotoxicity (ADCC). CAR NK cells have some limitations in terms of expanding and transducing NK cells from donors to achieve clinical response. Clinical trials are in scarcity regarding the CAR NK cell-based cancer therapies. The CAR NK cells short life span following irradiation before infusion limits their efficiency inhibiting their in vivo expansion. The CAR NK cells efficacy enhancement in terms of lifespan TME preparation and stability is a goal for melanoma treatment. Combination therapies using CAR NK cells and chemotherapy can also overcome therapy limitations.

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.

Opportunities and obstacles for the melanoma immunotherapy using T cell and chimeric antigen receptor T (CAR-T) applications: a literature review.

Chimeric antigen receptor T (CAR-T) cell therapy procedure includes taking personal T cells and processing or genetic engineering using specific antigens and in vitro expanding and eventually infusing into the patient's body to unleash immune responses. Adoptive cell therapy (ACT) includes lymphocytes taking, in vitro selection and expansion and processing for stimulation or activation and infusion into the patient's body. Immune checkpoint inhibitors (ICIs), ACT and CAR-T cell therapies have demonstrated acceptable results. However, rare CAR-T cells tissue infiltration, off-target toxicity and resistance development include main disadvantages of CAR-T cell based therapy. Selection of suitable target antigens and novel engineered immune cells are warranted in future studies using "surfaceome" analysis. Employment of cytokines (IL-2, IL-7) for T cells activation has been also associated with specific anti-melanoma function which overcome telomeres shortening and further T cells differentiation. In resistant cases, rapidly accelerated fibrosarcoma B-type and mitogen-activated extracellular signal-regulated kinase inhibitors have been mostly applied. The aim of this study was evaluation of CAR-T cell and adoptive cell therapies efficiency for the treatment of melanoma.

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.

Upregulation of hsa_circ_0004812 promotes COVID-19 cytokine storm via hsa-miR-1287-5p/IL6R, RIG-I axis.

BACKGROUND: SARS-CoV-2 is one of the most contagious viruses in the Coronaviridae (CoV) family, which has become a pandemic. The aim of this study is to understand more about the role of hsa_circ_0004812 in the SARS-CoV-2 related cytokine storm and its associated molecular mechanisms. MATERIALS AND METHODS: cDNA synthesis was performed after total RNA was extracted from the peripheral blood mononuclear cells (PBMC) of 46 patients with symptomatic COVID-19, 46 patients with asymptomatic COVID-19, and 46 healthy controls. The expression levels of hsa_circ_0004812, hsa-miR-1287-5p, IL6R, and RIG-I were determined using qRT-PCR, and the potential interaction between these molecules was confirmed by bioinformatics tools and correlation analysis. RESULTS: hsa_circ_0004812, IL6R, and RIG-I are expressed higher in the severe symptom group compared with the negative control group. Also, the relative expression of these genes in the asymptomatic group is lower than in the severe symptom group. The expression level of hsa-miR-1287-5p was positively correlated with symptoms in patients. The results of the bioinformatics analysis predicted the sponging effect of hsa_circ_0004812 as a competing endogenous RNA on hsa-miR-1287-5p. Moreover, there was a significant positive correlation between hsa_circ_0004812, RIG-I, and IL-6R expressions, and also a negative expression correlation between hsa_circ_0004812 and hsa-miR-1287-5p and between hsa-miR-1287-5p, RIG-I, and IL-6R. CONCLUSION: The results of this in-vitro and in silico study show that hsa_circ_0004812/hsa-miR-1287-5p/IL6R, RIG-I can play an important role in the outcome of COVID-19.

A Proposed TUSC7/miR-211/Nurr1 ceRNET Might Potentially be Disturbed by a cer-SNP rs2615499 in Breast Cancer.

Evidence and in silico analyses showed that TUSC7, miR-211, and Nurr1 may be involved in BC pathogenesis by ceRNET signaling axis. This study aimed to investigate the potential role of TUSC7/miR-211/Nurr1 ceRNET and rs2615499 variant as a novel cer-SNP in BC subjects. The expression assays were conducted by qPCR on tumor tissues (n = 50), tumor-adjacent normal tissues (TANTs) (n = 50), and clinically healthy control tissues (n = 50). The expression of TUSC7 and Nurr1 significantly decreased, but the level of miR-211 significantly increased in tumor tissues compared to TANTs and healthy normal tissues. Altered expression of TUSC7 and miR-211 was associated with poor prognosis of patients. The Nurr1 exhibited a double-edged sword-like activity in BC. In addition, TUSC7, Nurr1, and miR-211 expressions were significantly related to a novel BC-associated rs2615499 (A > C) located in the miR-211 binding site on Nurr1 3'-UTR. In the second part of the study, a case-control study was performed on BC patients (n = 100) and matched healthy controls (n = 100). The genomic DNA was isolated and genotyping was performed using Tetra-Primer ARMS PCR. The CC and AC genotypes were associated with higher expression levels of Nurr1 and worse outcomes of the disease. Our findings revealed that TUSC7 functions as a tumor suppressor in BC potentially via miR-211/Nurr1, which might be disturbed by the cer-SNP rs2615499. However, functional studies are needed to validate these results.

Hsa_circ_0000479/Hsa-miR-149-5p/RIG-I, IL-6 Axis: A Potential Novel Pathway to Regulate Immune Response against COVID-19.

Background: COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global pandemic and mortality of people around the world. Some circular RNAs (circRNAs), one of the new types of noncoding RNAs (ncRNAs), act as competing endogenous RNAs (ceRNAs) and compete with mRNAs for shared miRNAs, to regulate gene expression. In the present study, we aimed to evaluate the expression and roles of hsa_circ_0000479/hsa-miR-149-5p/RIG-I, IL-6 in COVID-19 infection. Materials and Methods: After extraction of total RNA from peripheral blood mononuclear cells (PBMC) of 50 patients with symptomatic COVID-19, 50 patients with nonsymptomatic COVID-19, and 50 normal controls, cDNA synthesis was performed. Online in silico tools were applied to evaluate the interaction between the genes in the hsa_circ_0000479/hsa-miR-149-5p/RIG-I, IL-6 axis, and its role in COVID-19-related pathways. Quantification of the expression of these genes and confirmation of their interaction was done using the quantitative real-time PCR (qRT-PCR) technique. Results: The expression levels of hsa_circ_0000479, RIG-I, and IL-6 were increased in COVID-19 patients compared to healthy controls, while hsa-miR-149-5p expression was decreased. Moreover, there was a significant negative correlation between hsa-miR-149-5p and hsa_circ_0000479, RIG-I, IL-6 expressions, and also a positive expression correlation between hsa_circ_0000479 and IL-6, RIG-I. Then, bioinformatics tools revealed the role of hsa_circ_0000479/hsa-miR-149-5p/RIG-I, IL-6 axis in PI3K-AKT and STAT3 signaling pathways. Conclusion: Upregulation of hsa_circ_0000479, RIG-I, and IL-6, and downregulation of hsa-miR-149-5p, along with correlation studies, indicate that hsa_circ_0000479/hsa-miR-149-5p/RIG-I, IL-6 axis could play a role in regulating the immune response against SARS-CoV-2. However, more studies are needed in this area.

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.

Expression profiles and functional prediction of long non-coding RNAs LINC01133, ZEB1-AS1 and ABHD11-AS1 in the luminal subtype of breast cancer.

BACKGROUND: Luminal breast cancer (BC) is the most frequent subtype accounting for more than 70% of BC. LncRNAs, a class of non-coding RNAs with more than 200 nucleotides, are involved in a variety of cellular processes and biological functions. Abberant expression is related to the development of various cancers, such as breast cancer. LINC01133, ZEB1-AS1, and ABHD11-AS1 were reported to be dysregulated in different cancers. However, their expression level in luminal BC remains poorly known. The aim of the present study was to evaluate the potential roles of these lncRNAs in BC, especially in luminal subtypes. METHODS: A comprehensive analysis was performed using the Lnc2Cancer database to identify novel cancer-associated lncRNA candidates. After conducting a literature review, three novel lncRNAs named LINC01133, ZEB1-AS1, and ABHD11-AS1 were chosen as target genes of the present study. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to evaluate the expression level of the mentioned lncRNAs in both luminal BC tissues and cell lines. Then, the correlation of the three mentioned lncRNAs expression with clinicopathological characteristics of the patients was studied. Moreover, several datasets were used to discover the potential roles and functions of LINC01133, ZEB1-AS1 and ABHD11-AS1 in luminal subtype of BC. RESULTS: According to the qRT-PCR assay, the expression levels of LINC01133 and ZEB1-AS1 were decreased in luminal BC tissues and cell lines. On the other hand, ABHD11-AS1 was upregulated in the above-mentioned samples. The expression levels of LINC01133, ZEB1-AS1, and ABHD11-AS1 were not associated with any of the clinical features. Also, the results obtained from the bioinformatics analyses were consistent with qRT-PCR data. Functional annotation of the co-expressed genes with the target lncRNAs, protein-protein interactions and significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways across luminal BC were also obtained using bioinformatics analysis. CONCLUSIONS: Taken together, our findings disclosed the dysregulation of LINC01133, ZEB1-AS1, and ABHD11-AS1 in luminal BC. It was revealed that LINC01133 and ZEB1-AS1 expression was significantly downregulated in luminal BC tissues and cell lines, while ABHD11-AS1 was upregulated considerably in the mentioned tissues and cell lines. Also, bioinformatics and systems biology analyses have helped to identify the possible role of these lncRNAs in luminal BC. However, further analysis is needed to confirm the current findings.

Circular RNA hsa_circ_0044234 as distinct molecular signature of triple negative breast cancer: a potential regulator of GATA3.

BACKGROUND: Circular RNAs (circRNAs) have been implicated in the initiation and development of breast cancer as functional non-coding RNAs (ncRNA). The roles of circRNAs as the competing endogenous RNAs (ceRNAs) to sponge microRNAs (miRNAs) have also been indicated. However, the functions of circRNAs in breast cancer have not been totally elucidated. This study aimed to explore the clinical implications and possible roles of circ_0044234 in carcinogenesis of the most problematic BC subtype, triple negative breast cancer (TNBC), which are in desperate need of biomarkers and targeted therapies. METHODS: The importance of circ_0044234 as one of the most dysregulated circRNAs in TNBC was discovered through microarray expression profile analysis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to confirm the downregulation of circ_0044234 in triple negative tumors and cell lines versus non-triple negative ones. The bioinformatics prediction revealed that circ_0044234 could act as an upstream sponge in the miR-135b/GATA3 axis, two of the most dysregulated transcripts in TNBC. RESULTS: Our experimental investigation of circ_0044234 expressions in various BC subtypes as well as cell lines reveals that TNBC expresses circ_0044234 at a substantially lower level than non-TNBC. The ROC curve analysis indicates that it could be applied as a discriminative biomarker to identify TNBC from other BC subtypes. Moreover, circ_0044234 expression could be an independent prognostic biomarker in BC. Interestingly, a substantial inverse expression correlation was detected between circ_0044234 and miR-135b-5p as well as between miR-135b-5p and GATA3 in breast tumors. CONCLUSIONS: The possible clinical usefulness of circ_0044234 as a promising distinct biomarker and upcoming therapeutic target for TNBC have been indicated in this research. Our comprehensive approach revealed the potential circ_0044234/miR135b-5p/GATA3 ceRNA axis in TNBC.

Critical roles of microRNA-196 in normal physiology and non-malignant diseases: Diagnostic and therapeutic implications.

MicroRNAs (miRNAs) have emerged as a critical component of regulatory networks that modulate and fine-tune gene expression in a post-transcriptional manner. The microRNA-196 family is encoded by three loci in the human genome, namely hsa-mir-196a-1, hsa-mir-196a-2, and hsa-mir-196b. Increasing evidence supports the roles of different components of this miRNA family in regulating key cellular processes during differentiation and development, ranging from inflammation and differentiation of stem cells to limb development and remodeling and structure of adipose tissue. This review first discusses about the genomic context and regulation of this miRNA family and then take a bird's eye view on the updated list of its target genes and their biological processes to obtain insights about various functions played by members of the microRNA-196 family. We then describe evidence supporting the involvement of the human microRNA-196 family in regulating critical cellular processes both in physiological and non-malignant inflammatory conditions, highlighting recent seminal findings that carry implications for developing novel therapeutic or diagnostic strategies.

Peripheral Blood Mononuclear Cells Expression Levels of miR-196a and miR-100 in Coronary Artery Disease Patients.

As a chronic inflammatory disease, coronary artery disease (CAD) is a common cause of death worldwide. Dysregulation of microRNA expression levels in peripheral blood mononuclear cells (PBMCs) may contribute to CAD and serve as a potential diagnostic biomarker. Here, we evaluated PBMC expression of two CAD-related inflammatory miRNAs, miR-196a and miR-100, in PBMCs of CAD patients with significant stenosis (CAD, n: 72), patients with insignificant coronary stenosis (ICAD, n: 30), and controls (n: 74) and checked whether they can segregate study groups. MiRNA expression was evaluated using the standard stem-loop RT-qPCR method. MiR-196a expression was downregulated in ICAD compared to CADs and healthy groups. MiR100 expression levels were not different between groups. The receiver operating characteristic (ROC) curve analysis acquainted that miR-196a expression levels in PBMC could segregate CAD individuals or any of its clinical manifestations (i.e. unstable angina, stable angina, acute myocardial infarction) from ICADs. In conclusion, this study reported a distinct miR-196a expression pattern in PBMCs of all patient groups and recommended a biomarker potential for miR-196a in discriminating ICADs from CADs or healthy controls.