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Wiley Interdisciplinary Reviews. RNA Nov 2021In the last decade, an intriguing new paradigm of regulation has emerged in which some transcripts longer than 200 nucleotides and no coding potential, long noncoding... (Review)
Review
In the last decade, an intriguing new paradigm of regulation has emerged in which some transcripts longer than 200 nucleotides and no coding potential, long noncoding RNA (lncRNAs), exhibit the capability to control posttranslational modifications of nonhistone proteins in both invertebrates and vertebrates. The extent of such a regulation is still largely unknown. We performed a systematic review to identify and evaluate the potential impact of lncRNA-dependent methylation of nonhistone proteins. Collectively, these lncRNAs primarily act as scaffolds upon which methyltransferases (MTases) and targets are brought in proximity. In this manner, the N-MTase activity of EZH2, protein arginine-MTase 1/4/5, and SMYD2 is exploited to modulate the stability or the compartmentalization of several nonhistone proteins with roles in cell signaling, gene expression, and RNA processing. Moreover, these lncRNAs can indirectly affect the methylation of nonhistone proteins by transcriptional or posttranscriptional regulation of MTases. Strikingly, the lncRNAs/MTases/nonhistone proteins networking seem to be relevant to carcinogenesis and neurological disorders. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs.
Topics: Animals; Gene Expression Regulation; Methylation; Protein Processing, Post-Translational; RNA Processing, Post-Transcriptional; RNA, Long Noncoding
PubMed: 33913612
DOI: 10.1002/wrna.1661 -
Frontiers in Cell and Developmental... 2021Circular RNAs (circRNAs) are newly discovered RNAs with covalently looped structures. Due to their resistance to RNAase degradation and tissue-specific expression,...
Circular RNAs (circRNAs) are newly discovered RNAs with covalently looped structures. Due to their resistance to RNAase degradation and tissue-specific expression, circRNAs are expected to be potential biomarkers in early diagnosis and target treatment of many diseases. However, the role of circRNAs in melanoma still needs to be systematically reviewed for better understanding and further research. Based on published articles in PubMed, Embase, Cochrane Library, and Web of Science database, we systematically reviewed the implications and recent advances of circRNAs in melanoma, focusing on function, mechanism, and correlation with melanoma progression. According to inclusion and exclusion criteria, a total of 19 articles were finally included in this systematic review. Of the 19 studies, 17 used human samples, including melanoma tissues ( = 16) and blood serum of patients with melanoma ( = 1). The sample size of the study group ranged from 20 to 105 based on the reported data. Several studies explored the association between circRNAs and clinicopathological characteristics. circRNA dysregulation was commonly observed in melanoma patients. circRNAs function in melanoma by miRNA sponging and interaction with RNA binding proteins (RBP), ultimately controlling several important signaling pathways and cancer-related cellular processes, including proliferation, migration, invasion, metastasis, apoptosis, and glucose metabolism. circRNA expression could be associated with prognostic factors and drug responses, consolidating the potential clinical value in melanoma. Herein, we clarified the functional, prognostic, and predictive roles of circRNAs in melanoma in this systematic review, providing future directions for studies on melanoma-associated circRNAs.
PubMed: 33869186
DOI: 10.3389/fcell.2021.638548 -
Molecular Microbiology May 2021Trypanosoma and Leishmania parasites cause devastating tropical diseases resulting in serious global health consequences. These organisms have complex life cycles with...
Trypanosoma and Leishmania parasites cause devastating tropical diseases resulting in serious global health consequences. These organisms have complex life cycles with mammalian hosts and insect vectors. The parasites must, therefore, survive in different environments, demanding rapid physiological and metabolic changes. These responses depend upon regulation of gene expression, which primarily occurs posttranscriptionally. Altering the composition or conformation of RNA through nucleotide modifications is one posttranscriptional mechanism of regulating RNA fate and function, and modifications including N6-methyladenosine (m6A), N1-methyladenosine (m1A), N5-methylcytidine (m5C), N4-acetylcytidine (ac4C), and pseudouridine (Ψ), dynamically regulate RNA stability and translation in diverse organisms. Little is known about RNA modifications and their machinery in Trypanosomatids, but we hypothesize that they regulate parasite gene expression and are vital for survival. Here, we identified Trypanosomatid homologs for writers of m1A, m5C, ac4C, and Ψ and analyze their evolutionary relationships. We systematically review the evidence for their functions and assess their potential use as therapeutic targets. This work provides new insights into the roles of these proteins in Trypanosomatid parasite biology and treatment of the diseases they cause and illustrates that Trypanosomatids provide an excellent model system to study RNA modifications, their molecular, cellular, and biological consequences, and their regulation and interplay.
Topics: Animals; Epigenomics; Humans; Protozoan Proteins; RNA Processing, Post-Transcriptional; RNA, Protozoan; Transcriptome; Trypanosoma; Trypanosomiasis
PubMed: 33513291
DOI: 10.1111/mmi.14688 -
Diagnostics (Basel, Switzerland) Jan 2021Estimating the time of death remains the most challenging question in forensic medicine, because post-mortem interval (PMI) estimation can be a remarkably difficult goal... (Review)
Review
Estimating the time of death remains the most challenging question in forensic medicine, because post-mortem interval (PMI) estimation can be a remarkably difficult goal to achieve. The aim of this review is to analyze the potential of microRNAs (miRNAs) to evaluate PMI. MiRNAs have been studied as hallmarks and biomarkers in several pathologies and have also showed interesting applications in forensic science, such as high sensible biomarkers in body fluid and tissue, for wound age determination and PMI evaluation due to their low molecular weight and tissue-specific expression. The present systematic review was carried out according to the Preferred Reporting Items for Systematic Review (PRISMA) standards. We performed an electronic search of PubMed, Science Direct Scopus, and Excerpta Medica Database (EMBASE) from the inception of these databases to 12 August 2020. The search terms were ("PMI miRNA" or "PMI micro RNA") and ("miRNA" and "time of death") in the title, abstract and keywords. Through analysis of scientific literature regarding forensic uses of miRNAs, has emerged that the intrinsic characteristics of such molecules, and their subsequent resistance to degradation, make them suitable as endogenous markers in order to determine PMI. However, further and larger studies with human samples and standardized protocols are still needed.
PubMed: 33401603
DOI: 10.3390/diagnostics11010064 -
Neurobiology of Disease Feb 2021Neurodegenerative disorders such as Alzheimer's disease (AD), Lewy body diseases (LBD), and the amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD)... (Meta-Analysis)
Meta-Analysis
Neurodegenerative disorders such as Alzheimer's disease (AD), Lewy body diseases (LBD), and the amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) spectrum are defined by the accumulation of specific misfolded protein aggregates. However, the mechanisms by which each proteinopathy leads to neurodegeneration remain elusive. We hypothesized that there is a common "pan-neurodegenerative" gene expression signature driving pathophysiology across these clinically and pathologically diverse proteinopathies. To test this hypothesis, we performed a systematic review of human CNS transcriptomics datasets from AD, LBD, and ALS-FTD patients and age-matched controls in the Gene Expression Omnibus (GEO) and ArrayExpress databases, followed by consistent processing of each dataset, meta-analysis, pathway enrichment, and overlap analyses. After applying pre-specified eligibility criteria and stringent data pre-processing, a total of 2600 samples from 26 AD, 21 LBD, and 13 ALS-FTD datasets were included in the meta-analysis. The pan-neurodegenerative gene signature is characterized by an upregulation of innate immunity, cytoskeleton, and transcription and RNA processing genes, and a downregulation of the mitochondrial electron transport chain. Pathway enrichment analyses also revealed the upregulation of neuroinflammation (including Toll-like receptor, TNF, and NFκB signaling) and phagocytosis, and the downregulation of mitochondrial oxidative phosphorylation, lysosomal acidification, and ubiquitin-proteasome pathways. Our findings suggest that neuroinflammation and a failure in both neuronal energy metabolism and protein degradation systems are consistent features underlying neurodegenerative diseases, despite differences in the extent of neuronal loss and brain regions involved.
Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Brain; Energy Metabolism; Frontotemporal Dementia; Humans; Inflammation; Inflammation Mediators; Lewy Body Disease; Neurodegenerative Diseases; Proteostasis; Transcriptome
PubMed: 33347974
DOI: 10.1016/j.nbd.2020.105225 -
The Science of the Total Environment Apr 2021Although an increasing body of data reports the detection of SARS-CoV-2 RNA in air, this does not correlate to the presence of infectious viruses, thus not evaluating... (Review)
Review
BACKGROUND
Although an increasing body of data reports the detection of SARS-CoV-2 RNA in air, this does not correlate to the presence of infectious viruses, thus not evaluating the risk for airborne COVID-19. Hence there is a marked knowledge gap that requires urgent attention. Therefore, in this systematic review, viability/stability of airborne SARS-CoV-2, SARS-CoV and MERS-CoV viruses is discussed.
METHODS
A systematic literature review was performed on PubMed/MEDLINE, Web of Science and Scopus to assess the stability and viability of SARS-CoV, MERS-CoV and SARS-CoV-2 on air samples.
RESULTS AND DISCUSSION
The initial search identified 27 articles. Following screening of titles and abstracts and removing duplicates, 11 articles were considered relevant. Temperatures ranging from 20 °C to 25 °C and relative humidity ranging from 40% to 50% were reported to have a protective effect on viral viability for airborne SARS-CoV and MERS-CoV. As no data is yet available on the conditions influencing viability for airborne SARS-CoV-2, and given the genetic similarity to SARS-CoV and MERS-CoV, one could extrapolate that the same conditions would apply. Nonetheless, the effect of these conditions seems to be residual considering the increasing number of cases in the south of USA, Brazil and India, where high temperatures and humidities have been observed.
CONCLUSION
Higher temperatures and high relative humidity can have a modest effect on SARS-CoV-2 viability in the environment, as reported in previous studies to this date. However, these studies are experimental, and do not support the fact that the virus has efficiently spread in the tropical regions of the globe, with other transmission routes such as the contact and droplet ones probably being responsible for the majority of cases reported in these regions, along with other factors such as human mobility patterns and contact rates. Further studies are needed to investigate the extent of aerosol transmission of SARS-CoV-2 as this would have important implications for public health and infection-control policies.
Topics: Brazil; COVID-19; Humans; India; Middle East Respiratory Syndrome Coronavirus; RNA, Viral; SARS-CoV-2
PubMed: 33071145
DOI: 10.1016/j.scitotenv.2020.142802 -
Pharmacological Reviews Oct 2020RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various...
RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.
Topics: Aptamers, Nucleotide; Betacoronavirus; COVID-19; Chemistry Techniques, Analytical; Clustered Regularly Interspaced Short Palindromic Repeats; Coronavirus Infections; Drug Delivery Systems; Drug Development; Drug Discovery; Humans; MicroRNAs; Oligonucleotides, Antisense; Pandemics; Pneumonia, Viral; RNA; RNA, Antisense; RNA, Messenger; RNA, Ribosomal; RNA, Small Interfering; RNA, Viral; Ribonucleases; Riboswitch; SARS-CoV-2
PubMed: 32929000
DOI: 10.1124/pr.120.019554 -
Cancers Aug 2020Glioblastoma (GBM) is the most lethal primary brain tumor of the central nervous system in adults. Despite advances in surgical and medical neuro-oncology, the median... (Review)
Review
Glioblastoma (GBM) is the most lethal primary brain tumor of the central nervous system in adults. Despite advances in surgical and medical neuro-oncology, the median survival is about 15 months. For this reason, initial diagnosis, prognosis, and targeted therapy of GBM represent very attractive areas of study. Aptamers are short three-dimensional structures of single-stranded nucleic acids (RNA or DNA), identified by an in vitro process, named systematic evolution of ligands by exponential enrichment (SELEX), starting from a partially random oligonucleotide library. They bind to a molecular target with high affinity and specificity and can be easily modified to optimize binding affinity and selectivity. Thanks to their properties (low immunogenicity and toxicity, long stability, and low production variability), a large number of aptamers have been selected against GBM biomarkers and provide specific imaging agents and therapeutics to improve the diagnosis and treatment of GBM. However, the use of aptamers in GBM diagnosis and treatment still represents an underdeveloped topic, mainly due to limited literature in the research world. On these bases, we performed a systematic review aimed at summarizing current knowledge on the new promising DNA and RNA aptamer-based molecules for GBM diagnosis and treatment. Thirty-eight studies from 2000 were included and investigated. Seventeen involved the use of aptamers for GBM diagnosis and 21 for GBM therapy. Our findings showed that a number of DNA and RNA aptamers are promising diagnostic and therapeutic tools for GBM management.
PubMed: 32764266
DOI: 10.3390/cancers12082173 -
Journal of Genetics 2020The relationship between the long noncoding RNA (lncRNA) expression and oesophageal cancer prognosis has been widely studied, but less consensus has been reached. We... (Meta-Analysis)
Meta-Analysis
The relationship between the long noncoding RNA (lncRNA) expression and oesophageal cancer prognosis has been widely studied, but less consensus has been reached. We conducted this study to evaluate the relationship between the expression of lncRNAs and the prognosis and clinical pathology of oesophageal cancer. We conducted a systematic search of PubMed, EMBASE and Cochrane Library until 25 January 2019. Studies that evaluated the associations of a specific lncRNA with survival and/or clinicopathology of oesophageal cancer were included. Pooled hazard ratios (HRs), odds ratios (ORs), and corresponding 95% confidence intervals (CIs) were calculated using fixed or random-effect models. Sensitivity analysis was used to verify the stability of results. Publication bias was detected usingBegg tests and adjusted utilizing the trim-and-fill method if a bias existed. A total of 51 studies comprising 6510 patients and regarding 41 lncRNAs were included in the present systematic review and meta-analysis. The results showed that dysregulation of lncRNAs was associated with overall survival, disease-free survival, and progression-free survival. The expression of lncRNAs was related to some certain clinicopathological parameters of oesophageal cancer, including tumour size, T classification, lymph node metastasis, tumour node metastasis (TNM) stage and differentiation. Among these findings, lncRNA AK001796, CASC9, HOTAIR, MALAT1 and UCA1 were identified and were expected to be ideal biomarkers for the prognosis and clinicopathology of oesophageal cancer. Although significant publication bias was observed in some studies, the results were not changed after adjustment using the trim-and-fill method. Abnormal lncRNA-expression profiles could serve as a promising indicator for prognostic evaluation of patients with oesophageal cancer. The combination of these lncRNAs will contribute to clinical decision-making in the future.
Topics: Biomarkers, Tumor; Esophageal Neoplasms; Gene Expression Regulation, Neoplastic; Prognosis; RNA, Long Noncoding
PubMed: 32529986
DOI: No ID Found -
Journal of Neuromuscular Diseases 2020Eteplirsen, the first FDA-approved RNA-modifying therapy for DMD, is applicable to ∼13% of patients with DMD. Because multiple exonic deletions are amenable to exon 51...
BACKGROUND
Eteplirsen, the first FDA-approved RNA-modifying therapy for DMD, is applicable to ∼13% of patients with DMD. Because multiple exonic deletions are amenable to exon 51 skipping, the isoforms resulting from the various exon 51-skipped transcripts may vary in stability, function, and phenotype.
OBJECTIVE/METHODS
We conducted a detailed review of dystrophinopathy published literature and unpublished databases to compile phenotypic features of patients with exon 51 "skip-equivalent" deletions.
RESULTS
Theoretically, 48 different in-frame transcripts may result from exon 51 skipping. We found sufficient clinical information on 135 patients carrying mutations that would result in production of 11 (23%) of these transcripts, suggesting the remainder have not been identified in vivo. The majority had mild phenotypes: BMD (n = 81) or isolated dilated cardiomyopathy (n = 3). Particularly interesting are the asymptomatic (n = 10) or isolated hyperCKemia (n = 20) patients with deletions of exons 45- 51, 48- 51, 49- 51 and 50- 51. Finally, 16 (12%) had more severe phenotypes described as intermediate (n = 2) or DMD (n = 14), and 6 reports had no definitive phenotype.
CONCLUSIONS
This review shows that the majority of exon 51 "skip-equivalent" deletions result in milder (BMD) phenotypes and supports that exon 51 skipping therapy could provide clinical benefit, although we acknowledge that other factors, such as age at treatment initiation or ongoing standard of care, may influence the degree of benefit.
Topics: Humans; Muscular Dystrophy, Duchenne
PubMed: 32417793
DOI: 10.3233/JND-200483