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Biological Chemistry Oct 2023MicroRNA (miRNA)-guided gene silencing is a key regulatory process in various organisms and linked to many human diseases. MiRNAs are processed from precursor molecules... (Review)
Review
MicroRNA (miRNA)-guided gene silencing is a key regulatory process in various organisms and linked to many human diseases. MiRNAs are processed from precursor molecules and associate with Argonaute proteins to repress the expression of complementary target mRNAs. Excellent work by numerous labs has contributed to a detailed understanding of the mechanisms of miRNA function. However, miRNA effects have mostly been analyzed and viewed as isolated events and their natural environment as part of complex RNA-protein particles (RNPs) is often neglected. RNA binding proteins (RBPs) regulate key enzymes of the miRNA processing machinery and furthermore RBPs or readers of RNA modifications may modulate miRNA activity on mRNAs. Such proteins may function similarly to miRNAs and add their own contributions to the overall expression level of a particular gene. Therefore, post-transcriptional gene regulation might be more the sum of individual regulatory events and should be viewed as part of a dynamic and complex RNP world.
Topics: Humans; RNA Interference; MicroRNAs; Gene Expression Regulation; RNA-Binding Proteins; Argonaute Proteins
PubMed: 37739934
DOI: 10.1515/hsz-2023-0203 -
Current Issues in Molecular Biology Apr 2024This review aims to highlight the structures of ADAR proteins that have been crucial in the discernment of their functions and are relevant to future therapeutic... (Review)
Review
This review aims to highlight the structures of ADAR proteins that have been crucial in the discernment of their functions and are relevant to future therapeutic development. ADAR proteins can correct or diversify genetic information, underscoring their pivotal contribution to protein diversity and the sophistication of neuronal networks. ADAR proteins have numerous functions in RNA editing independent roles and through the mechanisms of A-I RNA editing that continue to be revealed. Provided is a detailed examination of the ADAR family members-ADAR1, ADAR2, and ADAR3-each characterized by distinct isoforms that offer both structural diversity and functional variability, significantly affecting RNA editing mechanisms and exhibiting tissue-specific regulatory patterns, highlighting their shared features, such as double-stranded RNA binding domains (dsRBD) and a catalytic deaminase domain (CDD). Moreover, it explores ADARs' extensive roles in immunity, RNA interference, and disease modulation, demonstrating their ambivalent nature in both the advancement and inhibition of diseases. Through this comprehensive analysis, the review seeks to underline the potential of targeting ADAR proteins in therapeutic strategies, urging continued investigation into their biological mechanisms and health implications.
PubMed: 38785511
DOI: 10.3390/cimb46050243 -
Journal of Biomedical Science Oct 2023RNA has emerged as a revolutionary and important tool in the battle against emerging infectious diseases, with roles extending beyond its applications in vaccines, in... (Review)
Review
RNA has emerged as a revolutionary and important tool in the battle against emerging infectious diseases, with roles extending beyond its applications in vaccines, in which it is used in the response to the COVID-19 pandemic. Since their development in the 1990s, RNA interference (RNAi) therapeutics have demonstrated potential in reducing the expression of disease-associated genes. Nucleic acid-based therapeutics, including RNAi therapies, that degrade viral genomes and rapidly adapt to viral mutations, have emerged as alternative treatments. RNAi is a robust technique frequently employed to selectively suppress gene expression in a sequence-specific manner. The swift adaptability of nucleic acid-based therapeutics such as RNAi therapies endows them with a significant advantage over other antiviral medications. For example, small interfering RNAs (siRNAs) are produced on the basis of sequence complementarity to target and degrade viral RNA, a novel approach to combat viral infections. The precision of siRNAs in targeting and degrading viral RNA has led to the development of siRNA-based treatments for diverse diseases. However, despite the promising therapeutic benefits of siRNAs, several problems, including impaired long-term protein expression, siRNA instability, off-target effects, immunological responses, and drug resistance, have been considerable obstacles to the use of siRNA-based antiviral therapies. This review provides an encompassing summary of the siRNA-based therapeutic approaches against viruses while also addressing the obstacles that need to be overcome for their effective application. Furthermore, we present potential solutions to mitigate major challenges.
Topics: Humans; RNA, Small Interfering; Pandemics; COVID-19; RNA Interference; Viruses; Antiviral Agents; RNA, Viral
PubMed: 37845731
DOI: 10.1186/s12929-023-00981-9 -
Frontiers in Bioengineering and... 2023Chemotherapy often faces some obstacles such as low targeting effects and drug resistance, which introduce the low therapeutic efficiency and strong side effects. Recent... (Review)
Review
Chemotherapy often faces some obstacles such as low targeting effects and drug resistance, which introduce the low therapeutic efficiency and strong side effects. Recent advances in nanotechnology allows the use of novel nanosystems for targeted drug delivery, although the chemically synthesized nanomaterials always show unexpected low biocompability. The emergence of exosome research has offered a better understanding of disease treatment and created novel opportunities for developing effective drug delivery systems with high biocompability. Moreover, RNA interference has emerged as a promising strategy for disease treatments by selectively knocking down or over-expressing specific genes, which allows new possibilities to directly control cell signaling events or drug resistance. Recently, more and more interests have been paid to develop optimal delivery nanosystems with high efficiency and high biocompability for drug and functional RNA co-delivery to achieve enhanced chemotherapy. In light of the challenges for developing drug and RNA co-delivery system, exosomes have been found to show very attractive prospects. This review aims to explore current technologies and challenges in the use of exosomes as drug and RNA co-delivery system with a focus on the emerging trends and issues associated with their further applications, which may contribute to the accelerated developments of exosome-based theraputics.
PubMed: 37823027
DOI: 10.3389/fbioe.2023.1254356 -
Drugs Jun 2024Increasing evidence has implicated lipoprotein(a) [Lp(a)] in the causality of atherosclerosis and calcific aortic stenosis. This has stimulated immense interest in... (Review)
Review
Increasing evidence has implicated lipoprotein(a) [Lp(a)] in the causality of atherosclerosis and calcific aortic stenosis. This has stimulated immense interest in developing novel approaches to integrating Lp(a) into the setting of cardiovascular prevention. Current guidelines advocate universal measurement of Lp(a) levels, with the potential to influence cardiovascular risk assessment and triage of higher-risk patients to use of more intensive preventive therapies. In parallel, considerable activity has been undertaken to develop novel therapeutics with the potential to achieve selective and substantial reductions in Lp(a) levels. Early studies of antisense oligonucleotides (e.g., mipomersen, pelacarsen), RNA interference (e.g., olpasiran, zerlasiran, lepodisiran) and small molecule inhibitors (e.g., muvalaplin) have demonstrated effective Lp(a) lowering and good tolerability. These agents are moving forward in clinical development, in order to determine whether Lp(a) lowering reduces cardiovascular risk. The results of these studies have the potential to transform our approach to the prevention of cardiovascular disease.
Topics: Humans; Lipoprotein(a); Cardiovascular Diseases; Oligonucleotides, Antisense; Atherosclerosis; RNA Interference; Oligonucleotides; Animals
PubMed: 38849700
DOI: 10.1007/s40265-024-02046-z -
Current Opinion in Plant Biology Dec 2023Spray-induced gene silencing (SIGS) is a powerful and eco-friendly method for crop protection. Based off the discovery of RNA uptake ability in many fungal pathogens,... (Review)
Review
Spray-induced gene silencing (SIGS) is a powerful and eco-friendly method for crop protection. Based off the discovery of RNA uptake ability in many fungal pathogens, the application of exogenous RNAs targeting pathogen/pest genes results in gene silencing and infection inhibition. However, SIGS remains hindered by the rapid degradation of RNA in the environment. As extracellular vesicles are used by plants, animals, and microbes in nature to transport RNAs for cross-kingdom/species RNA interference between hosts and microbes/pests, nanovesicles and other nanoparticles have been used to prevent RNA degradation. Efforts examining the effect of nanoparticles on RNA stability and internalization have identified key attributes that can inform better nanocarrier designs for SIGS. Understanding sRNA biogenesis, cross-kingdom/species RNAi, and how plants and pathogens/pests naturally interact are paramount for the design of SIGS strategies. Here, we focus on nanotechnology advancements for the engineering of innovative RNA-based disease control strategies against eukaryotic pathogens and pests.
Topics: Animals; RNA, Small Interfering; Crop Protection; RNA Interference; Gene Silencing; Plants
PubMed: 37696727
DOI: 10.1016/j.pbi.2023.102441 -
Marine Life Science & Technology Nov 2023Exogenous RNA poses a continuous threat to genome stability and integrity across various organisms. Accumulating evidence reveals complex mechanisms underlying the... (Review)
Review
Exogenous RNA poses a continuous threat to genome stability and integrity across various organisms. Accumulating evidence reveals complex mechanisms underlying the cellular response to exogenous RNA, including endo-lysosomal degradation, RNA-dependent repression and innate immune clearance. Across a variety of mechanisms, the natural anti-sense RNA-dependent defensive strategy has been utilized both as a powerful gene manipulation tool and gene therapy strategy named RNA-interference (RNAi). To optimize the efficiency of RNAi silencing, a comprehensive understanding of the whole life cycle of exogenous RNA, from cellular entry to its decay, is vital. In this paper, we review recent progress in comprehending the recognition and elimination of foreign RNA by cells, focusing on cellular entrance, intracellular transportation, and immune-inflammatory responses. By leveraging these insights, we highlight the potential implications of these insights for advancing RNA interference efficiency, underscore the need for future studies to elucidate the pathways and fates of various exogenous RNA forms, and provide foundational information for more efficient RNA delivery methods in both genetic manipulation and therapy in different organisms.
PubMed: 38045546
DOI: 10.1007/s42995-023-00209-7 -
Cell Reports Aug 2023Arthropod-borne viruses (arboviruses) transmitted by Aedes aegypti mosquitoes are an increasing threat to global health. The small interfering RNA (siRNA) pathway is...
Arthropod-borne viruses (arboviruses) transmitted by Aedes aegypti mosquitoes are an increasing threat to global health. The small interfering RNA (siRNA) pathway is considered the main antiviral immune pathway of insects, but its effective impact on arbovirus transmission is surprisingly poorly understood. Here, we use CRISPR-Cas9-mediated gene editing in vivo to mutate Dicer2, a gene encoding the RNA sensor and key component of the siRNA pathway. The loss of Dicer2 enhances early viral replication and systemic viral dissemination of four medically significant arboviruses (chikungunya, Mayaro, dengue, and Zika viruses) representing two viral families. However, Dicer2 mutants and wild-type mosquitoes display overall similar levels of vector competence. In addition, Dicer2 mutants undergo significant virus-induced mortality during infection with chikungunya virus. Together, our results define a multifaceted role for Dicer2 in the transmission of arboviruses by Ae. aegypti mosquitoes and pave the way for further mechanistic investigations.
Topics: Animals; Humans; Arboviruses; Aedes; Mosquito Vectors; Zika Virus; RNA, Small Interfering; Zika Virus Infection
PubMed: 37573505
DOI: 10.1016/j.celrep.2023.112977 -
Nature Communications Jan 2024CRISPR-Cas13 is widely used for programmable RNA interference, imaging, and editing. In this study, we develop a light-inducible Cas13 system called paCas13 by fusing...
CRISPR-Cas13 is widely used for programmable RNA interference, imaging, and editing. In this study, we develop a light-inducible Cas13 system called paCas13 by fusing Magnet with fragment pairs. The most effective split site, N351/C350, was identified and found to exhibit a low background and high inducibility. We observed significant light-induced perturbation of endogenous transcripts by paCas13. We further present a light-inducible base-editing system, herein called the padCas13 editor, by fusing ADAR2 to catalytically inactive paCas13 fragments. The padCas13 editor enabled reversible RNA editing under light and was effective in editing A-to-I and C-to-U RNA bases, targeting disease-relevant transcripts, and fine-tuning endogenous transcripts in mammalian cells in vitro. The padCas13 editor was also used to adjust post-translational modifications and demonstrated the ability to activate target transcripts in a mouse model in vivo. We therefore present a light-inducible RNA-modulating technique based on CRISPR-Cas13 that enables target RNAs to be diversely manipulated in vitro and in vivo, including through RNA degradation and base editing. The approach using the paCas13 system can be broadly applicable to manipulating RNA in various disease states and physiological processes, offering potential additional avenues for research and therapeutic development.
Topics: Animals; Mice; RNA; CRISPR-Cas Systems; Gene Editing; RNA Editing; RNA Interference; Mammals
PubMed: 38253589
DOI: 10.1038/s41467-024-44867-2 -
Stem Cells Translational Medicine Aug 2023The progressive appreciation that multiple types of RNAs regulate virtually all aspects of tissue function and the availability of effective tools to deliver RNAs in... (Review)
Review
The progressive appreciation that multiple types of RNAs regulate virtually all aspects of tissue function and the availability of effective tools to deliver RNAs in vivo now offers unprecedented possibilities for obtaining RNA-based therapeutics. For the heart, RNA therapies can be developed that stimulate endogenous repair after cardiac damage. Applications in this area include acute cardioprotection after ischemia or cancer chemotherapy, therapeutic angiogenesis to promote new blood vessel formation, regeneration to form new cardiac mass, and editing of mutations to cure inherited cardiac disease. While the potential of RNA therapeutics for all these conditions is exciting, the field is still in its infancy. A number of roadblocks need to be overcome for RNA therapies to become effective, in particular, related to the problem of delivering RNA medicines into the cells and targeting them specifically to the heart.
Topics: Heart; Regeneration; RNA, Antisense; Aptamers, Nucleotide; RNA Interference; RNA, Guide, CRISPR-Cas Systems; Gene Editing; Humans; Animals
PubMed: 37440203
DOI: 10.1093/stcltm/szad038