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Advanced Research on Nucleic Acids: Therapeutic Potential and Applications, 2nd Edition

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 4138

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Dr. Veronica Esposito

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Department of Pharmacy, Università degli Studi di Napoli Federico II, 80131 Naples, Italy
Interests: G-quadruplex; aptamers; nucleic acid chemistry; nuclear magnetic resonance; electrophoretic tecniques; circular dichroism; G4-catalysts
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Dr. Antonella Virgilio

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Department of Pharmacy, Università degli Studi di Napoli Federico II, 80131 Naples, Italy
Interests: G-quadruplex; aptamers; nucleic acid chemistry; circular dichroism; electrophoresis
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Dear Colleagues,

This Special Issue, entitled “Advanced Research on Nucleic Acids: Therapeutic Potential and Applications”, will present a selection of original research, reviews, and commentaries focused on diverse topics in this field, with particular attention being paid to advancements in nucleic acid research at the molecular level. Nucleic acid therapeutics represent an innovative and challenging research field. Oligonucleotide (ON)-based therapy has become an alternative to classical approaches in the search for novel therapeutics involving gene-related diseases. Nucleic-acid-based drugs can be designed to modulate cellular pathways that are not readily druggable, and different nucleic acid chemical modifications can be optimally combined in the context of various targeting mechanisms, in order to circumvent the main pharmacokinetic restrictions for therapeutic ON applications. The wide versatility of the mechanism of action of ONs, combined with various designs and multiple choices of chemical modifications, provide the concept of ON targeting with vast potential. Clinically relevant applications and remaining challenges in this field are still numerous and exciting.

Dr. Veronica Esposito
Dr. Antonella Virgilio
Guest Editors

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Keywords

aptamer
decoy
DNAzyme
ribozyme
siRNA
miRNA
antisense oligonucleotide
antigene strategy
G-quadruplex
triplex

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Advanced Research on Nucleic Acids: Therapeutic Potential and Applications in International Journal of Molecular Sciences (8 articles)

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Research

16 pages, 2188 KiB

Open AccessArticle

Probing the Effects of Chemical Modifications on Anticoagulant and Antiproliferative Activity of Thrombin Binding Aptamer

by Antonella Virgilio, Daniela Benigno, Carla Aliberti, Ivana Bello, Elisabetta Panza, Martina Smimmo, Valentina Vellecco, Veronica Esposito and Aldo Galeone

Int. J. Mol. Sci. 2025, 26(1), 134; https://doi.org/10.3390/ijms26010134 - 27 Dec 2024

Viewed by 264

Abstract

Thrombin binding aptamer (TBA) is one of the best-known G-quadruplex (G4)-forming aptamers that efficiently binds to thrombin, resulting in anticoagulant effects. TBA also possesses promising antiproliferative properties. As with most therapeutic oligonucleotides, chemical modifications are critical for therapeutic applications, particularly to improve thermodynamic stability, resistance in biological environment, and target affinity. To evaluate the effects of nucleobase and/or sugar moiety chemical modifications, five TBA analogues have been designed and synthesized considering that the chair-like G4 structure is crucial for biological activity. Their structural and biological properties have been investigated by Circular Dichroism (CD), Nuclear Magnetic Resonance (NMR), native polyacrylamide gel electrophoresis (PAGE) techniques, and PT and MTT assays. The analogue TBAB contains 8-bromo-2′-deoxyguanosine (B) in G-syn glycosidic positions, while TBAL and TBAM contain locked nucleic acid guanosine (L) or 2′-O-methylguanosine (M) in G-anti positions, respectively. Instead, both the two types of modifications have been introduced in TBABL and TBABM with the aim of obtaining synergistic effects. In fact, both derivatives include B in syn positions, exhibiting in turn L and M in the anti ones. The most appealing results have been obtained for TBABM, which revealed an interesting cytotoxic activity against breast and prostate cancer cell lines, while in the case of TBAB, extraordinary thermal stability (T_m approximately 30 °C higher than that of TBA) and an anticoagulant activity higher than original aptamer were observed, as expected. These data indicate TBAB as the best TBA anticoagulant analogue here investigated and TBABM as a promising antiproliferative derivative. Full article

(This article belongs to the Special Issue Advanced Research on Nucleic Acids: Therapeutic Potential and Applications, 2nd Edition)

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Figure 1

Figure 1
Schematic representation of the TBA G-quadruplex. Deoxyguanosines in syn and anti glycosidic conformations are in purple and light blue, respectively (A); chemical structures of 8-bromo-2′-deoxyguanosine (B) (inserted into the G-syn positions of the original sequence), 2′-O-methylguanosine (M), and locked nucleic acid guanosine (L) (inserted into the G-anti positions of the original sequence) (B). Full article ">Figure 2
CD spectra at 37 °C of TBA and its studied analogues. Panel (A): TBA, TBAB, TBABL, TBABM; Panel (B): TBA, TBAL, TBAM. Full article ">Figure 3
PAGE analysis of TBA and its investigated analogues. Lane 1: TBA; lane 2: TBABM; lane 3: TBABL; lane 4: TBAB; lane 5: TBAL; lane 6: TBAM. See <a href="#sec4-ijms-26-00134" class="html-sec">Section 4</a> for experimental details. Full article ">Figure 4
Imino proton regions of 1H-NMR spectra (700 MHz) of TBA and its investigated analogues. Full article ">Figure 5
Effect of TBA and its analogues on MDA-MB-231 (Panel A) and DU145 (Panel B) cell proliferation. Cell proliferation was measured using an MTT assay and evaluated at 48 h. Each experiment (n = 3) was run in quadruplicate. * p < 0.05; ** p < 0.01; *** p < 0.001 vs. CTL. Full article ">Figure 6
Effect of TBA and its analogues on PT assay. PT values of modified TBAs and natural counterpart were evaluated at 2 µM (Panel A) and 20 µM (Panel B). *** p < 0.001 vs. vehicle, ◦◦ p < 0.01, ◦◦◦ p < 0.001 vs. TBA. Full article ">

16 pages, 3290 KiB

Open AccessArticle

A Surface-Enhanced Raman Spectroscopy-Based Aptasensor for the Detection of Deoxynivalenol and T-2 Mycotoxins

by Rugiya Alieva, Svetlana Sokolova, Natalia Zhemchuzhina, Dmitrii Pankin, Anastasia Povolotckaia, Vasiliy Novikov, Sergey Kuznetsov, Anatoly Gulyaev, Maksim Moskovskiy and Elena Zavyalova

Int. J. Mol. Sci. 2024, 25(17), 9534; https://doi.org/10.3390/ijms25179534 - 2 Sep 2024

Viewed by 870

Abstract

The quality of food is one of the emergent points worldwide. Many microorganisms produce toxins that are harmful for human and animal health. In particular, mycotoxins from Fusarium fungi are strictly controlled in cereals. Simple and robust biosensors are necessary for ‘in field’ control of the crops and processed products. Nucleic acid-based sensors (aptasensors) offer a new era of point-of-care devices with excellent stability and limits of detection for a variety of analytes. Here we report the development of a surface-enhanced Raman spectroscopy (SERS)-based aptasensor for the detection of T-2 and deoxynivalenol in wheat grains. The aptasensor was able to detect as low as 0.17% of pathogen fungi in the wheat grains. The portable devices, inexpensive SERS substrate, and short analysis time encourage further implementation of the aptasensors outside of highly equipped laboratories. Full article

(This article belongs to the Special Issue Advanced Research on Nucleic Acids: Therapeutic Potential and Applications, 2nd Edition)

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Figure 1

Figure 1
Structures of T-2 toxin, deoxynivalenol, and DNA aptamer selected to T-2 toxin by Chen et al. [<a href="#B7-ijms-25-09534" class="html-bibr">7</a>]. The secondary structure of the aptamer was built using RNAfold [<a href="#B8-ijms-25-09534" class="html-bibr">8</a>]. Full article ">Figure 2
Optimization of the secondary structure of the aptamer to T-2 toxin. Twenty nucleotides were truncated from aptamer Seq.16, providing aptamer Fus. Aptamer Fus was modified with Raman dye (Cyanine-3, Cy3) at the 3′-end as well as with thiol group at the 5′-end. Full article ">Figure 3
Comparison of SERS intensity of the different dyes in Buffers A and B. Full article ">Figure 4
Performance of the aptasensor with purified toxins. SERS spectra of aptamer SH-Fus-Cy3 in the presence of T-2 (A) and DON (B) in Buffer A. The dependence of SERS intensity on T-2 and DON concentration in Buffers A (C) and B (D). A schematic explanation of the reason for SERS intensity changes is shown (E). The changes in distance between cyanine 3 and silver nanoparticles affect SERS intensity of the cyanine 3 bands in spectra. Full article ">Figure 5
Optimization of extraction procedure with pure cultures of Fusarium fungi. The dependence of normalized SERS intensity on the content of Fusarium fungi added. Comparison of target and off-target fungi with the content of 20 µg per probe; the relative contents of toxins are shown as +++ (high), ++ (medium), + (low), and − (absent) (A). Heating procedure (B) and ultrasound procedure (C) are compared with normalization of SERS signal of Fusarium sporotrichioides to the signal of Fusarium oxysporum. Buffer A was used for concentration dependencies; Buffer B was used for a comparison of the target and off-target fungi. Full article ">Figure 6
SERS spectra of isopropanol extracts of uninfected wheat grains and grains infected with Fusarium graminearum. The components of the extracts disrupt nanoparticle aggregation in concentration-dependence manner. Full article ">Figure 7
The robustness of the aptasensor in determination of wheat grains infected with Fusarium graminearum. The dependence of the SERS signal of the sensor on the amount of wheat grains subjected to extraction with acetonitrile (A). The fraction of the Fusarium graminearum-infected grains in the mix with uninfected grains (B). Fus. gram. is Fusarium graminearum; Alt. alt. is Alternaria alternata. Uninfected grains were treated with a buffer. An artificial mixture of uninfected wheat grains with Fusarium culmorum was also studied (C); the linearization of the dependence is shown in subset (D). The fungus concentration is shown in mg per 1 g of wheat grains. Full article ">

15 pages, 4120 KiB

Open AccessArticle

Circular RNA Profile in Atherosclerotic Disease: Regulation during ST-Elevated Myocardial Infarction

by Fredric A. Holme, Camilla Huse, Xiang Yi Kong, Kaspar Broch, Lars Gullestad, Anne Kristine Anstensrud, Geir Ø. Andersen, Brage H. Amundsen, Ola Kleveland, Ana Quiles-Jimenez, Sverre Holm, Pål Aukrust, Ingrun Alseth, Bente Halvorsen and Tuva B. Dahl

Int. J. Mol. Sci. 2024, 25(16), 9014; https://doi.org/10.3390/ijms25169014 - 19 Aug 2024

Viewed by 1333

Abstract

Circular (circ) RNAs are non-coding RNAs with important functions in the nervous system, cardiovascular system, and cancer. Their role in atherosclerosis and myocardial infarction (MI) remains poorly described. We aim to investigate the potential circRNAs in immune cells during atherogenesis and examine the most regulated during MI and the modulation by interleukin (IL)-6 receptor inhibition by tocilizumab. Wild-type (WT) and ApoE^−/− mice were fed an atherogenic diet for 10 weeks, and the circRNA profile was analyzed by circRNA microarray. Whole blood from patients with ST-elevated MI (STEMI) and randomized to tocilizumab (n = 21) or placebo (n = 19) was collected at admission, 3–7 days, and at 6 months, in addition to samples from healthy controls (n = 13). Primers for human circRNA were designed, and circRNA levels were measured using RT-qPCR. mRNA regulation of predicted circRNA targets was investigated by RNA sequencing. The expression of 867 circRNAs differed between atherogenic and WT mice. In STEMI patients, circUBAC2 was significantly lower than in healthy controls. CircANKRD42 and circUBAC2 levels were inversely correlated with troponin T, and for circUBAC2, an inverse correlation was also seen with final infarct size at 6 months. The predicted mRNA targets for circUBAC2 and circANKRD42 were investigated and altered levels of transcripts involved in the regulation of inflammatory/immune cells, apoptosis, and mitochondrial function were found. Finally, tocilizumab induced an up-regulation of circANKRD42 and circUBAC2 3–7 days after percutaneous coronary intervention. CircRNA levels were dysregulated in STEMI, potentially influencing the immune system, apoptosis, and mitochondrial function. Full article

(This article belongs to the Special Issue Advanced Research on Nucleic Acids: Therapeutic Potential and Applications, 2nd Edition)

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Graphical abstract
Full article ">Figure 1
Murine circRNA profile in atherogenic ApoE−/− mice. (A) Atherosclerotic lesions in the aortic root from wild type (WT) and ApoE−/− after 10 weeks on an atherogenic diet, stained with Oil-Red-O. (B) Volcano-plot showing the circRNA regulation. Significantly differentially expressed circRNAs, with an FC > 5 and p-value < 0.05, from splenic cells in WT and ApoE−/− mice marked in red. (C) Normalized intensity of the circRNAs from the circRNA murine array between ApoE−/− vs. WT. * p < 0.05, ** p < 0.01, **** p < 0.0001. Full article ">Figure 2
Relative circRNA expression of whole blood from STEMI patients at admission vs. healthy controls. The figure presents the FGE regulation of the circRNA targets in a subgroup of patients from the ASSAIL-MI. Samples were collected at admission before the patients were randomized to tocilizumab or placebo. Comparison between STEMI patients (n = 40) and healthy HC (n = 13) were made by an unpaired t-test. ** p < 0.01. Full article ">Figure 3
Correlation analysis between circRNA and clinical parameters from STEMI patients. (A) Inverse correlation with peak TnT and admission circRNA levels for circANKRD42 and circUBAC2 was conducted with a Spearman correlation analysis. (B) Inverse correlation between admission circRNA levels for circUBAC2 and the finale infarct size at 6 months, measured by % of left ventricular mass. * p < 0.05, ** p < 0.01. Full article ">Figure 4
Overview of circRNA, miRNA, and mRNA interactions in patient samples. An overview of the miRNAs regulated by circUBAC2 and circANKRD42. We also show the mRNA targets for the different miRNAs and how they are regulated. * p < 0.05, ** p < 0.01, **** p < 0.0001. Full article ">Figure 5
Fold gene expression of circRNA targets in immune cells in STEMI patients treated with tocilizumab (n = 21) or placebo (n = 19). The figure shows the regulation of the circRNAs after ST-elevation myocardial infarction (STEMI) at different time points in the tocilizumab and the placebo group. Unpaired t-test between the different groups. * p < 0.05, **** p < 0.0001. Full article ">

15 pages, 2800 KiB

Open AccessArticle

DNA Aptamer Raised against Advanced Glycation End Products Improves Sperm Concentration, Motility, and Viability by Suppressing Receptors for Advanced Glycation End Product-Induced Oxidative Stress and Inflammation in the Testes of Diabetic Mice

by Yusaku Mori, Michishige Terasaki, Naoya Osaka, Tomoki Fujikawa, Hironori Yashima, Tomomi Saito, Yurie Kataoka, Makoto Ohara, Yuichiro Higashimoto, Takanori Matsui and Sho-ichi Yamagishi

Int. J. Mol. Sci. 2024, 25(11), 5947; https://doi.org/10.3390/ijms25115947 - 29 May 2024

Cited by 3 | Viewed by 1100

Abstract

Type 2 diabetes mellitus (T2DM) is a risk factor for male infertility, but the underlying molecular mechanisms remain unclear. Advanced glycation end products (AGEs) are pathogenic molecules for diabetic vascular complications. Here, we investigated the effects of the DNA aptamer raised against AGEs (AGE-Apt) on testicular and sperm abnormalities in a T2DM mouse model. KK-Ay (DM) and wild-type (non-DM) 4- and 7-week-old male mice were sacrificed to collect the testes and spermatozoa for immunofluorescence, RT-PCR, and histological analyses. DM and non-DM 7-week-old mice were subcutaneously infused with the AGE-Apt or control-aptamer for 6 weeks and were then sacrificed. Plasma glucose, testicular AGEs, and Rage gene expression in 4-week-old DM mice and plasma glucose, testicular AGEs, oxidative stress, and pro-inflammatory gene expressions in 7-week-old DM mice were higher than those in age-matched non-DM mice, the latter of which was associated with seminiferous tubular dilation. AGE-Apt did not affect glycemic parameters, but it inhibited seminiferous tubular dilation, reduced the number of testicular macrophages and apoptotic cells, and restored the decrease in sperm concentration, motility, and viability of 13-week-old DM mice. Our findings suggest that AGEs-Apt may improve sperm abnormality by suppressing AGE–RAGE-induced oxidative stress and inflammation in the testes of DM mice. Full article

(This article belongs to the Special Issue Advanced Research on Nucleic Acids: Therapeutic Potential and Applications, 2nd Edition)

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Figure 1

Figure 1
AGE-Apt inhibited oxidative stress and inflammation in the testes of diabetic mice. (A) Schema of animal experiments. (B) Representative immunofluorescence images for AGEs in each group. (C) Testicular AGE accumulation levels. (D) Representative immunofluorescence images for 8-OHdG in each group. (E) Testicular 8-OHdG levels. (F) Testicular gene expression levels of Rage, Mcp-1, and Tnf-α in non-diabetic and diabetic mice. Data exhibit relative levels of target molecules for the housekeeping gene, 18S ribosomal RNA. (G,H) Number of macrophages (G) and apoptotic cells (H) in the testes of non-diabetic and diabetic mice. The upper panels indicate representative immunofluorescence images for F4/80 (G) and TUNEL (H) in each group. (B,D,G,H) Yellow dotted lines denote the outer edge of seminiferous tubules, whereas arrows show TUNEL-positive cells within seminiferous tubules. Magnification: ×200; bars: 200 μm. (C,E,F), n = 6–8 per group; (G,H), n = 3 per group. * p < 0.05, ** p < 0.01 vs. non-DM at the same age; a p < 0.05 vs. non-DM+CTR-Apt; b p < 0.05 vs. DM+AGE-Apt. Non-DM: non-diabetic mouse; DM: diabetic mouse; AGEs: advanced glycation end products; CTR-Apt: control aptamer; AGE-Apt: AGE-inhibitory aptamer; w: week; RAGE: receptor for AGEs; MCP-1: monocyte chemoattractant protein-1; TNF-α: tumor necrosis factor-α; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling. Full article ">Figure 2
AGE-Apt attenuated seminiferous tubular dilation and sperm abnormalities in diabetic mice. (A) Representative images of the seminiferous tubules of non-diabetic and diabetic mice stained with H&E. Magnification: ×40; bars: 200 μm. (B,C) Seminiferous tubule area (B) and lumen area (C). (D) Representative images of spermatids in the testes of non-diabetic and diabetic mice at 13 weeks of age stained with H&E. Magnification: ×400; bars: 20 μm. (E) The number of spermatids. (F) Testicular gene expression levels of Cldn-3 and Ocln in non-diabetic and diabetic mice. Data demonstrate relative levels of target molecules to the housekeeping gene 18S ribosomal RNA. (G) Sperm concentration. (H) Sperm normal motility. (I) Sperm viability. (J) Sperm normal motility after 6 h of incubation with TNFα. (K) Sperm viability after 24 h of incubation with TNFα. (B,C,F–I), n = 6–8 per group; (E), n = 4 per group; (H), n = 6 per group; (I), n = 3 per group. ** p < 0.01 vs. non-DM at the same number of weeks old; a p < 0.05 vs. non-DM+CTR-Apt; b p < 0.05 vs. DM+AGE-Apt; ## p < 0.01 vs. control. Non-DM: non-diabetic mouse; DM: diabetic mouse; AGEs: advanced glycation end products; CTR-Apt: control aptamer; AGE-Apt: AGE-inhibitory aptamer; w: week; Ocln: occludin; Cldn3: claudin-3. Full article ">Figure 3
. Proposed mechanism of AGE-induced sperm abnormalities in T2DM and their blockade by AGE-Apt. AGEs: advanced glycation end products; RAGE: receptor for AGEs; MCP-1: monocyte chemoattractant protein-1; TNF-α: tumor necrosis factor-α; ROS: reactive oxygen species. Full article ">

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