Mesial temporal lobe epilepsy (mTLE) is one of the most common and refractory focal epilepsy syndromes. The molecular mechanisms of TLE are not completely understood. The aim of this study was to investigate the expression and potential function of plasma exosomal miRNAs (miR-483-5p, miR-671-5p, and miR-150-3p) in a mouse mode and in temporal lobe epilepsy patients. It was found that exosomal miRNAs were differentially expressed in three phases of the mouse mode, and exosomal miRNAs were down-regulated in mTLE patients compared with healthy controls. A bioinformatics analysis showed that target genes of exosomal miRNAs were significantly involved in the apoptotic process, cell adhesion, nervous system development, neurotrophin signaling pathway, PI3K-Akt signaling pathway, and metabolic pathways. The areas under the curve of miR-483-5p and miR-150-3p were 0.8714 (sensitivity = 75.00%, specificity = 91.65%) and 0.8213 (sensitivity = 67.50%, specificity = 90.00%), respectively. More importantly, the exosomal miRNAs were significantly associated with clinical parameters. Exosomal miRNAs may have the potential to become diagnostic and therapeutic biomarkers.

Age-related sarcopenia meaningfully increases the risks of functional limitations and mortality in the elderly. Although circulating microRNAs (c-miRNAs) are associated with aging-related cellular senescence and inflammation, the relationships between c-miRNAs and sarcopenia in the elderly remain unclear. This study investigates whether circulating myo-miRNAs and inflammation-related miRNAs are associated with sarcopenia in the elderly. This study recruited 77 eligible subjects (41 males and 36 females) from 597 community-dwelling older adults, and then divided into normal (n=24), dynapenic (loss of muscular function without mass, n=35), and sarcopenic groups (loss of muscular function with mass, n=18). Moreover, myo-miRNAs (c-miRNA-133a and c-miRNA-486), inflammation-related miRNAs (c-miRNA-21 and c-miRNA-146a), and inflammatory-related cytokine levels in plasma were determined using quantitative polymerase chain reaction and ELISA, respectively. The results demonstrated that sarcopenic group exhibited lesser skeletal muscle mass index (SMI), handgrip strength, and gait speed, as well as, lower c-miR-486 and c-miR-146a levels, compared to those of normal and dynapenic groups. Moreover, c-miR-486 level was positively related to SMI (r=0.334, P=0.003), whereas c-miR-146a level was positively associated with SMI (r=0.240, P=0.035) and handgrip strength (r=0.253, P=0.027). In the receiver operating characteristic analysis for predicting sarcopenia, the area under the curve in c-miR-486 was 0.708 (95% confidence interval: 0.561-0.855, P=0.008) and c-miR-146a was 0.676 (95% CI: 0.551-0.801, P=0.024). However, no significant relationships were observed between SMI/ handgrip strength/gait speed and plasma myeloperoxidase/interleukin-1?/interleukin-6 levels. In conclusion, myo-miRNA (c-miR-486) and inflammation-related miRNA (c-miR-146a) are superior to inflammatory peroxide/cytokines in plasma for serving as critical biomarkers of age-related sarcopenia.

The pig is an important source of meat production and provides a valuable model for certain human diseases. MicroRNA (miRNA), which is non-coding RNA and regulates gene expression at the posttranscriptional level, plays a critical role in various biological processes. Studies on identification and function of mature miRNAs in multiple pig tissues are increasing, yet the literature is limited. Therefore, we reviewed current research to determine the miRNAs expressed in specific pig tissues that are involved in carcass values (including muscle and adipocytes), reproduction (including pituitary, testis, and ovary), and development of some solid organs (e.g., brain, lung, kidney, and liver). We also discuss the possible regulating mechanisms of miRNA. Finally, as pig organs are suitable candidates for xenotransplantation, biomarkers of their miRNA in xenotransplantation were evaluated.

The World Health Organization has estimated an annual occurrence of approximately 392 million dengue virus (DENV) infections in more than 100 countries where the virus is endemic, and this represents a serious threat to humanity. DENV is a serologic group with four distinct serotypes (DENV1, DENV2, DENV3, and DENV4) belonging to the genus Flavivirus, family Flaviviridae. Dengue is the most widespread mosquito-borne disease in the world. The ~10.7 kb DENV genome encodes three structural proteins (capsid [C], pre-membrane [prM], and envelope [E]) and seven non-structural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The NS1 protein is found both as a membrane-associated dimer and as a secreted, lipid-associated hexamer. Dimeric NS1 is found on membranes both in cellular compartments and on the cell surface. Secreted NS1 (sNS1) is often present in patient serum at very high levels, which correlates with severe dengue symptoms. This study was carried out to find out how the NS1 protein, miRNAs 15 and 16, and apoptosis are related to each other during DENV4 infection in human liver cell line culture. The Huh 7.5 and HepG2 strains were infected with DENV4, and after different times of infection, miRNA-15 and miRNA-16, viral load, NS1 protein, and caspases 3 and 7 were quantified. This study demonstrated that miRNAs 15 and 16 are overexpressed during infection of HepG2 and HuH7.5 cells by DENV4 and have a relationship with NS1 protein expression, VDEN4 viral load, and caspase pathways 3 and 7, thus making these miRNAs interesting targets for markers of injuries during VDEN infection in human hepatocyte cells.

Background/Aims: Screening for gestational diabetes mellitus (GDM) are currently done at 24 - 28 weeks of conception, missing out on the most vulnerable period of organogenesis and thus preventing clinicians from starting treatments until the late second or third trimester. MicroRNAs (miR) are small non-coding RNA molecules that could aid in detecting or predicting GDM through establishing a novel non-invasive prenatal testing (NIPT) tool. The objective of this study was to summarize the most recent updates on plasma microRNAs as GDM diagnostic biomarkers. Methods: Between April and June 2021, a PubMed literature search was undertaken to review recent articles on human plasma miR associated with GDM. Animal studies and papers that are written in languages other than English were excluded. Only plasma miRNAs were used to avoid coagulation biases. Results: A total of 31 miRNAs were found significantly upregulated in the plasma samples of patients with GDM. It was found mainly during the 2nd or 3rd trimester except for miR-223 and miR-23a that were upregulated at 9 – 11 weeks of gestation. Conclusion: Though extensive prospective cohort studies are required, miR-223 and miR-23a should be considered the most promising to develop a successful NIPT tool because they were found to be upregulated earliest, during the first trimester.

In our modern days, macromolecular biomolecules are dethroning classical small molecule therapeutics because of improved targeting and delivery properties. Protamine – a small polycationic peptide represents such a promising candidate. In nature, it binds and protects DNA against degradation during spermatogenesis due to electrostatic interaction between the negatively charged DNA-Phosphate backbone and the positively charged protamine. Researchers are mimicking this technique in order to develop innovative nanopharmaceutical drug delivery systems, incorporating protamine as carrier for biologically active components such as DNA or RNA. The first key part of this review highlights ongoing investigation in the field of protamine-associated nanotechnology, discussing the self-assembling manufacturing process and nanoparticle engineering. Immune-modulating properties of protamine are referred which lead to the second key part protamine in novel vaccine technologies. Protamine-based RNA delivery systems in vaccines (some of them belong to the new class of mRNA-vaccines) against infectious disease and their use in cancer treatment are reviewed and an update on the current state of latest developments with protamine as pharmaceutical excipient for vaccines is given.

Plasma microRNAs are considered to be potential diagnostic biomarkers for endometriosis. Increasing evidence has shown that a huge amount of miRNAs are abnormally expressed in endometriosis plasma and play irreplaceable roles in diagnosis. The aim of the our study was to identify the differential expression of circular miRNA by reviewing the PubMed, ScienceDirect, and Cochrane databases between normal women and women with endometriosis and analyzing the miRNA data downloaded from the GEO database. Because of the differential miRNA expression in this review, we evaluated the diagnostic values of the differentially expressed miRNAs, particularly during the menstrual phases. According to the cut-off criteria with |log 2 FC|>1.0 and P < 0.05, 36 differentially expressed miRNAs were identified, including 13 upregulated miRNAs and 23 downregulated miRNAs. We developed miR-155, miR-574, miR-23a, and miR-520d via a Venn diagram. Functional enrichment analysis considered that the target miRNAs might be involved in various pathways related to endometriosis, including neurotrophin, Hippo, oocyte meiosis, ubiquitin mediated proteolysis, HTLV-Infection, FoxO, and Rap1 signaling pathways. CTNNB1, MYC, and ES R1 of transcription factors were related to the differentially expressed miRNAs. In summary, our study suggested that a four-miRNA could be included as a prognostic marker in endometriosis.

MicroRNA (miRNA) is a typical class of small RNAs that could modulate gene expression in trans at the post-transcriptional level. miRNAs bind to the miRNA binding sites (MBSs) in target mRNAs by sequence complementarity. Alternative splicing (AS) is another commonly occurred process in pre-mRNAs that changes the isoforms of a gene. It is hypothesized that there should be an interaction for gene regulation that involves both AS and miRNA targeting. Studies have verified this hypothesis in the model organism Arabidopsis thaliana. High-throughput sequencing data suggested that in Arabidopsis a considerably large fraction of MBSs are affected by AS events. The overlapping between MBS and AS exceeds the randomly simulated number. Functional experiments have indicated that the AS events are required for the gene expression changes of miRNA targets. Therefore, AS and MBS are mutually favored. The observed expression changes caused by miRNAs could also be contributed by AS events. In the present perspective article, we propose that the AS analysis should be incorporated in the differential-expression analysis of miRNA studies. When defining a differentially-expressed gene, it should be clarified whether the change in gene expression is caused by AS events or solely by miRNA targeting.

MicroRNAs (miRNAs) are small and non-coding RNAs displaying aberrant expression in the tissue and plasma of cancer patients in comparison to healthy individuals. In past decades, accumulating data proposed that miRNAs could be diagnostic and prognostic biomarkers in cancer patients. It has been identified that miRNAs can act either as oncogenes through silencing of tumor inhibitors or tumor suppressor via targeting oncoproteins. MiR-144 is located in chromosomal region 17q11.2 that was widely destroyed in many types of cancers. Several studies revealed that miR-144 has different target genes including rapamycin, zonula occludens1, SFRP1, and ANO1. MiR-144 acts as a tumor suppressor or oncogene by targeting specific genes. In this review, we define the role of miR‐144 and its targets in different cancers and provide understanding in tumor proliferation, migration, and apoptosis.

The wide range of applications of nanoparticles (NPs) has increased the probability of environmental and occupational exposure. In a previous comparative study on cell line A549, we observed that oxidative stress caused by Co₃O₄ NPs affects the energetic homeostasis and the detoxification capacity, preventing autophagy induced by TiO₂ NPs. In this study, we have investigated the effects of NPs on the cell cycle.Cytofluorimetric analysis showed a slow-down of the cell cycle progression for both NPs, with increases in the percentage of resting cells in the G0/G1. These observations were confirmed by a reduced expression of all cyclins, especially of CCNE1 and CDK2, involved in the late stages of the G1 phase, coupled with a significant increase in the expression of p21 only for Co₃O₄ NP exposure. On the contrary, the effects of TiO₂ NPs were modest. Cell cycle related miRNA-34a, miRNA-126 and miRNA-1290 resulted increased at different early time-points (4-8h) but were down-expressed at 24h-48h only after TiO₂ NP exposure. Our results show that NPs have an antiproliferative effect and deregulate cell cycle on A549 cells. These effects should not be underestimated because regulation of cycle progression is crucial for cell survival and repair of genetic damage.

Epigenetic alterations have contributed greatly to human carcinogenesis. Conventional epigenetic studies have been predominantly focused on DNA methylation, histone modifications and chromatin remodelling. However, recently, RNA modification (m6A-methylation) also termed ‘epitranscriptomics’ has emerged as a new layer of epigenetic regulation due to its diverse role in various biological processes. In this review, we have summarized the therapeutic potential of m6A-modifiers in controlling haematological disorders especially acute myeloid leukemia (AML). It is a type of blood cancer affecting specific subsets of blood-forming hematopoietic stem/progenitor cells (HSPCs) which proliferate rapidly and acquire self-renewable capacities with impaired terminal cell-differentiation and apoptosis leading to abnormal accumulation of white blood cells, and thus an alternative therapeutic approach is required urgently. Here, we have described how RNA m6A-modification machineries EEE (Editor/writer: Mettl3, Mettl14; Eraser/remover: FTO, ALKBH5 and Effector/reader: YTHDF-1/2) could be reformed into potential druggable candidate or as RNA modifying drug (RMD) to treat leukemia. Moreover, we have shed-light on the role of microRNA and suppressor of cytokine signalling (SOCS/CISH) in increasing anti-tumor immunity towards leukemia. We anticipate, our investigation will provide a fundamental knowledge in nurturing the potential of RNA modifiers in discovering novel therapeutics or immunotherapeutic procedures.

The environmental exposure of human in the daily and occupational activities to plasticizers may adversely affect human health, and thus represents a global issue. The altered expression of MicroRNAs (miRNAs) exerts an important pathogenic role linked also to the exposure to plasticizers. This systematic review summarizes the recent findings showing modified ex-pression of miRNAs in cancer due to plasticizers exposures. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, we performed a systematic review of the past ten years, focusing on the relationship between plasticizer exposures and expression of miRNAs cancer. Starting by 535 records, 17 articles were included. Results support the hypothesis that exposure to plasticizers cause changes or deregulation of a number of oncogenic miRNAs and showed that plasticizers interaction with several redundant miRNAs, such as let-7f, let-7g, miR-125b, miR-134, miR-146a, miR-22; miR-192, miR-222, miR-26a, miR-26b, miR-27b, miR-296, miR-324, miR-335, miR-122, miR-23b, miR-200, miR-29a and miR-21, might induce deep alterations. These genotoxic and oncogenic responses can eventually lead to abnormal cell signaling pathways and metabolisms that participate in many overlapped cellular processes, and miRNA level changes can be a useful tool for the toxicological assessment of environmental pollutants, including plastic additives and plasticizers

MicroRNAs are small non-coding RNAs that are implicated in several physiological processes such as cell development, proliferation, differentiation, apoptosis, immune response and angiogenesis. In the last couple of decades, several studies on miRNA profiling in OSCC have tried to associate miRNAs with clinical characteristics such as relapse, metastasis, and survival, however, the results have been found to vary considerably, sometimes even being contradictory. The main objective of our study was to analyse and verify miRNA expression in oral squamous cell carcinoma in a Spanish population. Second, we attempted to associate the identified deregulated miRNAs with molecular pathways. 8 Oral Squamous Cell Carcinoma patients and 8 healthy control samples were analysed by a microarray Affymetrix® miRNA 4.1 array plate and validated with 8 more cases using RT-qPCR. Deregulated miRNAs were studied using Diana Tools miRPath 3.0 to associate miRNA targets with molecular pathways. Microarray analysis identified 80 deregulated miRNAs (35 over-expressed and 45 under-expressed). Only miR-497-5p and miR-4417 maintained its deregulated expression after validation with qPCR. Among the molecular pathways in which deregulated miRNAs could be implicated, the most statistically significant pathway was ‘proteoglycans in cancer’. No relationship was found between miR-497-5p or miR-4417 expression and clinical or pathological parameters except of nodular affectation (high miR-4417 expression in patients with nodular affectation, p = 0.035) and radiotherapy (diminished miR-497-5p expression in patients who needed radiotherapy, p = 0.05). We have verified the altered expression of miR-497-5p and miR-4417 in Oral Squamous Cell Carcinoma samples and related the deregulated miRNAs with the ‘proteoglycans in cancer’ pathway.

Alfalfa, an important legume forage, is an ideal crop for sustainable agriculture and a potential bioenergy plant. Drought, one of the most common environmental stresses, substantially affects plants’ growth, development and productivity. MicroRNAs (miRNAs) are newly discovered gene expression regulators that have been linked to several plant stress responses. To elucidate the role of miRNAs in drought stress regulation of alfalfa, a high-throughput sequencing approach was used to analyze 12 small RNA libraries comprising of 4 samples, each with 3 biological replicates. We identified 348 known miRNAs, belonging to 80 miRNA families, from the 12 libraries and 281 novel miRNAs using Mireap software. 18 known miRNAs in roots and 12 known miRNAs in leaves were screened out as drought-responsive miRNAs. Except for miR319d and miR157a which were upregulated under drought stress, the expression pattern of drought-responsive miRNAs were different between roots and leaves in alfalfa. This is the first study discovering miR157a, miR1507, miR3512, miR3630, miR5213, miR5294, miR5368 and miR6173 are drought-responsive miRNAs. Target transcripts of drought-responsive miRNAs were computationally predicted. All 447 target genes for the known miRNAs were predicted using an online tool. This study provides a significant insight on understanding drought-responsive mechanisms of alfalfa.

MiRNAs are 20-22 nucleotide long single-stranded non-coding RNA sequences, which can regulate post transcriptional activity of mRNA by binding with it at 3’UTR region (untranslated region). Thus deregulation of miRNA expression is responsible for dysregulating mRNA function which contributes in developing various diseases as well as cancerous phenotypes. Alteration of single nucleotide in miRNA sequence is one of the reasons behind deregulation of miRNA expression. The most frequent carcinoma in current day is breast cancer which causes a high mortality among women around the world as well as India. Despite of the advancement of diagnostic tools, strategies and treatment, the cases of breast cancer is increasing every year. There are plenty of biomarkers like ER, PR, Her2, Ki-67, etc available which are frequently used in diagnosis and treatment of breast cancer. After the discovery of MiRNA in 1993 in Caenorhabiditis elegans, it is attracting all the limelight in diagnosis and treatment of different carcinomas as well as breast cancer. In this review we will discuss on involvement of different types of MiRNAs and miR SNPs in breast cancer occurrence and susceptibility in a detailed manner.

Breast (BC) and gynecological (GC) cancers constitute a group of female neoplasms that has a worldwide significant contribution to cancer morbidity and mortality. Evidence suggests that polymorphisms influencing miRNA function can provide useful information to predict the risk of female neoplasms. To facilitate the genetic screening of miRNA polymorphisms even during childhood or adolescence, and their use as predictors of future malignancies, inconsistent findings in the literature should be detected and resolved. This study represents a comprehensive systematic review and meta-analysis of the association between miRNA polymorphisms and the risk of female neoplasms. Meta-analysis was performed by pooling odds-ratios (ORs) and generalized ORs using a random-effects model for 15 miRNA polymorphisms. The results suggest that miR-146a rs2910164 is implicated in the susceptibility to GC. Moreover, miR-196a2 rs11614913-T had a moderate protective effect against female neoplasms, especially GC, in Asians but not in Caucasians. MiR-27a rs895819-G may pose a protective effect against BC among Caucasians. MiR-499 rs3746444-C may slightly increase the risk of female neoplasms especially BC. MiR-124 rs531564-G may be associated with a lower risk of female neoplasms. The current evidences do not support the association of the remaining polymorphisms and the risk of female neoplasms.

MicroRNAs (miRNAs) are a kind of conserved small non-coding RNAs that participate in regulating gene expression by targeting multiple molecules. Early studies have shown that the expression of miRNAs changes significantly in different tumor tissues and cancer cell lines. It is well acknowledged that such variation is involved in almost all biological processes, including cell proliferation, mobility, survival and differentiation. Increasing experimental data indicate that miRNA dysregulation is a biomarker of several pathological conditions including cancer, and that miRNA can exert a causal role, as oncogenes or tumor suppressor genes, in different steps of the tumorigenic process. Anticancer therapies based on miRNAs are currently being developed with a goal to improve outcomes of cancer treatment. In our present study, we review the function of miRNAs in tumorigenesis and development, and discuss the latest clinical applications and strategies of therapy targeting miRNAs in cancer.

Heart failure with preserved ejection fraction (HFpEF) remains a poorly characterized syndrome with many dark aspects related to different patients profile, various associated risk factors and wide aetiologies. It comprises several pathophysiological pathways related to endothelial dysfunction, myocardial fibrosis, extracellular matrix deposition and high inflammatory response. Up to now, it has been described only for clinical appearance and most common associated risk factors without an effective characterization of biological processes responsible for cardiovascular deteriorations. Recent advances in laboratory and metabolomic researches showed that HFpEF appears strictly related to specific cells and molecular mechanisms dysregulation. Some biomarkers are capable to early identify these processes adding new insights into diagnosis and risk stratification. Additionally recent advances on intermediate metabolites reflecting provide relevant information on intrinsic cellular and energetic substrate alterations. The systematic combination of clinical imaging and laboratory data may lead to a precision medicine approach providing prognostic and therapeutic advantages. Current review reports traditional and emerging biomarkers recently investigated in HFpEF setting, and it purpose a new diagnostic approach based on integrative information achieved from risk factors burden, hemodynamic dysfunction and biomarkers signature partnership.

This review aimed at synthesizing the mechanisms and outcomes of metabolic surgery on hormones, adipokines, metabolomics, and at the molecular level. We reviewed the endocrine, microRNA, and metabolomics changes in human and animal models following metabolic surgery for the treatment of obesity and diabetes. PubMed, Science Direct, Scopus, and Google Scholar databases were searched up to February 2022. The most relevant studies in the area over the past 17 years have been considered for this review. In most cases, metabolic procedures especially those that include intestinal bypass components, showed remission of type 2 diabetes. This involves a variety of weight-independent mechanisms to improve glucose homeostasis, improving insulin sensitivity, and secretion. The miRNAs’ dysregulated expressions have essential roles in metabolic processes. Metabolic surgery is a potentially sustainable treatment that can modify a patient’s physiology and glucose regulation mechanism. The feasibility and role of miRNA are important for potential targeted genetic pathways in future obesity with type 2 diabetes management.

Ongoing beta cell death in type 1 diabetes (T1D) can be detected using biomarkers selectively discharged by dying beta cells into plasma. MicroRNA-375 (miR-375) ranks among top biomarkers based on studies in animal models and human islet transplantation. Our objective was to identify additional microRNAs that are co-released with miR-375 proportionate to the amount of beta cell destruction. RT-PCR profiling of 733 microRNAs in a discovery cohort of T1D patients 1 hour before/after islet transplantation indicated increased plasma levels of 22 microRNAs. Sub-selection for beta cell selectivity resulted in 15 microRNAs that were subjected to double-blinded multicenter analysis. This led to identification of 8 microRNAs that were consistently increased during early graft destruction: besides miR-375, these included miR-132/204/410/200a/429/125b, microRNAs with known function and enrichment in beta cells. Their potential clinical translation was investigated in a third independent cohort of 46 transplant patients, by correlating post-transplant microRNA levels to C-peptide levels 2 months later. Only miR-375 and miR-132 had prognostic potential for graft outcome and none of the newly identified microRNAs outperformed miR-375 in multiple regression. In conclusion, this study reveals multiple beta cell-enriched microRNAs that are co-released with miR-375 and can be used as complementary biomarkers of beta cell death.

Background SARS-CoV-2 has generated a life-treating pandemic and is the main challenge of this century. Some untranslated regions (UTRs) in SARS-CoV-2 genome, specifically leader sequence and transcription regulatory sequence (TRS) in 5’UTR, can be considered as Achilles' heel of virus. Leader sequence are found at the 5' ends of all encoded transcripts that highlights its importance. TRS can explain the host range and pathogenicity of coronavirus. However, our knowledge on the evolution and the role of UTRs in SARS-CoV-2 pathogenicity is very limited. This study is a pioneering attempt to unravel the evolution of key regions in 5' UTR of SARS-CoV-2 and discover the inhibitory microRNAs against 5' UTR of virus. Methods Evolution of TRS and leader sequence was compared between human pathogenic (SARS-CoV-2, SARS, and MERS) and non-pathogenic (bovine) coronaviruses. Profiling of microRNAs that can inactive the key UTR regions of coronaviruses, UTR-inhibitory microRNAs, was carried out. Findings We found a distinguished pattern of evolution in leader sequence and TRS of SARS-CoV-2, compared to the other coronaviruses. Mining all available microRNA families against leader sequences of coronaviruses resulted in discovery of 39 microRNAs with an acceptable thermodynamic binding energy against SARS-COV-2, SARS, MERS, Bat Coronavirus, or Bovine Coronavirus. Multivariate analysis demonstrated a distinguished pattern of binding of leader sequence of SARS-CoV-2 against microRNAs, with a lower binding stability. hsa-MIR-5004-3p was the only human microRNA that can target leader sequence of SARS and SARS-CoV-2. However, its binding stability remarkably decreased in SARS-COV-2 (-19.4 kcal/mol), compared to SARS-COV-2 (-25.9 kcal/mol). We found an insertion-type mutation in leader sequence of SARS-COV-2 that results in lower binding stability and escaping of viral leader sequence from hsa-MIR-5004-3p. Altogether, we suggest lack of innate human inhibitory microRNAs to bind to leader sequence and TRS of SARS-CoV-2 contributes to its high replication in infected human cells. On the other hand, mining of two hundred million deposited human genomic variants led us to discovery of 49 missense and splice-disrupt mutations in genomic structure of hsa-MIR-5004-3p. These mutations can negatively affect hsa-MIR-5004-3p function in preventing SARS-CoV-2 replication. Interpretation This study unravels the evolution of key regions in 5’UTR of SARS-CoV-2. Inducing microRNAs to bind to the leader sequence and TRS regions by drugs or food supplements can reduce virus replication. Enhancing the microRNA defence machinery against TRS and leader of virus has a potential to prevent SARS-CoV-2 infection at the first place. The mentioned strategy is rapidly achievable against COVID-19. Missense variation in genomic sequence of 5’UTR inhibitory microRNAs, such as hsa-MIR-5004-3p, can be considered as risk factor of COVID-19.

Cervical cancer is known as one of the most important cancers in women worldwide. Chemotherapy is a standard treatment for advanced/recurrent cervical cancer in which the prognosis of the disease is really poor and the 1-year survival chance in these patients is maximally 20%. However, resistance to anticancer drugs is a major problem in treating cancer. Cervical cancer stem cells are considered as a fundamental cause of chemo and radio-resistance and also relapse after primary successful treatment. Signaling pathways include a wide range of molecular mechanisms contribute to drug resistance. Recently, microRNAs (miRNAs) are announced as a group of molecular biomarkers involving in response to chemotherapy in cancer patients. As the miRNAs, there are some long non-coding RNAs (LncRNAs) which their aberrant expression is considered as a biomarker for monitoring chemoresistance. In this review, we summarized current reports about the involvement of signaling pathways during chemoresistance in cervical cancer. Then, genes that have been demonstrated their involvement during drug resistance in cervical cancer were tabulated. Further, miRNAs that have been reported as biomarkers during treatment are listed. By bioinformatic analysis, we predictedmiR-335-5p and miR-16-5p as the most potential biomarkers for monitoring resistance to chemotherapy. Finally, long non-coding RNAs that have been introduced in recent studies as novel biomarkers during the response to chemotherapy were mentioned.

Background: Glioblastoma (GBM), a malignant grade IV tumor, is the most malignant brain tumor due to its hyper-proliferative and apoptosis-evading characteristics. The signal transducer and activators of transcription (STAT) family genes, including STAT3 and STAT5A, have been indicated to play important roles in GBM progression. Increasing number of reports suggest that Garcinol, a polyisoprenylated benzophenone and major bioactive component of Garcinia indica contains potent anti-cancer activities. Material & Methods: The present study investigated the anti-GBM effects of garcinol, focusing on the STAT3/STAT5A activation, using a combination of bioinformatics, in vitro, and ex vivo assays. Results: Our bioinformatics analysis of TCGA - GBM cohort (n=173) showed that STAT3 and STAT5A are preferentially elevated in primary and recurrent GBM, compared to non-tumor brain tissues, and is significantly correlated with reduced overall survival. In support, our immunohistochemical staining of a GBM cohort (n=30) showed an estimated 5.3-fold (p<0.001) elevation in STAT3 and STAT5A protein expression in primary and recurrent GBM versus the non-tumor group. In vitro, garcinol treatment significantly suppressed the proliferative, invasive, and migratory potential of U87MG or GBM8401 cells, dose-dependently. In addition, garcinol anticancer effect significantly attenuated the GBM stem cell-like phenotypes, as reflected by diminished ability of U87MG or GBM8401 to form colonies and tumorspheres and suppressed expression of OCT4 and SOX2. Furthermore, analysis on GBM transcriptome revealed an inverse correlation between the level of STAT3/5A and hsa-miR-181d. Garcinol-mediated anti-GBM effects were associated with an increased hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratio. Conclusion: We present evidence of anti-GBM efficacy of garcinol mediated by enhancing the hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratios in GBM cells. Our findings suggest a potential new therapeutic agent for combating aggressive GBM.

The risk of gastric cancer (GC) declines after Helicobacter pylori (H. pylori) eradication and long-term aspirin use. We evaluated the effects of H. pylori eradication (Cohort 1) and aspirin use (Cohort 2) on the methylation of microRNAs (miRNAs) such as miR-34c, miR-124a-3, miR-129-2, and miR-137 in the gastric mucosa with and without GC, i.e., atrophic mucosa (AM) and intestinal metaplasia (IM). DNA was isolated from AM and IM separately using laser caption microdissection. In Cohort 1, H. pylori eradication was associated with a significant reduction of miR-124a-3 methylation only in AM, but not in IM. miR-129-2 methylation in AM may be a surrogate marker of GC in H. pylori-infected patients. In Cohort 2, aspirin did not reverse miRNA methylation in either AM or IM irrespective of H. pylori infection. miR-129-2 methylation in AM was an independent predictive marker of GC in H. pylori-infected but not -eradicated patients. These results indicate that H. pylori eradication and aspirin use were less effective in improving methylation in IM compared with AM; thus, these interventions are recommended at an early stage prior to the development of IM to prevent GC development.

Tumor microenvironment including cancer-associated fibroblasts (CAF) has developed as an important target for understanding tumor progression, clinical prognosis and treatment responses of cancer. Cancer cells appear to transform normal fibroblasts (NF) into CAFs involving direct cell-cell communication and epigenetic regulations. This review summarizes the current understanding on miR involvement in cancer cell – tumor environment/stroma communication, transformation of NFs into CAFs, their involved targets and signaling pathways in these interactions; and clinical relevance of CAF-related miR expression profiles. There is evidence that miRs have very similar roles in activating hepatic (HSC) and pancreatic stellate cells (PSC) as part of precancerous fibrotic diseases. In summary, deregulated miRs affect various intracellular functional complexes, such as transcriptional factors, extracellular matrix, cytoskeleton, EMT/MET regulation, soluble factors, tyrosine kinase and G-protein signaling, apoptosis and cell cycle & differentiation, but also formation and composition of the extracellular microenvironment. These processes result in the clinical appearance of desmoplasia involving CAFs and fibrosis characterized by deregulated stellate cells. In addition, modulated release of soluble factors can act as (auto)activating feedback loop for transition of NFs into their pathological counterparts. Furthermore, epigenetic communication between CAFs and cancer cells may confer to cancer specific functional readouts and transition of NF into their pathological counterparts. MiR related epigenetic regulation with many similarities should be considered as key factor in development of cancer and fibrosis specific environment.

Breast cancer prevention is very important for a woman's health worldwide. We have demonstrated a correlation between mammography and ultrasound with diagnoses using passive microwave radiometry (MWR) and a miRNA oncopanel. While mammography screening dynamics could be completed in 3-6 months, MWR will provide us with a prediction in a matter of weeks or even days with the potential for complementary miRNA diagnostics. An early breast cancer diagnosis may be accomplished using either one of these novel techniques alone or in conjunction with more established techniques

MicroRNAs are used as biomarkers for classification of cancer subtypes since certain miRNAs are differentially expressed in normal and patient samples. Moreover, miRNAs target mRNAs and can heavily influence Gene Expressions. Thus, deregulation of miRNAs is linked to various disorders. Thus, miRNAs can be used for prognosis and developing personalized health solutions for patients. Given the importance of miRNAs, there has been substantial work done in the field. In this paper, recent works in the field of using miRNAs expressions of patients were considered. A total of 20 papers were surveyed which utilized feature selection ensembles, fuzzy logic as well as deep learning. 10 papers have been reported which offer insight into how miRNAs can be utilized for subtype-specific or generalized cancer diagnosis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus, is responsible for coronavirus disease 2019 (COVID-19) pandemic of 2020. Experimental evidence suggests that microRNA can mediate an intracellular defence mechanism against some RNA viruses. The purpose of this study was to identify microRNA with predicted binding sites in the SARS-CoV-2 genome, compare these to their microRNA expression profiles in lung epithelial tissue and make inference towards possible roles for microRNA in mitigating coronavirus infection. We hypothesize that high expression of specific coronavirus-targeting microRNA in lung epithelia may protect against infection and viral propagation, conversely low expression may confer susceptibility to infection. We have identified 128 human microRNA with potential to target the SARS-CoV-2 genome, most of which have very low expression in lung epithelia. Six of these 128 microRNA are differentially expressed upon in vitro infection of SARS-CoV-2. Twenty-eight and 23 microRNA also target the SARS-CoV and MERS-CoV, respectively. In addition, 48 and 32 microRNA are commonly identified in two other studies. Further research into identifying bona fide coronavirus targeting microRNA will be useful in understanding the importance of microRNA as cellular defence mechanism against pathogenic coronavirus infections.

Aberration in microRNA (miRNA) expression or DNA methylation is a causal factor for polycystic ovarian syndrome (PCOS), a common endocrine disorder and leading cause of infertility. However, the epigenetic interactions between miRNA and DNA methylation remain unexplored in PCOS. In this study, we conducted an integrated analysis of RNA-seq, miRNA-seq and MBD-seq on ovarian granulosa cells of PCOS and control groups to reveal the epigenetic interactions involved in the pathogenesis of PCOS. Firstly, we identified 830 genes and 30 miRNAs that were expressed differently in PCOS, and seven miRNAs were found to negatively regulate targeted mRNA expression. Next, in total, 130 miRNAs were found to be significantly differently methylated in promoter regions, while 13 were found to be associated with miRNA expression. Furthermore, the promoter hypermethylation of miR-429, miR-141-3p, and miR-126-3p was proven to suppress miRNA expression and therefore upregulate their corresponding genes, including XIAP, BRD3, MAPK14 and SLC7A5. Our results demonstrate that DNA methylation regulates miRNA expression and therefore controls its corresponding gene expression. The reactivation of the transcription of epigenetically silenced genes may be one of the key elements in PCOS pathogenesis. Meanwhile, the epigenetic mechanisms underlying the regulation of miRNA expression can provide a potential therapeutic target for PCOS in the future.

Background: Breast cancer is the leading cause of cancer mortality and morbidity among Indonesian women. Identification of biological pathways leading into therapeutic resistance through in vitro model is an important step to develop alternative effective therapy in breast cancer. Loss of PTEN expression has been associated with resistance to chemotherapy by involving PI3K/PTEN- dependent apoptosis pathway. We conducted in vitro experiment to investigate the association of hsa-miR-21 and PTEN expression in Doxorubicin-resistant MCF-7 cell line. Methods: Parental MCF-7 cells were periodically incubated with Doxorubicin to obtain specific Dox-resistant variant determined by IC50 using MTT assay. PTEN protein expression was analyzed using immunocytochemistry. Expression of mature has-miR-21 was measured using qRT-PCR. Results: The IC50 of Doxorubicin in parental MCF-7 and Doxorubicin-resistant MCF-7 cells (MCF-7/Dox) was 0.68 and 5.78 µg/ml, respectively. Hsa-miR-21 was significantly overexpressed in MCF-7/Dox cells compared to parental MCF cells (7.94 fold changes). Conclusion: PTEN and hsa-miR-21 expression levels were negatively correlated in Doxorubicin resistant-MCF cells. Further study to confirm the causal relationship of miR-21 overexpression and PTEN downregulation in MCF-7/Dox is required.

Retinoic acid (RA) is the biologically active metabolite of vitamin A and has become a well-established factor that induces neurite outgrowth and regeneration in both vertebrates and invertebrates. However, the underlying regulatory mechanisms that may mediate RA-induced neurite sprouting remain unclear. In the past decade, microRNAs have emerged as important regulators of nervous system development and regeneration, and have been shown to contribute to processes such as neurite sprouting. However, few studies have demonstrated the role of miRNAs in RA-induced neurite sprouting. By miRNA-Sequencing analysis, we identify 482 miRNAs in the regenerating CNS of the mollusc Lymnaea stagnalis, 219 of which represent potentially novel miRNAs. Of the remaining conserved miRNAs, 38 show a statistically significant up or downregulation in regenerating CNS as a result of RA treatment. We further characterized the expression of one neuronally-enriched miRNA upregulated by RA, miR-124. We demonstrate for the first time that miR-124 is expressed within the cell bodies and neurites of regenerating motorneurons. Moreover, we identify miR-124 expression within the growth cones of cultured ciliary motorneurons (Pedal A), whereas expression in the growth cones of another class of respiratory motorneurons (RPA) was absent in vitro. These findings support our hypothesis that miRNAs are important regulators of retinoic acid-induced neuronal outgrowth and regeneration in regeneration-competent species.

Retinoic acid (RA) is the biologically active metabolite of vitamin A,and has become a well-established factor that induces neurite outgrowth and regeneration in both vertebrates and invertebrates. However, the underlying regulatory mechanisms that may mediate RA-induced neurite sprouting remain unclear. In the past decade, microRNAs have emerged as important regulators of nervous system development and regeneration, and have been shown to contribute to processes such as neurite sprouting. However, few studies have demonstrated the role of miRNAs in RA-induced neurite sprouting. By R-Seq analysis, we identify 482 miRNAs in the regenerating CNS of the mollusc Lymnaea stagnalis, 219 of which represent potentially novel miRNAs. Of the remaining conserved miRNAs, 38 show a statistically significant up or downregulation in regenerating CNS as a result of RA treatment. We further characterized the expression of one neuronally-enriched miRNA upregulated by RA, miR-124. We demonstrate for the first time that miR-124 is expressed within the cell bodies and neurites of regenerating motorneurons. Moreover, we identify miR-124 expression within the growth cones of cultured ciliary motorneurons (Pedal A), whereas expression from the growth cones of another class of respiratory motorneurons (RPA) was absent in vitro. These findings support our hypothesis miRNAs are important regulators of retinoic acid induced neuronal outgrowth and regeneration in regeneration-competent species.

Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct. The effect of current chemotherapy regimens against cholangiocarcinoma is limited, and the prognosis of patients with cholangiocarcinoma is poor. Aberrant DNA methylation and histone modification induce silencing of tumor suppressor genes and chromosomal instability during carcinogenesis. Studies have shown that the tumor suppressor genes and microRNAs (miRNAs) including MLH1, p14, p16, DAPK, miR-370 and miR-376c are frequently methylated in cholangiocarcinoma. Silencing of these tumor suppressor genes and miRNAs plays critical roles in the initiation and progression of cholangiocarcinoma. In addition, recent studies have demonstrated that DNA methylation inhibitors induce expression of endogenous retroviruses and exert the anti-tumor effect of via an anti-viral immune response. Aberrant DNA methylation of tumor suppressor genes and miRNAs could be a powerful biomarker for diagnosis and treatment of cholangiocarcinoma. Epigenetic therapy with DNA methylation inhibitors hold considerable promise for the treatment of cholangiocarcinoma through re-activation of tumor suppressor genes and miRNAs as well as induction of an anti-viral immune response.

Brain stem cells (neural stem cells or NSCs) and neurons of a chosen kind reprogramming is a potential technique for cell therapy. It is possible to reprogram non-neuronal cells, for example, by using a predetermined group of factors, nuclear transfer, and the induced transcriptional factors (TFs) expression in a related lineage of cells, and non-coding microRNAs (miRNAs). Researchers have additionally been attempting to improve reprogramming methods, whether it is by employing unique sets of biomolecules and particular TFs or by delivering relevant miRNA and Biomolecules. The technique of miRNA mediated is intriguing for its capability to quickly create a range of biologically desirable cell types for therapy from different lineages of cells. Current findings have made significant advancements towards changing the somatic cells to diverse particular neuronal subgroups with greater efficiency, using reprogramming of miRNA-mediated neural cells, despite the fact that the precise processes need to be discovered. To further understand how miRNAs might direct somatic cells to become neural, we need to look at the latest research on their function in neural reprogramming over the differentiated cells. Recent findings on the role of miRNAs in the initiation of cell reprogramming and the determination of the neuronal subtype's destiny are the primary focus of this comprehensive overview. Furthermore, we cover the far more latest results concerning certain miRNAs' activity in controlling different phases of neuronal differentiation, which contributes in comprehending the interaction network of miRNAs and their receptors.

Inhalational anesthetics was previously reported to suppress glioma cell malignancy, but underlying mechanisms remain unclear. The present study aims to investigate the effects of sevoflurane and desflurane on glioma cell malignancy changes via microRNA (miRNA) modulation. The cultured H4 cells were exposed to 3.6% sevoflurane or 10.3% desflurane for 2 hrs. The miR-138, -210 and -335 expression were determined with qRT-PCR. Cell proliferation and migration were assessed with wound healing assay, Ki67 staining and cell count kit 8 (CCK8) assay with/without miR-138/-210/-335 inhibitor transfections. The miRNA downstream proteins, hypoxia inducible factor-1α (HIF-1α) and matrix metalloproteinase 9 (MMP9), were also determined with immunofluorescent staining. Sevoflurane and desflurane exposure to glioma cells inhibited their proliferation and migration. Sevoflurane exposure increased miR-210 expression whereas desflurane exposure upregulated both miR-138 and miR-335 expressions. The administration of inhibitor of miR-138, -210 or -335 inhibited the suppressing effects of sevoflurane or desflurane on cell proliferation and migration, in line with the HIF-1α and MMP9 expression changes. These data indicated that inhalational anesthetics, sevoflurane and desflurane, inhibited glioma cell malignancy via miRNA upregulation and their downstream effectors, HIF-1α and MMP9, downregulation. The implication of the current study warrants further study.

Endometriosis is a disease that affects women of reproductive age and has a significant impact on their well-being. The main symptoms are dysmenorrhea, chronic pelvic pain and infertility. The diagnostic process in many cases is very long and can take up to 8-12 years. Laparoscopy, which is an invasive method, is still necessary to confirm final identification. Therefore, the development of diagnostic markers seems to be crucial for the diagnosis and proper treatment of women affected by endometriosis as soon as possible. Still the most frequently studied and used marker is Cancer Antigen 125 (CA-125). Other glycoproteins, growth factors and immune markers seem to play an important role. However, the search for the ideal endometriosis marker is still ongoing. Developing researches on endometriosis pathogenesis help to identify potential biomarkers or sets of biomarkers in order to improve and speed up the diagnostic process in a non-invasive way.

Arterial wall remodeling underlies increased pulmonary vascular resistance and right heart failure in pulmonary arterial hypertension (PAH). None of the established vasodilator drug therapies for PAH prevents or reverses established arterial wall thickening, stiffening and hypercontractility. Therefore, new approaches are needed to achieve long-acting prevention and reversal of occlusive pulmonary vascular remodeling. Several promising new drug classes are emerging from better understanding of pulmonary vascular gene expression programs. In this review potential epigenetic targets for small molecules and oligonucleotides will be described. Most are in preclinical studies aimed at modifying growth of vascular wall cells in vitro or normalizing vascular remodeling in PAH animal models. Initial success with lung-directed delivery of oligonucleotides targeting microRNAs suggests other epigenetic mechanisms might also be suitable drug targets. Those targets include DNA methylation, proteins of the chromatin remodeling machinery and long noncoding RNAs, all of which act as epigenetic regulators of vascular wall structure and function. Progress in testing small molecules and oligonucleotide-based drugs in PAH models is summarized.

Mental stress represents a pivotal factor in cardiovascular diseases. The mechanism by which stress produces its deleterious effects is still under study but one of the most explored pathway is cell senescence. In this scenario, circulating microRNAs appear to be mobile regulatory elements of the telomerase activity and alternative splicing within the ”senectome” network. Anti-stress techniques seem to be able to slow-down aging process. As we have recently verified how the practice of Relaxation Response (RR), counteracting psychological stress, determines favorable changes of some inflammatory genes expression, of some neurotransmitters, hormones, cytokines and inflammatory circulating microRNAs, we aimed to verify a possible change even in serum levels of 4 senectome micro-RNAs (SE-miRNAs -20, -30, -410, -515), testing the activity of telomerase in peripheral blood mononuclear cells-PBMCs. We analyzed also alternative splicing microRNAs 134 and 183. According to our data, miRNA-20 and -30 levels and PBMCs-telomerase activity increase during the RR while -410 and -515 levels decrease. Moreover, during the RR sessions both miRNA-134 and -183 decrease. The mediators considered in this work seem to vary rapidly according to a (stress)-relaxation condition showing that psychic activity should be part of the study of aging factors.

Extracellular vesicles are considered a novel therapeutic tool, due to their ability to transfer their cargoes to target cells. Different strategies to directly load extracellular vesicles with RNA species have been proposed. Electroporation has been used for the loading of non-active vesicles, however the engineering of vesicles already carrying a therapeutically active cargo is still under investigation. We here set up a coincubation method to increase the anti-tumor effect of extracellular vesicles isolated from human liver stem cells (HLSC-EVs). Using the coincubation protocol, vesicles were loaded with the anti-tumor miRNA-145, and their effect was evaluated on renal cancer stem cell invasion. Loaded HLSC-EVs maintained their integrity and miR transfer ability, and miR-145 was protected by RNAse digestion possibly due to its binding to RNA-binding proteins on HLSC-EV surface, such as Annexin A2. Moreover, miR-145 coincubated HLSC-EVs were more effective in inhibiting the invasive properties of cancer stem cells, in comparison to naïve vesicles. The protocol reported here exploits a well-described property of extracellular vesicles to bind nucleic acids on their surface and protect them from degradation, in order to obtain an effective miRNA loading that results in the increase of the effect of naïve active extracellular vesicles.

RNA editing involves the insertion, deletion or substitution of single nucleotides within a RNA molecule, without altering the DNA sequence. Adenosine to inosine (A-to-I) editing consists of an RNA modification where single adenosines along the RNA sequence are converted into inosines. Such a biochemical transformation is catalyzed by enzymes belonging to the family of adenosine deaminases acting on RNA (ADARs) and occurs either co- or post-transcriptionally. Initially, the A-to-I RNA editing phenomenon was discovered and studied in messenger RNAs (mRNAs), where it can influence RNA splicing and cause the recoding of codon sequences. The employment of more powerful, high-throughput detection methods has recently revealed that A-to-I editing widely occurs in non-coding RNAs, including microRNAs (miRNAs). MiRNAs are a class of small regulatory non-coding RNAs (ncRNAs) acting as translation inhibitors, known to exert relevant roles in controlling cell cycle, proliferation, and cancer development. Indeed, a growing number of recent researches have evidenced the importance of miRNA editing in cancer biology by exploiting various detection and validation methods. Herein, we briefly overview early and currently available A-to-I miRNA editing detection and validation methods and discuss the significance of A-to-I miRNA editing in human cancer.

Atrial fibrillation (AF) is a form of sustained cardiac arrhythmia and microRNAs (miRs) play crucial roles in pathophysiology of AF. To identify novel miR-mRNA pairs, we performed RNAseq from atrial biopsies of AF and non-AF patients. Differentially expressed miRs (11-down and 9-up) and mRNAs (95-up and 82-down) were identified and hierarchically clustered in a heat-map. Subsequently, GO, KEGG, and GSEA analyses were run to identify deregulated pathways. Then, miR targets were predicted in miRDB database, and a regulatory network of negatively correlated miR-mRNA pairs was constructed using Cytoscape. To select potential candidate genes from GSEA analysis, top-50 enriched genes in GSEA were overlaid with predicted targets of differentially deregulated miRs. Besides, protein-protein-interaction (PPI) network of enriched genes in GSEA was constructed, and subsequently GO and canonical pathway analyses were run for genes in PPI network. Our analyses showed that TNF-α, p53, EMT, and SYDECAN1 signaling were among the highly affected pathways in AF samples. SDC-1 (syndecan-1) was the top-enriched gene in p53, EMT, and SYDECAN1 signaling. Consistently, SDC-1 mRNA and protein levels were significantly higher in atrial samples of AF patients. Among negatively correlated miRs, miR-302b-3p was experimentally validated to suppress SDC-1 transcript levels. Overall, our results suggested that miR-302b-3p/SDC-1 axis may involve in pathogenesis of AF.

Formation of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels are major events associated with most epithelial malignancies, including breast cancer. Angiogenesis is essential for cancer cell survival. Lymphangiogenesis is critical in maintaining tumoral interstitial fluid balance and importing tumor-facilitatory immune cells. Both vascular routes also serve as conduits for cancer metastasis. Intratumoral hypoxia promotes both events by stimulating multiple angiogenic/lymphangiogenic growth factors. Studies on tumor-associated lymphangiogenesis and its exploitation for therapy have received less attention from the research community than those on angiogenesis. Inflammation is a key mediator of both processes, hijacked by many cancers by aberrant expression of the inflammation-associated enzyme cyclo-oxygenase (COX)-2. In this review, we focus on breast cancer and show that COX-2 is a major promoter of both events, primarily resulting from the activation of Prostaglandin (PG) E receptor EP4 on tumor cells, tumor-infiltrating immune cells, and endothelial cells; and induction of oncogenic microRNAs. COX-2/EP4 pathway also promotes additional events in breast cancer progression, such as cancer cell migration, invasion, and stimulation of stem–like cells. Based on a combination of studies using multiple breast cancer models, we show that EP4 antagonists hold a major promise in breast cancer therapy in combination with other modalities including immune check-point inhibitors

DNA double-strand breaks (DSBs) are deleterious lesions that are generated in response to ionizing radiation or replication fork collapse that can lead to genomic instability and cancer. Eukaryotes have evolved two major pathways, namely homologous recombination (HR) and non-homologous end joining (NHEJ) to repair DSBs. Whereas the roles of protein-DNA interactions in HR and NHEJ have been fairly well defined, the functions of small and long non-coding RNAs and RNA-DNA hybrids in the DNA damage response is just beginning to be elucidated. This review summarizes recent discoveries on the identification of non-coding RNAs and RNA-mediated regulation of DSB repair

The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Besides, from pharmacogenomic research it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1 and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarkers microRNA could serve as tools for personalized medicine, and as potential therapeutic targets in the future.

Downregulated microRNA-142-3p signaling contributes to the pathogenesis of endometriosis [1] [2], an invasive disease where the lining of the uterus grows at ectopic locations, by yet incompletely understood mechanisms. Using bioinformatics and in vitro assays, this study identifies cytoskeletal regulation and integrin signaling as two relevant categories of miR-142-3p targets. qPCR revealed that miR-142-3p upregulation in St-T1b cells downregulates ROCK2, CFL2, RAC1, WASL and ITGAV. qPCR and Western-blotting showed miR-142-3p effect on WASL and ITGAV was significant also in primary endometriotic stroma cells. Luciferase reporter assays in ST-T1b cells then confirmed direct regulation of ITGAV and WASL. On the functional side, miR-142-3p upregulation significantly reduced ST-T1b cell size, the size of vinculin plaques, migration through fibronectin-coated transwell filters and the ability of ST-T1b and primary endometriotic stroma cells to contract collagen I gels. These results suggest that miR-142-3p has a strong mechanoregulatory effect on endometrial stroma cells and its external administration reduces the invasive endometrial phenotype. Within the limits of an in vitro investigation, our study provides new mechanistic insights into the pathogenesis of endometriosis and provides a perspective for the development of miR-142-3p based drugs for inhibiting invasive growth of endometriotic cells.

Background: Osteoclastic bone resorption in the compression zone of periodontal ligament (PDL) plays a role in orthodontic tooth movement, and is regulated by the balance of RANKL and OPG. Compression downregulates OPG, conversely, tension upregulates OPG in PDL cells. However, the regulatory mechanism of OPG expression in PDL cells under different mechanical stresses remains unclear. Methods: To study microRNA (miRNA) expression profiles, compression (2g/cm²) or tension (15%-elongation) was applied to immortalized human PDL (HPL) cells, and miRNA was extracted. The miRNA expression was analyzed using a human miRNA microarray, and the changes of the miRNA expression were confirmed by real-time RT-PCR. In addition, miR-3198-mimic and -inhibitor were transfected into HPL cells to understand the resulting OPG expression and production. Results: Certain miRNAs were expressed differentially under compression and tension. Some miRNAs including miR-3198 were upregulated only by compression. Real-time RT-PCR confirmed that compression induced miR-3198, but tension reduced it, in HPL cells. miR-3198-inhibitor upregulated and miR-3198-mimic reduced OPG in HPL cells. miR-3198-inhibitor rescued the compression-mediated downregulation of OPG. On the other hand, miR-3198-mimic reduced OPG expression under tension. Conclusion: We conclude that miR-3198 is upregulated by compression and is downregulated by tension, suggesting that miR-3198 downregulates OPG in response to mechanical stress.

Analysis of the expression activity of small noncoding RNA (sRNA), including microRNA, piwi-interacting RNA, small rRNA-derived RNA, and tRNA-derived small RNA, is a novel and quickly developing field. The nature of sRNA calls for bioinformatical approaches, adapted for the specific structure of the data. Despite a number of approaches proposed, selecting and adapting a particular pipeline for transcriptomic analysis of sRNA remains a challenge. This article is dedicated to identifying the optimal pipeline configurations for each step of sRNA analysis, including reads trimming, filtering, mapping, transcript abundance quantification and differential expression analysis. For categorical factors and two groups of biosamples, we suggest approaches for the most crucial stages of sRNA analysis pipeline such as: (1) trimming with the lower length bound = 15 and the upper length bound = Readlength−40%Adapterlength; (2) mapping on a reference genome with bowtie aligner with one mismatch allowed (-v 1 parameter); (3) filtering by mean threshold &gt; 5; and (4) analyzing differential expression with DESeq2 with adjusted p-value &lt; 0.05 or limma with p-value &lt; 0.05 if there is very little signal and few transcripts.

In the past decade, RNA fragments derived from full length small nucleolar RNAs (snoRNAs) have been shown to be specifically excised and functional. These sno-derived RNAs (sdRNAs) have been implicated as gene regulators in a multitude of cancers, controlling a variety of genes post-transcriptionally via association with the RNA-induced silencing complex (RISC). In this review, we have summarized the literature connecting sdRNAs to cancer gene regulation. SdRNAs possess miRNA-like functions, and are able to fill the role of tumor-suppressor or tumor-promoter in a tissue context-dependent manner. Indeed, there are many miRNAs that are actually derived from snoRNA transcripts, meaning that they are truly sdRNAs and as such are included in this review. As sdRNAs are frequently discarded from ncRNA analyses, we emphasize that sdRNAs are functionally relevant gene regulators and likely represent an overlooked subclass of miRNAs. Based on the evidence provided by the papers reviewed here, we propose that sdRNAs deserve more extensive study to better understand their underlying biology and to identify previously overlooked biomarkers and therapeutic targets for a multitude of human cancers.

Fibromyalgia (FM) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are diseases of unknown etiology presenting complex and often overlapping symptomatology. Despite promising advances on the study of miRNomes of these diseases, no validated molecular diagnostic biomarker yet exists. Since FM and ME/CFS patient treatments commonly include polypharmacy it is of concern that biomarker miRNAs are masked by drug interactions. Aiming at discriminating between drug-effects and true disease-associated differential miRNA expression, we evaluated the potential impact of commonly prescribed drugs on disease miRNomes, as reported by the literature. By using the web search tools SM2miR, Pharmaco-miR and repoDB, we found a list of commonly prescribed drugs that impact on FM and ME/CFS miRNomes and therefore could be interfering in the process of biomarker discovery. On another end, disease-associated miRNomes may incline patient´s response to treatment and toxicity. Here, we explored treatments for diseases in general that could be affected by FM and ME/CFS miRNomes finding a long list of them, including treatments for lymphoma, a type of cancer affecting ME/CFS patients at a higher rate than healthy population. We conclude that FM and ME/CFS miRNomes could help refine pharmacogenomic/pharmacoepigenomic analysis to elevate future personalized medicine and precision medicine programs in the clinic.