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Nanoscale May 2021Nucleic acid-based nanodevices have been widely used in the fields of biosensing and nanomedicine. Traditionally, the majority of these nanodevices were first... (Review)
Review
Nucleic acid-based nanodevices have been widely used in the fields of biosensing and nanomedicine. Traditionally, the majority of these nanodevices were first constructed in vitro using synthetic DNA or RNA oligonucleotides and then delivered into cells. Nowadays, the emergence of genetically encoded RNA nanodevices has provided a promising alternative approach for intracellular analysis and regulation. These genetically encoded RNA-based nanodevices can be directly transcribed and continuously produced inside living cells. A variety of highly precise and programmable nanodevices have been constructed in this way during the last decade. In this review, we will summarize the recent advances in the design and function of these artificial genetically encoded RNA nanodevices. In particular, we will focus on their applications in regulating cellular gene expression, imaging, logic operation, structural biology, and optogenetics. We believe these versatile RNA-based nanodevices will be broadly used in the near future to probe and program cells and other biological systems.
Topics: Logic; Nanomedicine; Nucleic Acids; Oligonucleotides; RNA
PubMed: 33885099
DOI: 10.1039/d0nr08301a -
Chemistry (Weinheim An Der Bergstrasse,... Dec 2021The assembly of ancient informational polymers from nucleotide precursors is the central challenge of life's origin on our planet. Among the possible solutions, dry...
The assembly of ancient informational polymers from nucleotide precursors is the central challenge of life's origin on our planet. Among the possible solutions, dry polymerization of 3',5'-cyclic guanosine monophosphate (3',5'-cGMP) has been proposed as a candidate to create oligonucleotides of 15-20 units in length. However, the reported sensitivity of the reaction to the presence of cations raised questions of whether this chemistry could be relevant in a geological context. The experiments in this study show that the presence of cations is not restrictive as long as the reaction is conducted in an acidic environment, in contrast to previous reports that suggested optimal conditions at pH 9.
Topics: Catalysis; Cyclic GMP; Oligonucleotides; Polymerization; RNA
PubMed: 34726799
DOI: 10.1002/chem.202103672 -
International Journal of Molecular... Jul 2023Osteoarthritis (OA) is characterized by degeneration of the joint cartilage, inflammation, and a change in the chondrocyte phenotype. Inflammation also promotes cell...
Osteoarthritis (OA) is characterized by degeneration of the joint cartilage, inflammation, and a change in the chondrocyte phenotype. Inflammation also promotes cell hypertrophy in human articular chondrocytes (HC-a) by activating the NF-κB pathway. Chondrocyte hypertrophy and inflammation promote extracellular matrix degradation (ECM). Chondrocytes depend on Smad signaling to control and regulate cell hypertrophy as well as to maintain the ECM. The involvement of these two pathways is crucial for preserving the homeostasis of articular cartilage. In recent years, Polynucleotides Highly Purified Technology (PN-HPT) has emerged as a promising area of research for the treatment of OA. PN-HPT involves the use of polynucleotide-based agents with controlled natural origins and high purification levels. In this study, we focused on evaluating the efficacy of a specific polynucleotide sodium agent, known as CONJURAN, which is derived from fish sperm. Polynucleotides (PN), which are physiologically present in the matrix and function as water-soluble nucleic acids with a gel-like property, have been used to treat patients with OA. However, the specific mechanisms underlying the effect remain unclear. Therefore, we investigated the effect of PN in an OA cell model in which HC-a cells were stimulated with interleukin-1β (IL-1β) with or without PN treatment. The CCK-8 assay was used to assess the cytotoxic effects of PN. Furthermore, the enzyme-linked immunosorbent assay was utilized to detect MMP13 levels, and the nitric oxide assay was utilized to determine the effect of PN on inflammation. The anti-inflammatory effects of PN and related mechanisms were investigated using quantitative PCR, Western blot analysis, and immunofluorescence to examine and analyze relative markers. PN inhibited IL-1β induced destruction of genes and proteins by downregulating the expression of MMP3, MMP13, iNOS, and COX-2 while increasing the expression of aggrecan (ACAN) and collagen II (COL2A1). This study demonstrates, for the first time, that PN exerted anti-inflammatory effects by partially inhibiting the NF-κB pathway and increasing the Smad2/3 pathway. Based on our findings, PN can potentially serve as a treatment for OA.
Topics: Animals; Humans; Male; NF-kappa B; Matrix Metalloproteinase 13; Polynucleotides; Cells, Cultured; Semen; Inflammation; Osteoarthritis; Chondrocytes; Anti-Inflammatory Agents; Hypertrophy; Interleukin-1beta
PubMed: 37569659
DOI: 10.3390/ijms241512282 -
European Biophysics Journal : EBJ Oct 2023Peptide nucleic acid (PNA) is a nucleic acid mimic with high specificity and binding affinity to natural DNA or RNA, as well as resistance to enzymatic degradation. PNA... (Review)
Review
Peptide nucleic acid (PNA) is a nucleic acid mimic with high specificity and binding affinity to natural DNA or RNA, as well as resistance to enzymatic degradation. PNA sequences can be designed to selectively silence gene expression, which makes PNA a promising tool for antimicrobial applications. However, the poor membrane permeability of PNA remains the main limiting factor for its applications in cells. To overcome this obstacle, PNA conjugates with different molecules have been developed. This mini-review focuses on covalently linked conjugates of PNA with cell-penetrating peptides, aminosugars, aminoglycoside antibiotics, and non-peptidic molecules that were tested, primarily as PNA carriers, in antibacterial and antiviral applications. The chemistries of the conjugation and the applied linkers are also discussed.
Topics: Peptide Nucleic Acids; Anti-Bacterial Agents; Amino Acid Sequence; Cell-Penetrating Peptides
PubMed: 37610696
DOI: 10.1007/s00249-023-01673-w -
Nature Communications Aug 2021Ligand-oligonucleotide transduction provides the critical pathway to integrate non-nucleic acid molecules into nucleic acid circuits and nanomachines for a variety of...
Ligand-oligonucleotide transduction provides the critical pathway to integrate non-nucleic acid molecules into nucleic acid circuits and nanomachines for a variety of strand-displacement related applications. Herein, a general platform is constructed to convert the signals of ligands into desired oligonucleotides through a precise kinetic control. In this design, the ligand-aptamer binding sequence with an engineered duplex stem is introduced between the toehold and displacement domains of the invading strand to regulate the strand-displacement reaction. Employing this platform, we achieve efficient transduction of both small molecules and proteins orthogonally, and more importantly, establish logical and cascading operations between different ligands for versatile transduction. Besides, this platform is capable of being directly coupled with the signal amplification systems to further enhance the transduction performance. This kinetically controlled platform presents unique features with designing simplicity and flexibility, expandable complexity and system compatibility, which may pave a broad road towards nucleic acid-based developments of sophisticated transduction networks.
Topics: Aptamers, Nucleotide; Kinetics; Ligands; Models, Genetic; Models, Molecular; Nucleic Acid Amplification Techniques; Nucleic Acid Conformation; Oligonucleotides; Signal Transduction; Spectrometry, Fluorescence
PubMed: 34341342
DOI: 10.1038/s41467-021-24962-4 -
Drug Discovery Today Nov 2022It is well established that microRNA (miRNA) dysregulation is involved in the development and progression of various diseases, especially cancer. Emerging evidence... (Review)
Review
It is well established that microRNA (miRNA) dysregulation is involved in the development and progression of various diseases, especially cancer. Emerging evidence suggests that small molecule and peptide agents can interfere with miRNA disease pathways. Despite this, very little is known about structural features that drive drug-miRNA interactions and subsequent inhibition. In this review, we highlight the advances made in the development of small molecule and peptide inhibitors of miRNA processing. Specifically, we attempt to draw attention to peptide features that may be critical for interaction with the miRNA secondary structure to regulate miRNA expression. We hope that this review will help to establish peptides as exciting miRNA expression modulators and will contribute towards the development of the first miRNA-targeting peptide therapy.
Topics: Humans; Oligonucleotides; MicroRNAs; Peptides; Neoplasms
PubMed: 35995360
DOI: 10.1016/j.drudis.2022.08.005 -
Molecular Cancer Jan 2023Pancreatic cancer (PC) is a fatal disease that has a poor 5-year survival rate. The poor prognosis can be attributed to both troublesome detections at the initial stage,... (Review)
Review
Pancreatic cancer (PC) is a fatal disease that has a poor 5-year survival rate. The poor prognosis can be attributed to both troublesome detections at the initial stage, which makes the majority of the treatment options largely unsuccessful and leads to extensive metastasis, as well as to its distinct pathophysiological characteristics, such as rich desmoplastic tumours bounded by dysplastic and hypo perfused vessels restricting the mobility of therapeutic agents. Continued attempts have been made to utilise innovative measures for battling PC to increase the therapeutic effectiveness of therapies and overcome their cytotoxicity. Combined cancer targeting and gene silencing approach has shown improved outcomes in patients' survival rates and quality of life, offering a potential solution to therapeutic complications. It particularly targets various barriers to alleviate delivery problems and diminish tumour recurrence and metastasis. While aptamers, a type of single-stranded nucleic acids with strong binding affinity and specificity to target molecules, have recently surfaced as a viable PC strategy, siRNA can interfere with the expression of certain genes. By concurrently suppressing genes and boosting targeted approach, the cocktail of siRNA/Aptamer and other therapeutic drugs can circumvent the multi-drug resistance phenomena. Additionally, combination therapy with additive or synergistic effects can considerably increase the therapeutic efficacy of anti-cancer medications. This study outlines the primary difficulties in treating PC, along with recent developments in siRNA/Aptamer mediated drug delivery to solve the major hiccup of oncology field.
Topics: Humans; RNA, Small Interfering; Antineoplastic Agents; Quality of Life; Aptamers, Nucleotide; Neoplasm Recurrence, Local; Pancreatic Neoplasms
PubMed: 36635659
DOI: 10.1186/s12943-022-01696-5 -
Cells Jun 2021Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis, but is not the only player with an angiogenic function. Fibroblast growth factor-2... (Review)
Review
Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis, but is not the only player with an angiogenic function. Fibroblast growth factor-2 (FGF2), which was discovered before VEGF, is also an angiogenic growth factor. It has been shown that FGF2 plays positive pathophysiological roles in tissue remodeling, bone health, and regeneration, such as the repair of neuronal damage, skin wound healing, joint protection, and the control of hypertension. Targeting FGF2 as a therapeutic tool in disease treatment through clinically useful inhibitors has not been developed until recently. An isolated inhibitory RNA aptamer against FGF2, named RBM-007, has followed an extensive preclinical study, with two clinical trials in phase 2 and phase 1, respectively, underway to assess the therapeutic impact in age-related macular degeneration (wet AMD) and achondroplasia (ACH), respectively. Moreover, showing broad therapeutic potential, preclinical evidence supports the use of RBM-007 in the treatment of lung cancer and cancer pain.
Topics: Animals; Aptamers, Nucleotide; Cancer-Associated Fibroblasts; Disease; Fibroblast Growth Factor 2; Humans; Models, Biological
PubMed: 34203430
DOI: 10.3390/cells10071617 -
RNA (New York, N.Y.) Apr 2023Splice-modulating antisense oligonucleotides (ASOs) offer treatment options for rare neurological diseases, including those with very rare mutations, where...
Splice-modulating antisense oligonucleotides (ASOs) offer treatment options for rare neurological diseases, including those with very rare mutations, where patient-specific, individualized ASOs have to be developed. Inspired by the development of milasen, the 1 Mutation 1 Medicine (1M1M) and Dutch Center for RNA Therapeutics (DCRT) aim to develop patient-specific ASOs and treat eligible patients within Europe and the Netherlands, respectively. Treatment will be provided under a named patient setting. Our initiatives benefited from regulatory advice from the European Medicines Agency (EMA) with regard to preclinical proof-of-concept studies, safety studies, compounding and measuring benefit and safety in treated patients. We here outline the most important considerations from these interactions and how we implemented this advice into our plan to develop and treat eligible patients within Europe.
Topics: Humans; Oligonucleotides; Oligonucleotides, Antisense; Brain; Europe; Brain Diseases
PubMed: 36669889
DOI: 10.1261/rna.079540.122 -
Sensors (Basel, Switzerland) Dec 2021Cytokines are proteins secreted by immune cells. They promote cell signal transduction and are involved in cell replication, death, and recovery. Cytokines are immune... (Review)
Review
Cytokines are proteins secreted by immune cells. They promote cell signal transduction and are involved in cell replication, death, and recovery. Cytokines are immune modulators, but their excessive secretion causes uncontrolled inflammation that attacks normal cells. Considering the properties of cytokines, monitoring the secretion of cytokines in vivo is of great value for medical and biological research. In this review, we offer a report on recent studies for cytokine detection, especially studies on aptasensors using aptamers. Aptamers are single strand nucleic acids that form a stable three-dimensional structure and have been receiving attention due to various characteristics such as simple production methods, low molecular weight, and ease of modification while performing a physiological role similar to antibodies.
Topics: Aptamers, Nucleotide; Biosensing Techniques; Cytokines
PubMed: 34960590
DOI: 10.3390/s21248491