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International Journal of Molecular... Oct 2021Depression is an effect of complex interactions between genetic, epigenetic and environmental factors. It is well established that stress responses are associated with... (Review)
Review
Depression is an effect of complex interactions between genetic, epigenetic and environmental factors. It is well established that stress responses are associated with multiple modest and often dynamic molecular changes in the homeostatic balance, rather than with a single genetic factor that has a strong phenotypic penetration. As depression is a multifaceted phenotype, it is important to study biochemical pathways that can regulate the overall allostasis of the brain. One such biological system that has the potential to fine-tune a multitude of diverse molecular processes is RNA interference (RNAi). RNAi is an epigenetic process showing a very low level of evolutionary diversity, and relies on the posttranscriptional regulation of gene expression using, in the case of mammals, primarily short (17-23 nucleotides) noncoding RNA transcripts called microRNAs (miRNA). In this review, our objective was to examine, summarize and discuss recent advances in the field of biomedical and clinical research on the role of miRNA-mediated regulation of gene expression in the development of depression. We focused on studies investigating post-mortem brain tissue of individuals with depression, as well as research aiming to elucidate the biomarker potential of miRNAs in depression and antidepressant response.
Topics: Animals; Biological Evolution; Depression; Depressive Disorder, Major; Epigenesis, Genetic; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Humans; MicroRNAs; Multifactorial Inheritance; RNA Interference; Transcriptome
PubMed: 34768740
DOI: 10.3390/ijms222111312 -
Cell Death & Disease Apr 2023Extrachromosomal circular DNAs (eccDNAs) participate in tumorigenesis and tumor progression. However, the role and mechanism of eccDNAs have yet to be elucidated in...
Extrachromosomal circular DNAs (eccDNAs) participate in tumorigenesis and tumor progression. However, the role and mechanism of eccDNAs have yet to be elucidated in non-small cell lung cancer (NSCLC). In our research, three surgically matched NSCLC tissue samples, NSCLC cell lines (H1299, A549, and H460), and a normal lung cell line (MRC-5) were used as study objects. High-throughput eccDNA sequencing and bioinformatics analysis were performed to study the distribution pattern and level of eccDNA expression. The upregulated candidate eccDNA-encoding PLCG2 was validated by routine PCR. Plasmid transfection, RNA interference, qRT‒PCR and western blotting experiments were used to verify the expression level of PLCG2. Our results showed that the chromosome distribution, length distribution, and genomic annotation of the eccDNAs were comparable between the NSCLC and normal groups. Nevertheless, there were no significant differences in eccDNAs between NSCLC tissues and matched normal lung tissues. The eccDNA derived from PLCG2 was upregulated in NSCLC cells. TCGA analysis and immunohistochemistry showed that PLCG2 was highly expressed in lung cancer tissues and tended to be associated with poor outcome. We also demonstrated that PLCG2 can promote metastasis through the regulation of mitochondrial respiration. These results suggested that PLCG2 identified by eccDNA sequencing acts as an oncogene and might be a new biomarker for NSCLC diagnosis and prognosis evaluation.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Cell Line; RNA Interference; Respiration
PubMed: 37031207
DOI: 10.1038/s41419-023-05755-7 -
Viruses Feb 2022Multiple antiviral immunities were developed to defend against viral infection in hosts. RNA interference (RNAi)-based antiviral innate immunity is evolutionarily... (Review)
Review
Multiple antiviral immunities were developed to defend against viral infection in hosts. RNA interference (RNAi)-based antiviral innate immunity is evolutionarily conserved in eukaryotes and plays a vital role against all types of viruses. During the arms race between the host and virus, many viruses evolve viral suppressors of RNA silencing (VSRs) to inhibit antiviral innate immunity. Here, we reviewed the mechanism at different stages in RNAi-based antiviral innate immunity in plants and the counteractions of various VSRs, mainly upon infection of RNA viruses in model plant Arabidopsis. Some critical challenges in the field were also proposed, and we think that further elucidating conserved antiviral innate immunity may convey a broad spectrum of antiviral strategies to prevent viral diseases in the future.
Topics: Arabidopsis; Host-Pathogen Interactions; Immunity, Innate; Plant Diseases; Plant Immunity; RNA Interference; RNA Virus Infections
PubMed: 35216025
DOI: 10.3390/v14020432 -
Nature Cell Biology Dec 2022The endoplasmic reticulum (ER) coordinates mRNA translation and processing of secreted and endomembrane proteins. ER-associated degradation (ERAD) prevents the...
The endoplasmic reticulum (ER) coordinates mRNA translation and processing of secreted and endomembrane proteins. ER-associated degradation (ERAD) prevents the accumulation of misfolded proteins in the ER, but the physiological regulation of this process remains poorly characterized. Here, in a genetic screen using an ERAD model substrate in Caenorhabditis elegans, we identified an anti-viral RNA interference pathway, referred to as ER-associated RNA silencing (ERAS), which acts together with ERAD to preserve ER homeostasis and function. Induced by ER stress, ERAS is mediated by the Argonaute protein RDE-1/AGO2, is conserved in mammals and promotes ER-associated RNA turnover. ERAS and ERAD are complementary, as simultaneous inactivation of both quality-control pathways leads to increased ER stress, reduced protein quality control and impaired intestinal integrity. Collectively, our findings indicate that ER homeostasis and organismal health are protected by synergistic functions of ERAS and ERAD.
Topics: RNA Interference; Endoplasmic Reticulum
PubMed: 36471127
DOI: 10.1038/s41556-022-01025-4 -
International Journal of Molecular... Dec 2022MicroRNAs (miRNAs) act as master regulators of gene expression in homeostasis and disease. Despite the rapidly growing body of evidence on the theranostic potential of... (Review)
Review
MicroRNAs (miRNAs) act as master regulators of gene expression in homeostasis and disease. Despite the rapidly growing body of evidence on the theranostic potential of restoring miRNA levels in pre-clinical models, the translation into clinics remains limited. Here, we review the current knowledge of miRNAs as T-cell targeting immunotherapeutic tools, and we offer an overview of the recent advances in miRNA delivery strategies, clinical trials and future perspectives in RNA interference technologies.
Topics: MicroRNAs; T-Lymphocytes; RNA Interference; Precision Medicine; Immunotherapy
PubMed: 36613706
DOI: 10.3390/ijms24010250 -
Virus Research May 2022Viroids are small (250-400 nucleotides), single-stranded, circular RNAs without protein-coding capacity that infect a large number of ornamental and crop plant species,... (Review)
Review
Viroids are small (250-400 nucleotides), single-stranded, circular RNAs without protein-coding capacity that infect a large number of ornamental and crop plant species, causing high economic losses worldwide. Strategies to control viroid diseases have included the use of naturally resistant cultivars in breeding programs, the superinfection exclusion with mild strains, the expression of ribonucleases, sense or antisense (catalytic) RNAs and, more recently, RNA interference (RNAi)-based tools. Here, I review the different RNAi strategies used to control viroid infections in plants, with particular focus on highly specific artificial small RNA (art-sRNA)-based tools such as artificial microRNAs and synthetic trans-acting small interfering RNAs. The advantages and future perspectives of art-sRNA-based RNAi for controlling viroid diseases are discussed.
Topics: Plant Breeding; Plant Diseases; RNA Interference; RNA, Small Interfering; RNA, Viral; Viroids
PubMed: 35263623
DOI: 10.1016/j.virusres.2022.198729 -
Expert Opinion on Biological Therapy May 2021In the retina, noncoding RNA (ncRNA) plays an integral role in regulating apoptosis, inflammatory responses, visual perception, and photo-transduction, with altered... (Review)
Review
INTRODUCTION
In the retina, noncoding RNA (ncRNA) plays an integral role in regulating apoptosis, inflammatory responses, visual perception, and photo-transduction, with altered levels reported in diseased states.
AREAS COVERED
MicroRNA (miRNA), a class of ncRNA, regulates post-transcription gene expression through the binding of complementary sites of target messenger RNA (mRNA) with resulting translational repression. Small-interfering RNA (siRNA) is a double-stranded RNA (dsRNA) that regulates gene expression, leading to selective silencing of genes through a process called RNA interference (RNAi). Another form of RNAi involves short hairpin RNA (shRNA). In age-related macular degeneration (AMD) and diabetic retinopathy (DR), miRNA has been implicated in the regulation of angiogenesis, oxidative stress, immune response, and inflammation.
EXPERT OPINION
Many RNA-based therapies in development are conveniently administered intravitreally, with the potential for pan-retinal effect. The majority of these RNA therapeutics are synthetic ncRNA's and hold promise for the treatment of AMD, DR, and inherited retinal diseases (IRDs). These RNA-based therapies include siRNA therapy with its high specificity, shRNA to 'knock down' autosomal dominant toxic gain of function-mutated genes, antisense oligonucleotides (ASOs), which can restore splicing defects, and translational read-through inducing drugs (TRIDs) to increase expression of full-length protein from genes with premature stop codons.
Topics: Humans; MicroRNAs; Oligonucleotides, Antisense; RNA Interference; RNA, Small Interfering; Retinal Diseases
PubMed: 33307874
DOI: 10.1080/14712598.2021.1856365 -
Clinical Pharmacokinetics Mar 2021Cemdisiran, an N-acetylgalactosamine (GalNAc) conjugated RNA interference (RNAi) therapeutic, is currently under development for the treatment of complement-mediated... (Randomized Controlled Trial)
Randomized Controlled Trial
Pharmacokinetic and Pharmacodynamic Properties of Cemdisiran, an RNAi Therapeutic Targeting Complement Component 5, in Healthy Subjects and Patients with Paroxysmal Nocturnal Hemoglobinuria.
BACKGROUND
Cemdisiran, an N-acetylgalactosamine (GalNAc) conjugated RNA interference (RNAi) therapeutic, is currently under development for the treatment of complement-mediated diseases by suppressing liver production of complement 5 (C5) protein. This study was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cemdisiran in healthy subjects and in patients with paroxysmal nocturnal hemoglobinuria (PNH) in order to support dose selection for late-stage clinical trials.
METHODS
Healthy volunteers (HVs; n = 32, including 12 Japanese subjects) were randomized (3:1) to receive single doses of subcutaneous cemdisiran (50-900 mg) or placebo, or repeat doses of subcutaneous cemdisiran (100-600 mg) or placebo weekly, biweekly, weekly/biweekly, or weekly/monthly for 5, 8, or 13 weeks (n = 24). Cemdisiran 200 or 400 mg was administered weekly in an open-label manner, for varying durations, as monotherapy in three eculizumab-naïve PNH patients or in combination with eculizumab in three PNH patients who were receiving stable label doses of eculizumab (900 or 1200 mg biweekly) before the start of the study. After the last dose of cemdisiran, patients were followed for safety and ongoing pharmacologic effects with the eculizumab regimen (600 or 900 mg every month).
RESULTS
In HVs, cemdisiran was rapidly converted to a major active metabolite, AS(N-2)3'-cemdisiran, both declining below the lower limit of quantification (LLOQ) in plasma within 48 h, and showing minimal renal excretion. AS(N-2)3'-cemdisiran exhibited more than dose-proportional PK. The C5 protein reductions were dose-dependent, with > 90% reduction of C5 protein beginning on days 21-28 and maintained for 10-13 months following single and biweekly doses of 600 mg. The dose-response relationship, described by an inhibitory sigmoid maximum effect (E) model, estimated half-maximal effective dose (ED) of 14.0 mg and maximum C5 reduction of 99% at 600 mg. The PK and PD were similar between Japanese and non-Japanese subjects, and PNH patients and HVs. One of 48 subjects tested transiently positive for antidrug antibody with low titer, with no impact on PK or PD. In PNH patients, C5 suppression by cemdisiran enabled effective inhibition of residual C5 levels with lower dose and/or dosing frequency of eculizumab, which was maintained for 6-10 months after the last dose of cemdisiran.
CONCLUSIONS
Consistent with the PK/PD properties of liver targeting GalNac conjugates, cemdisiran and AS(N-2)3'-cemdisiran plasma concentrations declined rapidly while showing rapid and robust C5 suppression maintained up to 13 months following single and multiple doses, which indicates long residence times of cemdisiran within hepatocytes. The long PD duration of action in liver, low immunogenicity and acceptable safety profiles enables low, infrequent SC dosing and support further evaluation of cemdisiran in complement-mediated diseases as monotherapy or in combination with a C5 inhibitor antibody.
CLINICAL TRIAL REGISTRATION NO
NCT02352493.
Topics: Complement C5; Healthy Volunteers; Hemoglobinuria, Paroxysmal; Humans; RNA Interference; RNAi Therapeutics
PubMed: 33047216
DOI: 10.1007/s40262-020-00940-9 -
International Journal of Molecular... Jun 2023Antisense RNA was observed to elicit plant disease resistance and post-translational gene silencing (PTGS). The universal mechanism of RNA interference (RNAi) was shown... (Review)
Review
Antisense RNA was observed to elicit plant disease resistance and post-translational gene silencing (PTGS). The universal mechanism of RNA interference (RNAi) was shown to be induced by double-stranded RNA (dsRNA), an intermediate produced during virus replication. Plant viruses with a single-stranded positive-sense RNA genome have been instrumental in the discovery and characterization of systemic RNA silencing and suppression. An increasing number of applications for RNA silencing have emerged involving the exogenous application of dsRNA through spray-induced gene silencing (SIGS) that provides specificity and environmentally friendly options for crop protection and improvement.
Topics: RNA Interference; Gene Silencing; RNA, Double-Stranded; RNA, Small Interfering; Plants; Plant Diseases
PubMed: 37298705
DOI: 10.3390/ijms24119755 -
Annual Review of Virology Sep 2021Viroids are small, single-stranded, circular RNAs infecting plants. Composed of only a few hundred nucleotides and being unable to code for proteins, viroids represent... (Review)
Review
Viroids are small, single-stranded, circular RNAs infecting plants. Composed of only a few hundred nucleotides and being unable to code for proteins, viroids represent the lowest level of complexity for an infectious agent, even below that of the smallest known viruses. Despite the relatively small size, viroids contain RNA structural elements embracing all the information needed to interact with host factors involved in their infectious cycle, thus providing models for studying structure-function relationships of RNA. Viroids are specifically targeted to nuclei (family ) or chloroplasts (family ), where replication based on rolling-circle mechanisms takes place. They move locally and systemically through plasmodesmata and phloem, respectively, and may elicit symptoms in the infected host, with pathogenic pathways linked to RNA silencing and other plant defense responses. In this review, recent advances in the dissection of the complex interplay between viroids and plants are presented, highlighting knowledge gaps and perspectives for future research.
Topics: Plant Diseases; Plants; RNA Interference; RNA, Viral; Viroids
PubMed: 34255541
DOI: 10.1146/annurev-virology-091919-092331