A comprehensive review of online resources for microRNA-diseases associations: the state of the art.

MicroRNAs (miRNAs) as small 19- to 24-nucleotide noncoding RNAs regulate several mRNA targets and signaling pathways. Therefore, miRNAs are considered key regulators in cellular pathways as well as various pathologies. There is substantial interest in the relationship between disease and miRNAs, which made that one of the important research topics. Interestingly, miRNAs emerged as an attractive approach for clinical application, not only as biomarkers for diagnosis and prognosis or in the prediction of therapy response but also as therapeutic tools. For these purposes, the identification of crucial miRNAs in disease is very important. Databases provided valuable experimental and computational miRNAs-disease information in an accessible and comprehensive manner, such as miRNA target genes, miRNA related in signaling pathways and miRNA involvement in various diseases. In this review, we summarized miRNAs-disease databases in two main categories based on the general or specific diseases. In these databases, researchers could search diseases to identify critical miRNAs and developed that for clinical applications. In another way, by searching particular miRNAs, they could recognize in which disease these miRNAs would be dysregulated. Despite the significant development that has been done in these databases, there are still some limitations, such as not being updated and not providing uniform and detailed information that should be resolved in future databases. This survey can be helpful as a comprehensive reference for choosing a suitable database by researchers and as a guideline for comparing the features and limitations of the database by developer or designer. Short abstract We summarized miRNAs-disease databases that researchers could search disease to identify critical miRNAs and developed that for clinical applications. This survey can help choose a suitable database for researchers.

Targeting PCSK9 as a key player in lipid metabolism: exploiting the therapeutic and biosensing potential of aptamers.

The degradation of low-density lipoprotein receptor (LDLR) is induced by proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in elevated plasma concentrations of LDL cholesterol. Therefore, inhibiting the interactions between PCSK9 and LDLR is a desirable therapeutic goal for managing hypercholesterolemia. Aptamers, which are RNA or single-stranded DNA sequences, can recognize their targets based on their secondary structure. Aptamers exhibit high selectivity and affinity for binding to target molecules. The systematic evolution of ligands by exponential enrichment (SELEX), a combination of biological approaches, is used to screen most aptamers in vitro. Due to their unique advantages, aptamers have garnered significant interest since their discovery and have found extensive applications in various fields. Aptamers have been increasingly utilized in the development of biosensors for sensitive detection of pathogens, analytes, toxins, drug residues, and malignant cells. Furthermore, similar to monoclonal antibodies, aptamers can serve as therapeutic tools. Unlike certain protein therapeutics, aptamers do not elicit antibody responses, and their modified sugars at the 2'-positions generally prevent toll-like receptor-mediated innate immune responses. The focus of this review is on aptamer-based targeting of PCSK9 and the application of aptamers both as biosensors and therapeutic agents.

Effects of therapeutic probiotics on modulation of microRNAs.

Probiotics are beneficial bacteria that exist within the human gut, and which are also present in different food products and supplements. They have been investigated for some decades, due to their potential beneficial impact on human health. Probiotics compete with pathogenic microorganisms for adhesion sites within the gut, to antagonize them or to regulate the host immune response resulting in preventive and therapeutic effects. Therefore, dysbiosis, defined as an impairment in the gut microbiota, could play a role in various pathological conditions, such as lactose intolerance, gastrointestinal and urogenital infections, various cancers, cystic fibrosis, allergies, inflammatory bowel disease, and can also be caused by antibiotic side effects. MicroRNAs (miRNAs) are short non-coding RNAs that can regulate gene expression in a post-transcriptional manner. miRNAs are biochemical biomarkers that play an important role in almost all cellular signaling pathways in many healthy and disease states. For the first time, the present review summarizes current evidence suggesting that the beneficial properties of probiotics could be explained based on the pivotal role of miRNAs. Video Abstract.

Oncogenic viruses and chemoresistance: What do we know?

Chemoresistance is often referred to as a major leading reason for cancer therapy failure, causing cancer relapse and further metastasis. As a result, an urgent need has been raised to reach a full comprehension of chemoresistance-associated molecular pathways, thereby designing new therapy methods. Many of metastatic tumor masses are found to be related with a viral cause. Although combined therapy is perceived as the model role therapy in such cases, chemoresistant features, which is more common in viral carcinogenesis, often get into way of this kind of therapy, minimizing the chance of survival. Some investigations indicate that the infecting virus dominates other leading factors, i.e., genetic alternations and tumor microenvironment, in development of cancer cell chemoresistance. Herein, we have gathered the available evidence on the mechanisms under which oncogenic viruses cause drug-resistance in chemotherapy.

Decoy Technology as a Promising Therapeutic Tool for Atherosclerosis.

Cardiovascular diseases (CVDs) have been classified into several types of disease, of which atherosclerosis is the most prevalent. Atherosclerosis is characterized as an inflammatory chronic disease which is caused by the formation of lesions in the arterial wall. Subsequently, lesion progression and disruption ultimately lead to heart disease and stroke. The development of atherosclerosis is the underlying cause of approximately 50% of all deaths in westernized societies. Countless studies have aimed to improve therapeutic approaches for atherosclerosis treatment; however, it remains high on the global list of challenges toward healthy and long lives. Some patients with familial hypercholesterolemia could not get intended LDL-C goals even with high doses of traditional therapies such as statins, with many of them being unable to tolerate statins because of the harsh side effects. Furthermore, even in patients achieving target LDL-C levels, the residual risk of traditional therapies is still significant thus highlighting the necessity of ongoing research for more effective therapeutic approaches with minimal side effects. Decoy-based drug candidates represent an opportunity to inhibit regulatory pathways that promote atherosclerosis. In this review, the potential roles of decoys in the treatment of atherosclerosis were described based on the in vitro and in vivo findings.

Androgen receptor-related micro RNAs in prostate cancer and their role in antiandrogen drug resistance.

Prostate cancer (PCa) is one of the most common cancers and the fifth most common reason for cancer deaths in the males. Surgical castration combined with androgen deprivation therapy, antiandrogens, and androgen synthesis inhibitors is the current therapeutic modalities for PCa. These strategies inhibit androgen synthesis or reduce its binding to the androgen receptor (AR) but the development of resistance to these therapies and transient responsiveness are challenging issues in the treatment of this cancer. Deregulation of ARs has a vital role in the initiation and progression of PCa. Also, recent findings imply that micro RNAs (miRNAs) are involved in the evolution of PCa and mediate drug resistance in different cancers. Hence, discovering and targeting miRNAs might represent a novel therapeutic approach. This review paid particular attention to the AR pathway and existing information on the possible roles of miRNAs associated with AR pathway and drug resistance to two second-generation antiandrogens, that is, enzalutamide and abiraterone.

MicroRNAs and exosomes: Small molecules with big actions in multiple myeloma pathogenesis.

Multiple myeloma (MM), an incurable hematologic malignancy of plasma cells increasing in the bone marrow (BM), has a complex microenvironment made to support proliferation, survival, and drug resistance of tumor cells. MicroRNAs (miRNAs), short non-coding RNAs regulating genes expression at posttranscriptional level, have been indicated to be functionally deregulated or abnormally expressed in MM cells. Moreover, by means of miRNAs, tumor microenvironment also modulates the function of MM cells. Consistently, it has been demonstrated that miRNA levels regulation impairs their interaction with the microenvironment of BM as well as create considerable antitumor feature even capable of overcoming the protective BM milieu. Communication between cancer stromal cells and cancer cells is a key factor in tumor progression. Finding out this interaction is important to develop effective approaches that reverse bone diseases. Exosomes, nano-vehicles having crucial roles in cell-to-cell communication, through targeting their cargos (i.e., miRNAs, mRNAs, DNAs, and proteins), are implicated in MM pathogenesis.

Exosomes and cancer: From oncogenic roles to therapeutic applications.

Exosomes belong to extracellular vehicles that were produced and secreted from most eukaryotic cells and are involved in cell-to-cell communications. They are an effective delivery system for biological compounds such as mRNAs, microRNAs (miRNAs), proteins, lipids, saccharides, and other physiological compounds to target cells. In this way, they could influence on cellular pathways and mediate their physiological behaviors including cell proliferation, tumorigenesis, differentiation, and so on. Many research studies focused on their role in cancers and also on potentially therapeutic and biomarker applications. In the current study, we reviewed the exosomes' effects on cancer progression based on their cargoes including miRNAs, long noncoding RNAs, circular RNAs, DNAs, mRNAs, proteins, and lipids. Moreover, their therapeutic roles in cancer were considered. In this regard, we have given a brief overview of challenges and obstacles in using exosomes as therapeutic agents.

Exosomal microRNAs derived from mesenchymal stem cells: cell-to-cell messages.

Exosomes are extracellular vesicles characterized by their size, source, release mechanism and contents. MicroRNAs (miRNAs) are single stranded non-coding RNAs transcribed from DNA. Exosomes and miRNAs are widespread in eukaryotic cells, especially in mesenchymal stem cells (MSCs). MSCs are used for tissue regeneration, and also exert paracrine, anti-inflammatory and immunomodulatory effects. However, the use of MSCs is controversial, especially in the presence or after the remission of a tumor, due to their secretion of growth factors and their migration ability. Instead of intact MSCs, MSC-derived compartments or substances could be used as practical tools for diagnosis, follow up, management and monitoring of diseases. Herein, we discuss some aspects of exosomal miRNAs derived from MSCs in the progression, diagnosis and treatment of various diseases. Video Abstract.

Role of exosomes in malignant glioma: microRNAs and proteins in pathogenesis and diagnosis.

Malignant gliomas are the most common and deadly type of central nervous system tumors. Despite some advances in treatment, the mean survival time remains only about 1.25 years. Even after surgery, radiotherapy and chemotherapy, gliomas still have a poor prognosis. Exosomes are the most common type of extracellular vesicles with a size range of 30 to 100 nm, and can act as carriers of proteins, RNAs, and other bioactive molecules. Exosomes play a key role in tumorigenesis and resistance to chemotherapy or radiation. Recent evidence has shown that exosomal microRNAs (miRNAs) can be detected in the extracellular microenvironment, and can also be transferred from cell to cell via exosome secretion and uptake. Therefore, many recent studies have focused on exosomal miRNAs as important cellular regulators in various physiological and pathological conditions. A variety of exosomal miRNAs have been implicated in the initiation and progression of gliomas, by activating and/or inhibiting different signaling pathways. Exosomal miRNAs could be used as therapeutic agents to modulate different biological processes in gliomas. Exosomal miRNAs derived from mesenchymal stem cells could also be used for glioma treatment. The present review summarizes the exosomal miRNAs that have been implicated in the pathogenesis, diagnosis and treatment of gliomas. Moreover, exosomal proteins could also be involved in glioma pathogenesis. Exosomal miRNAs and proteins could also serve as non-invasive biomarkers for prognosis and disease monitoring. Video Abstract.

PIWI-interacting RNAs and PIWI proteins in glioma: molecular pathogenesis and role as biomarkers.

Glioma is the most common primary brain tumor, and is a major health problem throughout the world. Today, researchers have discovered many risk factors that are associated with the initiation and progression of gliomas. Studies have shown that PIWI-interacting RNAs (piRNAs) and PIWI proteins are involved in tumorigenesis by epigenetic mechanisms. Hence, it seems that piRNAs and PIWI proteins may be potential prognostic, diagnostic or therapeutic biomarkers in the treatment of glioma. Previous studies have demonstrated a relationship between piRNAs and PIWI proteins and some of the molecular and cellular pathways in glioma. Here, we summarize recent evidence and evaluate the molecular mechanisms by which piRNAs and PIWI proteins are involved in glioma. Video abstract.

Autophagy in cancers including brain tumors: role of MicroRNAs.

Autophagy has a crucial role in many cancers, including brain tumors. Several types of endogenous molecules (e.g. microRNAs, AKT, PTEN, p53, EGFR, and NF1) can modulate the process of autophagy. Recently miRNAs (small non-coding RNAs) have been found to play a vital role in the regulation of different cellular and molecular processes, such as autophagy. Deregulation of these molecules is associated with the development and progression of different pathological conditions, including brain tumors. It was found that miRNAs are epigenetic regulators, which influence the level of proteins coded by the targeted mRNAs with any modification of the genetic sequences. It has been revealed that various miRNAs (e.g., miR-7-1-3p, miR-340, miR-17, miR-30a, miR-224-3p, and miR-93), as epigenetic regulators, can modulate autophagy pathways within brain tumors. A deeper understanding of the underlying molecular targets of miRNAs, and their function in autophagy pathways could contribute to the development of new treatment methods for patients with brain tumors. In this review, we summarize the various miRNAs, which are involved in regulating autophagy in brain tumors. Moreover, we highlight the role of miRNAs in autophagy-related pathways in different cancers. Video abstract.

TGF-ß and WNT signaling pathways in cardiac fibrosis: non-coding RNAs come into focus.

Cardiac fibrosis describes the inappropriate proliferation of cardiac fibroblasts (CFs), leading to accumulation of extracellular matrix (ECM) proteins in the cardiac muscle, which is found in many pathophysiological heart conditions. A range of molecular components and cellular pathways, have been implicated in its pathogenesis. In this review, we focus on the TGF-ß and WNT signaling pathways, and their mutual interaction, which have emerged as important factors involved in cardiac pathophysiology. The molecular and cellular processes involved in the initiation and progression of cardiac fibrosis are summarized. We focus on TGF-ß and WNT signaling in cardiac fibrosis, ECM production, and myofibroblast transformation. Non-coding RNAs (ncRNAs) are one of the main players in the regulation of multiple pathways and cellular processes. MicroRNAs, long non-coding RNAs, and circular long non-coding RNAs can all interact with the TGF-ß/WNT signaling axis to affect cardiac fibrosis. A better understanding of these processes may lead to new approaches for diagnosis and treatment of many cardiac conditions. Video Abstract.

Autophagy-related microRNAs: Possible regulatory roles and therapeutic potential in and gastrointestinal cancers.

Gastrointestinal (GI) cancers with a high incidence rate and adverse complications are associated with severe morbidity and mortality around the world. It is well recognized that early detection of the disease results in longer survival rate and better quality of life. Autophagy, an intracellular regulatory process, has been shown to play an essential role in the pathogenesis of various malignancies including GI cancers. MicroRNAs (miRNAs) are small non-coding RNAs that have regulatory functions in tumor cells and possess potential diagnostic values in early detection of cancers. It has been recently demonstrated that these molecules have modulatory effects on multiple steps of autophagy process occurring in GI malignancies. In this review, we aimed to highlight the role of autophagy-related microRNAs on GI cancer as potential targets for cancer therapy.

Nanospheres for curcumin delivery as a precision nanomedicine in cancer therapy.

Cancer is ranked among the top causes of mortality throughout the world. Conventional therapies are associated with toxicity and undesirable side effects, rendering them unsuitable for prolonged use. Additionally, there is a high occurrence of resistance to anticancer drugs and recurrence in certain circumstances. Hence, it is essential to discover potent anticancer drugs that exhibit specificity and minimal unwanted effects. Curcumin, a polyphenol derivative, is present in the turmeric plant (Curcuma longa L.) and has chemopreventive, anticancer, radio-, and chemo-sensitizing activities. Curcumin exerts its anti-tumor effects on cancer cells by modulating the disrupted cell cycle through p53-dependent, p53-independent, and cyclin-dependent mechanisms. This review provides a summary of the formulations of curcumin based on nanospheres, since there is increasing interest in its medicinal usage for treating malignancies and tumors. Nanospheres are composed of a dense polymeric matrix, and have a size ranging from 10 to 200 nm. Lactic acid polymers, glycolic acid polymers, or mixtures of them, together with poly (methyl methacrylate), are primarily used as matrices in nanospheres. Nanospheres are suitable for local, oral, and systemic delivery due to their minuscule particle size. The majority of nanospheres are created using polymers that are both biocompatible and biodegradable. Previous investigations have shown that the use of a nanosphere delivery method can enhance tumor targeting, therapeutic efficacy, and biocompatibility of different anticancer agents. Moreover, these nanospheres can be easily taken up by mammalian cells. This review discusses the many curcumin nanosphere formulations used in cancer treatment.

Genomic Insights Into Statin Therapy: Differential Expression Analysis of Key Genes.

In this study, we utilized microarray profiles, specifically GSE71220 and GSE11393 obtained from the GEO database, which provide gene expression data from blood samples. Through a comparison of differentially expressed genes in both datasets, we successfully identified 11 key genes that exhibited differential expression in groups A and B, respectively. To gain insights into their functional roles, we performed gene ontology (GO) enrichment analysis using the "BiNGO" plugin in Cytoscape. This analysis revealed that these genes are primarily associated with primary metabolic processes. Notably, 8 genes, namely EIF2S3, GZMK, PIK3R1, RORA, SART3, TGM2, WTAP, and ABCG1, were found to be involved in these processes. To further explore the interactions and relationships among these key genes, we conducted protein-protein interaction analysis using the STRING database and co-expression network analysis using the GeneMANIA plugin in Cytoscape. The PPI analysis highlighted RORA, NR1D2, PIK3R1, CKAP4, and GZMK as central players within the network. To validate our findings, we examined the expression profiles of the key genes using the GSE86216 dataset, which comprises blood samples from individuals using statins. The results from this validation set largely corroborated our previous findings, with the exception of 3 genes: LAMP3, NR1D2, and PIK3R1, which exhibited different expression patterns. In conclusion, our study utilized microarray datasets to identify key genes that are influenced by statin treatments. The differential expression and functional analysis of these genes provide valuable insights into the mechanisms underlying the effects of statins.

Profiling of differentially expressed MicroRNAs in familial hypercholesterolemia via direct hybridization.

Background: Individuals with homozygous familial hypercholesterolemia (HoFH) have a severe clinical problem in their first decade of life, which is not usually present in heterozygous FH (HeFH) individuals. For this latter group of patients, FH diagnosis is mostly severely delayed with a significant increase in the risk of angina, myocardial infarction, peripheral artery disease, stroke, and cardiovascular and all-cause mortality. Methods: This study used various bioinformatics tools to analyze microarray data and identify critical miRNAs and their target genes associated with FH and its severity. Differentially expressed serum miRNAs from direct hybridization microarray data in three groups of subjects: healthy, HeFH, and HoFH. The differential expressed miRNAs were determined according to a log of fold-change (LFC) <-0.5 or >0.5 and of p < 0.05. Then, we assessed their target genes in silico. Gene ontology (GO) enrichment was applied by Cytoscape. The protein-protein interaction and co-expression network were analyzed by the STRING and GeneMANIA plugins of Cytoscape, respectively. Results: We identified increased expression of circulating hsa-miR-604, hsa-miR-652-5p, and hsa-miR-4451 as well as reduced expression of hsa-miR-3140-3p, hsa-miR-550a-5p, and hsa-miR-363-3p in both group of FH vs. healthy subjects. Higher levels of hsa-miR-1183, hsa-miR-1185-1-3p, hsa-miR-122-5p, hsa-miR-19a-3p, hsa-miR-345-3p, and hsa-miR-34c-5p were detected in HeFH in respect to HoFH when compared to healthy subjects. Most upregulated miRNAs mainly affected gene related to cardiac myofibrillogenesis, cholesterol synthesis, RNA editing for apolipoprotein B, and associated with LDL-cholesterol levels. In contrast, down-regulated miRNAs mainly affected gene related to plasma biomarker for coronary artery disease, lipids metabolism, cell adhesion and migration, genetic predictors of type 2 diabetes and cholesterol metabolism. The essential genes were primarily enriched in GO regarding biological regulation, intracellular nucleic acid binding, and the KEGG pathway of TGF-ß signaling. Conclusions: The case-control nature of this study precluded the possibility of assessing the predictive role of the identified differentially expressed miRNAs for cardiovascular events. Therefore, the signature of miRNAs reflecting the pathogenesis of both HeFH and HoFH.

Identification of Critical Genes Differentiating Stable and Unstable Atherosclerotic Plaques: A Bioinformatic and Computational Analysis.

BACKGROUND: Identification of biomarkers to distinguish between stable and unstable plaque formation would be very useful to predict plaque vulnerability. METHODS: We downloaded microarray profiles of gene set enrichment (GSE) accession numbers including GSE71226 and GSE20680 (group A: containing healthy vs stable plaque samples) and GSE62646 and GSE34822 (group B: containing stable vs unstable plaque samples) from Gene expression omnibus (GEO) database. Differentially expressed genes were compared in both data sets of each group. RESULTS: Ten and 12 key genes were screened in groups A and B, respectively. Gene Ontology (GO) enrichment was applied by the plugin "BiNGO" (Biological networks gene ontology tool) of the Cytoscape. The key genes were mostly enriched in the biological process of positive regulation of the cellular process. The protein-protein interaction and co-expression network were analyzed by the STRING (search tool for the retrieval of interacting genes/proteins) and GeneMANIA (gene multiple association network integration algorithm) plugin of Cytoscape, respectively, which showed that Epidermal growth factor (EGF), Heparin-binding EGF like growth factor (HBEGF), and Matrix metalloproteinase 9 (MMP9) were at the core of the network. Further validation of key genes using two datasets showed that Phosphodiesterase 5A (PDE5A) and Protein S (PROS1) were decreased in unstable plaques, while Suppressor of cytokine signaling (SOCS3), HBEGF, and Leukocyte immunoglobulin-like receptor B4 (LILRB4) were increased. CONCLUSION: The present study used several datasets to identify key genes associated with stable and unstable atherosclerotic plaque.

Therapeutic potential of decoys for prostate cancers: A review of recent updates.

Prostate cancer is ranked second among the most common male cancers. Androgen deprivation therapy (ADT) has long been the first-line treatment and the basis for all other therapies, reducing circulating androgens to castration levels and preventing disease development. Nevertheless, ADT monotherapy may not always limit disease development, and even at low testosterone levels, hormone-sensitive prostate cancer will become castration-resistant. Recent research demonstrates that prostate cancer can have a range of potentially actionable genetic abnormalities; no medications that target these variations have yet been shown to elicit therapeutic advantages. Despite their established efficacy in the management of other cancers, advanced genetic or immunological approaches are not regularly used to treat prostate cancer patients. As a result, there is an unmet demand for medicines that offer a better chance of survival than the existing castration-resistance prostate cancer (CRPC) therapy regimens. The use of oligodeoxynucleotides (ODN) and peptides in decoy technology have been developed as novel therapeutic approaches. Decoy ODNs bind to a particular transcription factor with high affinity and may suppress gene transcription. Peptide decoys bind to specific ligands with high specificity and inhibit signaling pathways. Recent evidence supports the notion that these techniques are promising and attractive in the fight against cancer. In the present review, we discuss the use of decoy technology as a novel therapeutic approach against prostate cancer.

Harnessing the Therapeutic Potential of Antimicrobial Peptides for Cancers: State of the Art.

Despite significant breakthroughs in cancer treatment, cancer remains a serious global health concern that takes thousands of lives each year. Still, drug resistance and adverse effects are the main problems in conventional cancer therapeutic approaches. Thus, the discovery of new anticancer agents with distinct mechanisms of action is a critical requirement that offers significant obstacles. Antimicrobial peptides (AMPs), which can be found in various forms of life, are recognized as defensive weapons against infections of microbial pathogens. Surprisingly, they are also capable of killing a variety of cancer cells. These powerful peptides can cause cell death in the gastrointestinal, urinary tract, and reproductive cancer cell lines. To emphasize the anti-cancer properties of AMPs, we summarize the research that examined their impact on cancer cell lines in this review.