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Briefings in Bioinformatics Sep 2019MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression via recognition of cognate sequences and interference of transcriptional, translational or... (Review)
Review
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression via recognition of cognate sequences and interference of transcriptional, translational or epigenetic processes. Bioinformatics tools developed for miRNA study include those for miRNA prediction and discovery, structure, analysis and target prediction. We manually curated 95 review papers and ∼1000 miRNA bioinformatics tools published since 2003. We classified and ranked them based on citation number or PageRank score, and then performed network analysis and text mining (TM) to study the miRNA tools development trends. Five key trends were observed: (1) miRNA identification and target prediction have been hot spots in the past decade; (2) manual curation and TM are the main methods for collecting miRNA knowledge from literature; (3) most early tools are well maintained and widely used; (4) classic machine learning methods retain their utility; however, novel ones have begun to emerge; (5) disease-associated miRNA tools are emerging. Our analysis yields significant insight into the past development and future directions of miRNA tools.
Topics: Algorithms; Computational Biology; Machine Learning; MicroRNAs; Nucleic Acid Conformation
PubMed: 29982332
DOI: 10.1093/bib/bby054 -
International Journal of Molecular... Jun 2022MicroRNAs (miRNAs) are a group of endogenous non-coding RNAs that regulate gene expression. Alteration in miRNA expression results in changes in the profile of genes... (Review)
Review
MicroRNAs (miRNAs) are a group of endogenous non-coding RNAs that regulate gene expression. Alteration in miRNA expression results in changes in the profile of genes involving a range of biological processes, contributing to numerous human disorders. With high stability in human fluids, miRNAs in the circulation are considered as promising biomarkers for diagnosis, as well as prognosis of disease. In addition, the translation of miRNA-based therapy from a research setting to clinical application has huge potential. The aim of the current review is to: (i) discuss how miRNAs traffic intracellularly and extracellularly; (ii) emphasize the role of circulating miRNAs as attractive potential biomarkers for diagnosis and prognosis; (iii) describe how circulating microRNA can be measured, emphasizing technical problems that may influence their relative levels; (iv) highlight some of the circulating miRNA panels available for clinical use; (v) discuss how miRNAs could be utilized as novel therapeutics, and finally (v) update those miRNA-based therapeutics clinical trials that could potentially lead to a breakthrough in the treatment of different human pathologies.
Topics: Biomarkers; Circulating MicroRNA; Humans; MicroRNAs
PubMed: 35806173
DOI: 10.3390/ijms23137167 -
The Journal of Pharmacology and... Jan 2023RNA interference (RNAi) provides researchers with a versatile means to modulate target gene expression. The major forms of RNAi molecules, genome-derived microRNAs... (Review)
Review
RNA interference (RNAi) provides researchers with a versatile means to modulate target gene expression. The major forms of RNAi molecules, genome-derived microRNAs (miRNAs) and exogenous small interfering RNAs (siRNAs), converge into RNA-induced silencing complexes to achieve posttranscriptional gene regulation. RNAi has proven to be an adaptable and powerful therapeutic strategy where advancements in chemistry and pharmaceutics continue to bring RNAi-based drugs into the clinic. With four siRNA medications already approved by the US Food and Drug Administration (FDA), several RNAi-based therapeutics continue to advance to clinical trials with functions that closely resemble their endogenous counterparts. Although intended to enhance stability and improve efficacy, chemical modifications may increase risk of off-target effects by altering RNA structure, folding, and biologic activity away from their natural equivalents. Novel technologies in development today seek to use intact cells to yield true biologic RNAi agents that better represent the structures, stabilities, activities, and safety profiles of natural RNA molecules. In this review, we provide an examination of the mechanisms of action of endogenous miRNAs and exogenous siRNAs, the physiologic and pharmacokinetic barriers to therapeutic RNA delivery, and a summary of the chemical modifications and delivery platforms in use. We overview the pharmacology of the four FDA-approved siRNA medications (patisiran, givosiran, lumasiran, and inclisiran) as well as five siRNAs and several miRNA-based therapeutics currently in clinical trials. Furthermore, we discuss the direct expression and stable carrier-based, in vivo production of novel biologic RNAi agents for research and development. SIGNIFICANCE STATEMENT: In our review, we summarize the major concepts of RNA interference (RNAi), molecular mechanisms, and current state and challenges of RNAi drug development. We focus our discussion on the pharmacology of US Food and Drug Administration-approved RNAi medications and those siRNAs and miRNA-based therapeutics that entered the clinical investigations. Novel approaches to producing new true biological RNAi molecules for research and development are highlighted.
Topics: RNA Interference; RNAi Therapeutics; RNA, Small Interfering; MicroRNAs; Bioengineering; Biological Products
PubMed: 35680378
DOI: 10.1124/jpet.122.001234 -
BioTechniques Oct 2019Several approaches for miRNA expression analysis have been developed in recent years. In this article, we provide an updated and comprehensive review of available... (Review)
Review
Several approaches for miRNA expression analysis have been developed in recent years. In this article, we provide an updated and comprehensive review of available qPCR-based methods for miRNA expression analysis and discuss their advantages and disadvantages. Existing techniques involve the use of stem-loop reverse transcriptase-PCR, polyadenylation of RNAs, ligation of adapters or RT with complex primers, using universal or miRNA-specific qPCR primers and/or probes. Many of these methods are oriented towards the expression analysis of mature miRNAs and few are designed for the study of pre-miRNAs and pri-miRNAs. We also discuss findings from articles that compare results from existing methods. Finally, we suggest key points for the improvement of available techniques and for the future development of additional methods.
Topics: Computer Simulation; DNA Primers; Gene Expression; High-Throughput Nucleotide Sequencing; MicroRNAs; Polyadenylation; Real-Time Polymerase Chain Reaction; Software
PubMed: 31560239
DOI: 10.2144/btn-2019-0065 -
Trends in Genetics : TIG Jun 2022MicroRNAs (miRNAs) are very powerful genetic regulators, as evidenced by the fact that a single miRNA can direct entire cellular pathways via interacting with a broad... (Review)
Review
MicroRNAs (miRNAs) are very powerful genetic regulators, as evidenced by the fact that a single miRNA can direct entire cellular pathways via interacting with a broad spectrum of target genes. This property renders miRNAs as highly interesting therapeutic tools to restore cell functions that are altered as part of a disease phenotype. However, this strength of miRNAs is also a weakness because their cellular effects are so numerous that off-target effects can hardly be avoided. In this review, we point out the main challenges and the strategies to specifically address the problems that need to be surmounted in the push toward a therapeutic application of miRNAs. Particular emphasis is given to approaches that have already found their way into clinical studies.
Topics: Humans; MicroRNAs; Neoplasms
PubMed: 35303998
DOI: 10.1016/j.tig.2022.02.006 -
Frontiers in Immunology 2022Preeclampsia is a common and serious complication of pregnancy, posing a threat to maternal and fetal safety due to the lack of effective biomarkers and treatment...
OBJECTIVE
Preeclampsia is a common and serious complication of pregnancy, posing a threat to maternal and fetal safety due to the lack of effective biomarkers and treatment strategies. This study aimed to identify potential biomarkers that can be used to predict preeclampsia and identify the molecular mechanisms of preeclampsia pathogenesis and drug prediction at the transcriptome level.
METHODS
We analyzed differential expression genes (DEGs) in preeclampsia and non-preeclampsia groups in the GSE75010 dataset, cross-linking with extracted inflammatory response-related genes to obtain differentially expressed inflammation-related genes (DINRGs). Enrichment analysis and protein-protein interaction (PPI) networks were constructed to understand the functions and enrichment pathways. Machine learning models were used to identify key genes associated with preeclampsia and build a nomogram in the training set, which was validated in the validation set. The R package RcisTarget was used to predict transcription factors, and Cytoscape was used to construct miRNA-mRNA pathways, which could identify the molecular mechanisms. Then, we conducted molecular docking of the obtained key genes (inhibin subunit beta A), (opioid receptor kappa 1), and (trophoblast glycoprotein), as well as predicted transcription factors with drug molecules. Additionally, the CIBERSORT method explored the differences in immune cell infiltration between preeclampsia and non-preeclampsia samples based on the GSE75010 dataset.
RESULTS
A total of 69 DINRGs associated with preeclampsia patients were screened. , and were the key genes based on machine learning models. A nomogram for prediction was further constructed, and the receiver operating curves (ROCs) showed good performance. Based on the transcriptome level of key genes, we proposed that RELA-miR-548K/miR-1206-TPBG may be a potential RNA regulatory pathway regulating the progression of early preeclampsia. Molecular docking suggested the effectiveness of curcumin in the treatment of preeclampsia. Additionally, regulatory T cells (Tregs) and resting mast cells were significantly different between the two groups.
CONCLUSION
In summary, we identified three key inflammation-associated genes, namely , and , which can be used as potential genetic biomarkers for preeclampsia prediction and treatment, and established a nomogram as a predictive model. Additionally, we provided insights into the mechanisms of preeclampsia development at the transcriptome level and performed corresponding drug predictions.
Topics: Female; Gene Regulatory Networks; Genetic Markers; Humans; Inflammation; MicroRNAs; Molecular Docking Simulation; Pre-Eclampsia; Pregnancy; Transcription Factors
PubMed: 35880174
DOI: 10.3389/fimmu.2022.883404 -
Biochimica Et Biophysica Acta. Reviews... Jan 2021Recent advances have begun to clarify the physiological and pathological roles of non-coding RNAs (ncRNAs) in various diseases, including cancer. Among these, microRNAs... (Review)
Review
Recent advances have begun to clarify the physiological and pathological roles of non-coding RNAs (ncRNAs) in various diseases, including cancer. Among these, microRNAs (miRNAs) have been the most studied and have emerged as key players that are involved in the regulation of important growth regulatory pathways in cancer pathogenesis. The ability of a single ncRNA to modulate the expression of multiple downstream gene targets and associated pathways, have provided a rationale to pursue them for therapeutic drug development in cancer. In this context, early data from pre-clinical studies have demonstrated that synthetic miRNA-based therapeutic molecules, along with various protective coating approaches, has allowed for their efficient delivery and anti-tumor activity. In fact, some of the miRNA-based cancer therapeutic strategies have shown promising results even in early-phase human clinical trials. While the enthusiasm for ncRNA-based cancer therapeutics continue to evolve, the field is still in the midst of unraveling a more precise understanding of the molecular mechanisms and specific downstream therapeutic targets of other lesser studied ncRNAs such as the long-non-coding RNAs, transfer RNAs, circular RNAs, small nucleolar RNAs, and piwi-interacting RNAs. This review article provides the current state of knowledge and the evolving principles for ncRNA-based therapeutic approaches in cancer, and specifically highlights the importance of data to date and the approaches that are being developed to overcome the challenges associated with their delivery and mitigating the off-target effects in human cancers.
Topics: Humans; MicroRNAs; Molecular Targeted Therapy; Neoplasms; RNA, Circular; RNA, Long Noncoding; RNA, Small Interfering; RNA, Untranslated
PubMed: 33316377
DOI: 10.1016/j.bbcan.2020.188491 -
BMC Cancer Nov 2019A severe lack of early diagnosis coupled with resistance to most available therapeutic options renders pancreatic cancer as a major clinical concern. The limited... (Review)
Review
A severe lack of early diagnosis coupled with resistance to most available therapeutic options renders pancreatic cancer as a major clinical concern. The limited efficacy of current treatments necessitates the development of novel therapeutic strategies that are based on an understanding of the molecular mechanisms involved in pancreatic cancer progression. MicroRNAs (miRNAs) are non-coding small RNAs that regulate the expression of multiple proteins in the post-translation process and thus have promise as biomarkers, prognostic agents, and as advanced pancreatic therapies. Profiling of deregulated miRNAs in pancreatic cancer can correlate to diagnosis, indicate optimal treatment and predict response to therapy. Furthermore, understanding the main effector genes in pancreatic cancer along with downstream pathways can identify possible miRNAs as therapeutic candidates. Additionally, obstacles to the translation of miRNAs into the clinic are also considered. Distinct miRNA expression profiles can correlate to stages of malignant pancreatic disease, and hold potential as biomarkers, prognostic markers and clinical targets. However, a limited understanding and validation of the specific role of such miRNAs stunts clinical application. Target prediction using algorithms provides a wide range of possible targets, but these miRNAs still require validation through pre-clinical studies to determine the knock-on genetic effects.
Topics: Biomarkers, Tumor; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasm Staging; Pancreatic Neoplasms; Prognosis
PubMed: 31752758
DOI: 10.1186/s12885-019-6284-y -
International Journal of Molecular... May 2022TRUE gene silencing is an RNA-mediated gene expression control technology and is termed after tRNase Z-utilizing efficacious gene silencing. In this review, I overview... (Review)
Review
TRUE gene silencing is an RNA-mediated gene expression control technology and is termed after tRNase Z-utilizing efficacious gene silencing. In this review, I overview the potentiality of small guide RNA (sgRNA) for TRUE gene silencing as novel therapeutics. First, I describe the physiology of tRNase Z and cellular small RNA, and then sgRNA and TRUE gene silencing. An endoribonuclease, tRNase Z, which can efficiently remove a 3' trailer from pre-tRNA, is thought to play the role in tRNA maturation in the nucleus and mitochondria. There exist various small RNAs including miRNA and fragments from tRNA and rRNA, which can function as sgRNA, in living cells, and human cells appear to be harnessing cytosolic tRNase Z for gene regulation together with these small RNAs. By utilizing the property of tRNase Z to recognize and cleave micro-pre-tRNA, a pre-tRNA-like or micro-pre-tRNA-like complex, as well as pre-tRNA, tRNase Z can be made to cleave any target RNA at any desired site under the direction of an artificial sgRNA that binds a target RNA and forms the pre-tRNA-like or micro-pre-tRNA-like complex. This general RNA cleavage method underlies TRUE gene silencing. Various examples of the application of TRUE gene silencing are reviewed including the application to several human cancer cells in order to induce apoptosis. Lastly, I discuss the potentiality of sgRNA as novel therapeutics for multiple myeloma.
Topics: Endoribonucleases; Gene Silencing; Humans; MicroRNAs; RNA Precursors; RNA, Transfer; RNA, Guide, CRISPR-Cas Systems
PubMed: 35628198
DOI: 10.3390/ijms23105387 -
Nature Neuroscience Nov 2022Huntington's disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms, but the mechanism by which aging drives the onset of...
Huntington's disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms, but the mechanism by which aging drives the onset of neurodegeneration in patients with HD remains unclear. In this study we examined striatal medium spiny neurons (MSNs) directly reprogrammed from fibroblasts of patients with HD to model the age-dependent onset of pathology. We found that pronounced neuronal death occurred selectively in reprogrammed MSNs from symptomatic patients with HD (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and control MSNs from age-matched healthy individuals. We observed age-associated alterations in chromatin accessibility between HD-MSNs and pre-HD-MSNs and identified miR-29b-3p, whose age-associated upregulation promotes HD-MSN degeneration by impairing autophagic function through human-specific targeting of the STAT3 3' untranslated region. Reducing miR-29b-3p or chemically promoting autophagy increased the resilience of HD-MSNs against neurodegeneration. Our results demonstrate miRNA upregulation with aging in HD as a detrimental process driving MSN degeneration and potential approaches for enhancing autophagy and resilience of HD-MSNs.
Topics: Humans; Animals; Huntington Disease; Corpus Striatum; Neurons; Autophagy; MicroRNAs; Disease Progression; Disease Models, Animal
PubMed: 36303071
DOI: 10.1038/s41593-022-01185-4