Analysis of Small RNA Species: Phylogenetic Trends
S. K. Dutta in DNA Systematics, 2019
Small RNAs can be synthesized de novo from ribonucleoside-5′-triphosphates by Escherichia coli Qβ replicase, an enzyme which also replicates Qβ RNA template, as well as satellite RNA of Qβ virion. Polynucleotide phosphorylase (PNPase) from bacteria can also synthesize RNA from ribonucleoside-5′-diphosphates.6 These facts and the observation that small RNAs from different origins can be transcribed into DNA, contribute to modifying notions about the origin and flow of information in cells. For these and other reasons, scientists have thus studied small RNAs and have visualized their possible participation in the creation of new genes and/or pseudogenes. In this chapter, we shall attempt to give an overview of many different small RNAs by describing their chemical and physical properties as well as their evident, or possible biological role. The phylogenetic trends between these RNAs will be evaluated on the basis of sequence data since at the present time the biological functions of the majority of small RNAs are unknown.
Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Two main technologies have been pursued to develop RNA-based therapeutics, antisense and RNA interference (RNAi), and these are described in detail below. Both antisense and RNAi therapeutics have taken many decades to develop, partly due to the fragility of RNA toward premature degradation. For this reason, many different types of backbone modified nucleic acid structures have been developed, and these are described below in a separate section, although they can be used for either of the main therapeutic strategies. Also, within the area of RNAi therapeutics, two types of small RNA molecules, small interfering RNAs (siRNAs) and microRNAs (miRNAs), have been developed and are described below. Finally, there has been significant amount of research into ribozymes, engineered RNA fragments with enzymic activity, and small molecules that can bind and target RNA. Although of academic interest and described below, neither of these technologies have reached late-stage clinical trials.
Nanoparticle-Mediated Small RNA Deliveries for Molecular Therapies
D. Sakthi Kumar, Aswathy Ravindran Girija in Bionanotechnology in Cancer, 2023
Nucleic acids, especially RNAs are prone to digestion by highly stable RNases (RNase 1–8), which are predominantly present in cells and other extracellular spaces, including the circulating bloodpool [3]. Hence, naked RNAs cannot be delivered for therapeutic applications directly via systemic blood circulation. That is the case despite our knowledge that a major delivery route for therapeutic delivery for many drugs is indeed by systemic intravenous injection, because this route provides accessibility to most body tissues. Moreover, small RNAs also need to reach the cytoplasm of target cells to show their biological functions. Hence, nanoparticles of various types may be regarded as efficient delivery vehicles for small RNAs into target tissues. Importantly, nanoparticles may also protect RNAs from nucleases while facilitating their delivery. Identifying optimal nanoparticles for small RNA delivery is very important; nanoparticles of small size (less than 10 nm) are rapidly filtered through the kidneys and reticuloendothelial system (RES). Contrastingly, nanoparticles with sizes in the range of 100 nm to 150 nm have been shown to be efficiently taken-up by cells, while also providing sufficient space for loading RNAs within the nanoparticles to protect them from nucleases [4, 5].
A comprehensive review of hormonal and biological therapies for endometriosis: latest developments
Published in Expert Opinion on Biological Therapy, 2019
Fabio Barra, Giovanni Grandi, Matteo Tantari, Carolina Scala, Fabio Facchinetti, Simone Ferrero
Small RNA molecules are involved in many biological functions: among these, they play important roles in the regulation of DNA transcription, RNA stability, and translation. Although the involvement of small RNA molecules in endometriosis is mostly obscure, several miRNAs/siRNAs have been identified as overexpressed or down-expressed [166]. In particular, studies in vitro on MiRNA-145, MiRNA-195 or MiRNA-503, known to be down regulated in endometriosis, has led preliminary interesting results. When transfected on eutopic and ectopic endometrial stroma cells, all these miRNAs were able to inhibit proliferation and invasiveness by targeting multiple cytoskeletal elements and pluripotency factors [167–169]. Currently, no study on these molecules is available in the animal model. Similarly, the use of some siRNA (such as those blocking STAT3, VEGF-C) have reported promising results on endometriotic cells [170,171]. Moreover, in a pre-clinical study on animals with surgically induced endometriosis, a siRNA blocking β-nerve growth factor (β-NGF) obtained a higher decrease of the spherical volumes of implants in comparison with the control group; the concentrations of β-NGF in the sera and supernatants of peritoneal fluid decreased in the treatment group unlike of the control group [172].
MicroRNAs as therapeutic targets for the treatment of diabetes mellitus and its complications
Published in Expert Opinion on Therapeutic Targets, 2018
Today, more than 2500 different miRNAs have been identified in humans (http://www.mirbase.org/). These small RNAs are usually produced from intergenic or intronic sequences. In the latter case, they are often co-regulated with their hosting genes but their expression may also be controlled independently [20]. Many miRNAs are ubiquitously expressed but some of them are restricted to a subset of cells. They are usually generated in the nucleus from long precursor molecules (pri-miRNAs) transcribed by RNA polymerase II [21]. Once produced, pri-miRNAs are processed by an enzymatic complex including the RNase III enzyme Drosha, releasing a ~70 nucleotide hairpin-shaped precursor called pre-miRNA. Pre-miRNA hairpins are translocated by the Exportin-5/Ran GTPase complex from the nucleus to the cytoplasm where they are further cleaved by Dicer, another RNase III-type endonuclease. This generates a short RNA duplex (21–24 bp), including the mature miRNA (guide strand) and a partially complementary sequence called the passenger strand (or miRNA*) which is usually rapidly degraded. The biogenesis of some miRNAs does not occur via the canonical pathway described above but are produced via alternative routes that bypass Drosha or Dicer cleavage [22].
siRNA drug development against hepatitis B virus infection
Published in Expert Opinion on Biological Therapy, 2018
Robert Flisiak, Jerzy Jaroszewicz, Mariusz Łucejko
Discovery of various classes of small RNA molecules in recent years has led to the development of a molecular biology subdivision sometimes called “RNA molecular biology” [25]. Small RNAs are double-stranded (dsRNA) and noncoding oligonucleotides, and precursors of molecules whose function is to regulate gene expression using the homologous mRNA sequences [25,26]. dsRNA particles are constructed of two strands: the passenger strand and the guide strand which is fully or highly complementary to the mRNA target particles. Their mechanism of action is inhibition of gene expression and is thus called RNA silencing. dsRNA is surprisingly effective and in a small amount is sufficient to trigger a strong response [27]. The silencing induced by small RNA can take place in two modes. The first is transcriptional gene silencing, in which it decreases mRNA synthesis capacity or completely inhibits transcription because of promoter methylation by DNA pairing or the dsRNA-induced inactivation of a transgenic promoter [28]. The second mode is based on posttranscriptional gene silencing (PTGS), in which specific degradation of the target mRNA occurs by homologous sequences of short RNA fragments – called RNAi. The latter method is most commonly used for the design of drugs for HBV infection.
Related Knowledge Centers
- Microrna
- Nucleotide
- Rna
- Rna Interference
- Small Interfering Rna
- Messenger Rna
- NON-Coding Rna
- Rna Silencing
- Complementarity
- Piwi-Interacting Rna