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Non-coding RNA Research Sep 2023Small interfering RNA (siRNAs) is a double-stranded RNA molecule which can hybridize with a specific mRNA sequence and block the translation of numerous genes to... (Review)
Review
Small interfering RNA (siRNAs) is a double-stranded RNA molecule which can hybridize with a specific mRNA sequence and block the translation of numerous genes to regulate endogenous genes and to defend the genome from invasive nucleic acids. The use of siRNAs has been studied as a treatment option for various skin conditions. One of the main obstacles in the dermal or transdermal delivery of this compound is low skin permeability, and application is limited by its negative charge, high polarity, susceptibility to degradation by nucleases, and difficulty in penetrating the skin barrier. Effective delivery of therapeutic biomolecules to their target is a challenging issue, which can be solved by innovations in drug delivery systems and lead to improvement of the efficiency of many new biopharmaceuticals. Designing of novel transdermal delivery systems garnered tremendous attention in both cosmeceutical and pharmaceutical research and industries, which offers a number of advantages. Developing safe and efficient siRNAs delivery vectors is essential for effective treatment of skin diseases. In recent years, significant progress has been made in the creation of delivery systems using lipids, polymers, cell-penetrating peptides, nanoparticles and other biologically active agents. In this review we will focus on the recent advancements in transdermal siRNAs delivery vectors, such as liposomes, dendrimers, cell-penetrating peptides, and spherical nucleic acid nanoparticles.
PubMed: 37275244
DOI: 10.1016/j.ncrna.2023.05.008 -
Nucleic Acids Research May 2024RNA interference (RNAi) is an endogenous process that can be harnessed using chemically modified small interfering RNAs (siRNAs) to potently modulate gene expression in...
RNA interference (RNAi) is an endogenous process that can be harnessed using chemically modified small interfering RNAs (siRNAs) to potently modulate gene expression in many tissues. The route of administration and chemical architecture are the primary drivers of oligonucleotide tissue distribution, including siRNAs. Independently of the nature and type, oligonucleotides are eliminated from the body through clearance tissues, where their unintended accumulation may result in undesired gene modulation. Divalent siRNAs (di-siRNAs) administered into the CSF induce robust gene silencing throughout the central nervous system (CNS). Upon clearance from the CSF, they are mainly filtered by the kidneys and liver, with the most functionally significant accumulation occurring in the liver. siRNA- and miRNA-induced silencing can be blocked through substrate inhibition using single-stranded, stabilized oligonucleotides called antagomirs or anti-siRNAs. Using APOE as a model target, we show that undesired di-siRNA-induced silencing in the liver can be mitigated through administration of liver targeting GalNAc-conjugated anti-siRNAs, without impacting CNS activity. Blocking unwanted hepatic APOE silencing achieves fully CNS-selective silencing, essential for potential clinical translation. While we focus on CNS/liver selectivity, coadministration of differentially targeting siRNA and anti-siRNAs can be adapted as a strategy to achieve tissue selectivity in different organ combinations.
Topics: Animals; Humans; Male; Mice; Acetylgalactosamine; Antagomirs; Apolipoproteins E; Central Nervous System; Gene Silencing; Liver; Mice, Inbred C57BL; MicroRNAs; RNA Interference; RNA, Small Interfering
PubMed: 38348876
DOI: 10.1093/nar/gkae100 -
Frontiers in Insect Science 2023Since its discovery in 1998, RNA interference (RNAi), a Nobel prize-winning technology, made significant contributions to advances in biology because of its ability to... (Review)
Review
Since its discovery in 1998, RNA interference (RNAi), a Nobel prize-winning technology, made significant contributions to advances in biology because of its ability to mediate the knockdown of specific target genes. RNAi applications in medicine and agriculture have been explored with mixed success. The past 25 years of research on RNAi resulted in advances in our understanding of the mechanisms of its action, target specificity, and differential efficiency among animals and plants. RNAi played a major role in advances in insect biology. Did RNAi technology fully meet insect pest and disease vector management expectations? This review will discuss recent advances in the mechanisms of RNAi and its contributions to insect science. The remaining challenges, including delivery to the target site, differential efficiency, potential resistance development and possible solutions for the widespread use of this technology in insect management.
PubMed: 38469536
DOI: 10.3389/finsc.2023.1209478 -
Molecular Plant Pathology Aug 2023Plants' response to pathogens is highly complex and involves changes at different levels, such as activation or repression of a vast array of genes. Recently, many... (Review)
Review
Plants' response to pathogens is highly complex and involves changes at different levels, such as activation or repression of a vast array of genes. Recently, many studies have demonstrated that many RNAs, especially small RNAs (sRNAs), are involved in genetic expression and reprogramming affecting plant-pathogen interactions. The sRNAs, including short interfering RNAs and microRNAs, are noncoding RNA with 18-30 nucleotides, and are recognized as key genetic and epigenetic regulators. In this review, we summarize the new findings about defence-related sRNAs in the response to pathogens and our current understanding of their effects on plant-pathogen interactions. The main content of this review article includes the roles of sRNAs in plant-pathogen interactions, cross-kingdom sRNA trafficking between host and pathogen, and the application of RNA-based fungicides for plant disease control.
Topics: Host-Pathogen Interactions; RNA, Small Interfering; MicroRNAs; RNA Interference; Plants
PubMed: 37026481
DOI: 10.1111/mpp.13329 -
RNA (New York, N.Y.) Aug 2023The potential for microRNAs (miRNAs) to regulate gene expression remains incompletely understood. DROSHA initiates the biogenesis of miRNAs while variants of Argonaute...
The potential for microRNAs (miRNAs) to regulate gene expression remains incompletely understood. DROSHA initiates the biogenesis of miRNAs while variants of Argonaute (AGO) and trinucleotide repeat containing six (TNRC6) family proteins form complexes with miRNAs to facilitate RNA recognition and gene regulation. Here we investigate the fate of miRNAs in the absence of these critical RNAi protein factors. Knockout of expression reduces levels of some miRNAs annotated in miRBase but not others. The identity of miRNAs with reduced expression matches the identity of miRNAs previously identified by experimental approaches. The MirGeneDB resource offers the closest alignment with experimental results. In contrast, the loss of TNRC6 proteins had much smaller effects on miRNA levels. Knocking out AGO proteins, which directly contact the mature miRNA, decreased expression of the miRNAs most strongly associated with AGO2 as determined from enhanced crosslinking immunoprecipitation (AGO2-eCLIP). Evaluation of miRNA binding to endogenously expressed AGO proteins revealed that miRNA:AGO association was similar for AGO1, AGO2, AGO3, and AGO4. Our data emphasize the need to evaluate annotated miRNAs based on approximate cellular abundance, DROSHA-dependence, and physical association with AGO when forming hypotheses related to their function.
Topics: MicroRNAs; RNA Interference; Argonaute Proteins; Gene Expression Regulation; Trinucleotide Repeats
PubMed: 37169394
DOI: 10.1261/rna.079647.123 -
Frontiers in Bioscience (Landmark... Sep 2023One of the crucial processes for small RNA synthesis and plant disease resistance is RNA interference (RNAi). Dicer-like (DCL), RNA-dependent RNA polymerase (RDR),...
BACKGROUND
One of the crucial processes for small RNA synthesis and plant disease resistance is RNA interference (RNAi). Dicer-like (DCL), RNA-dependent RNA polymerase (RDR), double-stranded RNA binding (DRB), and Argonaute are important proteins implicated in RNAi (AGO). Numerous significant woody plants belong to the Juglandaceae; walnut is one of the four groups of woody plants on earth and one of the four groups of dried fruits.
METHODS
In order to correlate walnuts and their homologues, this work integrated numerous web resources from structural analysis and transcriptome data collected from gene families in order to elucidate the evolution and functional differentiation of RNA-related proteins in the walnut () genome.
RESULTS
5 genes, 13 genes, 15 genes, and 15 genes are found in the walnut genome and encode conserved protein domains and motifs with similar subcellular distribution.There are three classes and seven subclasses of walnut AGO proteins. RDRS are primarily split into four categories, whereas DRBs can be divided into six. DCLs are separated into four groups. The walnut RDR1 copy number of 9 is the exception, with 7 of those copies being dispersed in clusters on chromosome 16. Proteins are susceptible to various levels of purification selection, but in walnut, purification selection drives gene creation. These findings also indicated some resemblance in other plants belonging to the walnut family. Under various tissues and stresses, many RNA-related genes in walnut produced abundant, selective expression.
CONCLUSIONS
In this study, the genome of the Juglandaceae's , , , and gene families were discovered and analysed for the first time. The evolution, structure, and expression characteristics of these families were also preliminary studied, offering a foundation for the development and breeding of the walnut RNAi pathway.
Topics: RNA Interference; Juglandaceae; Plants; RNA; RNA-Dependent RNA Polymerase; Gene Expression Regulation, Plant; Phylogeny
PubMed: 37796691
DOI: 10.31083/j.fbl2809218 -
Molecular Therapy : the Journal of the... Mar 2024Cardiovascular disease (CVD) continues to impose a significant global health burden, necessitating the exploration of innovative treatment strategies. Ribonucleic acid... (Review)
Review
Cardiovascular disease (CVD) continues to impose a significant global health burden, necessitating the exploration of innovative treatment strategies. Ribonucleic acid (RNA)-based therapeutics have emerged as a promising avenue to address the complex molecular mechanisms underlying CVD pathogenesis. We present a comprehensive review of the current state of RNA therapeutics in the context of CVD, focusing on the diverse modalities that bring about transient or permanent modifications by targeting the different stages of the molecular biology central dogma. Considering the immense potential of RNA therapeutics, we have identified common gene targets that could serve as potential interventions for prevalent Mendelian CVD caused by single gene mutations, as well as acquired CVDs developed over time due to various factors. These gene targets offer opportunities to develop RNA-based treatments tailored to specific genetic and molecular pathways, presenting a novel and precise approach to address the complex pathogenesis of both types of cardiovascular conditions. Additionally, we discuss the challenges and opportunities associated with delivery strategies to achieve targeted delivery of RNA therapeutics to the cardiovascular system. This review highlights the immense potential of RNA-based interventions as a novel and precise approach to combat CVD, paving the way for future advancements in cardiovascular therapeutics.
Topics: Humans; RNA; Cardiovascular Diseases; MicroRNAs
PubMed: 38291757
DOI: 10.1016/j.ymthe.2024.01.028 -
Microbiology Spectrum Aug 2023mosquitoes are the primary vectors for the transmission of malaria parasites, which poses a devastating burden on global public health and welfare. The recent invasion...
mosquitoes are the primary vectors for the transmission of malaria parasites, which poses a devastating burden on global public health and welfare. The recent invasion of Anopheles stephensi in Africa has made malaria eradication more challenging due to its outdoor biting behavior and widespread resistance to insecticides. To address this issue, we developed a new approach for mosquito larvae control using gut microbiota-mediated RNA interference (RNAi). We engineered a mosquito symbiotic gut bacterium, Serratia fonticola, by deleting its gene to produce double-stranded RNAs (dsRNAs) in the mosquito larval gut. We found that the engineered strains can stably colonize mosquito larval guts and produce dsRNAs ds or ds to activate RNAi and effectively suppress the expression of methoprene-tolerant gene and ecdysone receptor gene , which encode receptors for juvenile hormone and ecdysone pathways in mosquitoes, respectively. Importantly, the engineered strains markedly inhibit the development of A. stephensi larvae and leads to a high mortality, providing an effective dsRNA delivery system for silencing genes in insects and a novel RNAi-mediated pest control strategy. Collectively, our symbiont-mediated RNAi (smRNAi) approach offers an innovative and sustainable method for controlling mosquito larvae and provides a promising strategy for combating malaria. Mosquitoes are vectors for various diseases, imposing a significant threat to public health globally. The recent invasion of A. stephensi in Africa has made malaria eradication more challenging due to its outdoor biting behavior and widespread resistance to insecticides. RNA interference (RNAi) is a promising approach that uses dsRNA to silence specific genes in pests. This study presents the use of a gut symbiotic bacterium, Serratia fonticola, as an efficient delivery system of dsRNA for RNAi-mediated pest control. The knockout of , a dsRNA-specific endonuclease gene, in using CRISPR-Cas9 led to efficient dsRNA production. Engineered strains of can colonize the mosquito larval gut and effectively suppress the expression of two critical genes, and , which inhibit mosquito development and cause high mortality in mosquito larvae. This study highlights the potential of exploring the mosquito microbiota as a source of dsRNA for RNAi-based pest control.
Topics: Animals; RNA Interference; Anopheles; Larva; Insecticides; Ribonuclease III; Mosquito Vectors; RNA, Double-Stranded; Malaria
PubMed: 37458601
DOI: 10.1128/spectrum.01666-23 -
Frontiers in Genetics 2023
PubMed: 37811151
DOI: 10.3389/fgene.2023.1290714 -
Asian Journal of Pharmaceutical Sciences Sep 2023How to effectively transform the pro-oncogenic tumor microenvironments (TME) surrounding a tumor into an anti-tumoral never fails to attract people to study. Small... (Review)
Review
How to effectively transform the pro-oncogenic tumor microenvironments (TME) surrounding a tumor into an anti-tumoral never fails to attract people to study. Small interfering RNA (siRNA) is considered one of the most noteworthy research directions that can regulate gene expression following a process known as RNA interference (RNAi). The research about siRNA delivery targeting tumor cells and TME has been on the rise in recent years. Using siRNA drugs to silence critical proteins in TME was one of the most efficient solutions. However, the manufacture of a siRNA delivery system faces three major obstacles, , appropriate cargo protection, accurately targeted delivery, and site-specific cargo release. In the following review, we summarized the pharmacological actions of siRNA drugs in remolding TME. In addition, the delivery strategies of siRNA drugs and combination therapy with siRNA drugs to remodel TME are thoroughly discussed. In the meanwhile, the most recent advancements in the development of all clinically investigated and commercialized siRNA delivery technologies are also presented. Ultimately, we propose that nanoparticle drug delivery siRNA may be the future research focus of oncogene therapy. This summary offers a thorough analysis and roadmap for general readers working in the field.
PubMed: 37920650
DOI: 10.1016/j.ajps.2023.100852