Endogenous hydrogen sulfide persulfidates endothelin type A receptor to inhibit pulmonary arterial smooth muscle cell proliferation.

Background: The binding of endothelin-1 (ET-1) to endothelin type A receptor (ETAR) performs a critical action in pulmonary arterial smooth muscle cell (PASMC) proliferation leading to pulmonary vascular structural remodeling. More evidence showed that cystathionine γ-lyase (CSE)-catalyzed endogenous hydrogen sulfide (HS) was involved in the pathogenesis of cardiovascular diseases. In this study, we aimed to explore the effect of endogenous HS/CSE pathway on the ET-1/ETAR binding and its underlying mechanisms in the cellular and animal models of PASMC proliferation.

Tumor microenvironment-responsive multinucleated nanocomplexes loaded with carbon dots for combined photothermal/chemodynamic therapy of breast cancer.

Low cure rate and high death rate of cancers have seriously threatened human health. The combining multiple therapies is a promising strategy for cancer treatment. In this study, we construct a novel multinucleated nanocomplex loaded with carbon dots (CDs-SA@TAMn) that responds to tumor microenvironment for combined photothermal/chemodynamic cancer therapy.

Development of miRNA-based PROTACs targeting Lin28 for breast cancer therapy.

Lin28, a highly conserved carcinogenic protein, plays an important role in the generation of cancer stem cells, contributing to the unfavorable prognosis of cancer patients. This RNA binding protein specifically binds to pri/pre-microRNA (miRNA) lethal-7 (let-7), impeding its miRNA maturation. The reduced expression of tumor suppressor miRNA let-7 fosters development and progression-related traits such as proliferation, invasion, metastasis, and drug resistance.

In vitro digestion and fermentation characteristics of soluble dietary fiber from adlay (Coix lacryma-jobi L. var. ma-yuen Staft) bran modified by steam explosion.

Adlay bran is known for its nutrient-rich profile and multifunctional properties, and steam explosion (SE) is an emerging physical modification technique. However, the specific effects of SE on the activity composition and antioxidant capacity of adlay bran soluble dietary fiber (SDF) during in vitro digestion, as well as its influence on gut microbiota during in vitro fermentation, remain inadequately understood. This paper reports the in vitro digestion and fermentation characteristics of soluble dietary fiber from adlay bran modified by SE (SE-SDF).

Induced Self-Assembly of Vitamin E-Spermine/siRNA Nanocomplexes via Spermine/Helix Groove-Specific Interaction for Efficient siRNA Delivery and Antitumor Therapy.

Gene therapy has been one of potential strategies for the treatment of different diseases, where efficient and safe gene delivery systems are also extremely in need. Current lipid nanoparticles (LNP) technology highly depends on the packing and condensation of nucleic acids with amine moieties. Here, an attempt to covalently link two natural compounds, spermine and vitamin E, is made to develop self-assembled nucleic acid delivery systems.

Self-Assembly Nanostructure Induced by Regulation of G-Quadruplex DNA Topology via a Reduction-Sensitive Azobenzene Ligand on Cells.

The control of DNA assembly systems on cells has increasingly shown great importance for precisely targeted therapies. Here, we report a controllable DNA self-assembly system based on the regulation of G-quadruplex DNA topology by a reduction-sensitive azobenzene ligand. Specifically, three azobenzene multiamines are developed, and AzoDiTren is identified as the best G4 binder, which displays high affinity and specificity for G4 DNA.

Cathepsin B-activatable cyclic antisense oligonucleotides for cell-specific target gene knockdown and .

Trigger-activatable antisense oligonucleotides have been widely applied to regulate gene function. Among them, caged cyclic antisense oligonucleotides (cASOs) maintain a specific topology that temporarily inhibits their interaction with target genes. By inserting linkers that respond to cell-specific endogenous stimuli, they can be powerful tools and potential therapeutic agents for specific types of cancer cells with low off-target effects on normal cells.

Light-triggered site-directed RNA editing by endogenous ADAR1 with photolabile guide RNA.

RNA A-to-I editing is a post-transcriptional modification pervasively occurring in cells. Artificial intervention of A-to-I editing at specific sites of RNA could also be achieved with guide RNA and exogenous ADAR enzymes. In contrast to previous fused SNAP-ADAR enzymes for light-driven RNA A-to-I editing, we developed photo-caged antisense guide RNA oligonucleotides with simple 3'-terminal cholesterol modification, and successfully achieved light-triggered site-specific RNA A-to-I editing for the first time utilizing endogenous ADAR enzymes.

Allosteric Nucleic Acid Enzyme: A Versatile Stimuli-Responsive Tool for Molecular Computing and Biosensing Nanodevices.

Allostery is a naturally occurring mechanism in which effector binding induces the modulation and fine control of a related biomolecule function. Deoxyribozyme (DNAzyme) with catalytic activity and substrate recognition ability is ideal to be regulated by allosteric strategies. However, the current regulations frequently confront various obstacles, such as severe activity decay, signal leakage, and limited effectors.

Physicochemical, structure properties and hypoglycemic activity of soluble dietary fiber from adlay ( L. var. Stapf) bran treated by steam explosion.

To enhance the content of adlay bran soluble dietary fiber (SDF) and improve its functionality, we investigated the influences of steam explosion (SE) on the physicochemical, structural properties, and hypoglycemic activities of adlay bran SDF. The cellulose, hemicellulose, and lignin contents of adlay bran decreased significantly after SE treatment. When the SE strength was 0.

Triton modified polyethyleneimine conjugates assembled with growth arrest-specific protein 6 for androgenetic alopecia transdermal gene therapy.

Androgenetic alopecia is an androgen-dependent skin disorder that commonly affects hair follicle growth and hair loss. Gene therapy that can promote the proliferation and survival of hair follicle cells can be a potential choice for its cure. While transdermal application of therapeutic functional nucleic acids across the stratum corneum is quite difficult.

Reversible On-Off Photoswitching of DNA Replication Using a Dumbbell Oligodeoxynucleotide.

In most organisms, DNA extension is highly regulated; however, most studies have focused on controlling the initiation of replication, and few have been done to control the regulation of DNA extension. In this study, we adopted a new strategy for azODNs to regulate DNA extension, which is based on azobenzene oligonucleotide chimeras regulated by substrate binding affinity, and the conformation of the chimera can be regulated by a light source with a light wavelength of 365 nm. The results showed that the primer was extended with Taq DNA polymerase after visible light treatment, and DNA extension could be effectively hindered with UV light treatment.

Tetrazine-Induced Bioorthogonal Activation of Vitamin E-Modified siRNA for Gene Silencing.

The temporal activation of siRNA provides a valuable strategy for the regulation of siRNA activity and conditional gene silencing. The bioorthogonal bond-cleavage reaction of benzonorbonadiene and tetrazine is a promising trigger in siRNA temporal activation. Here, we developed a new method for the bio-orthogonal chemical activation of siRNA based on the tetrazine-induced bond-cleavage reaction.

Major Advances in Emerging Degrader Technologies.

Recently, degrader technologies have attracted increasing interest in the academic field and the pharmaceuticals industry. As one of the degrader technologies, proteolysis-targeting chimeras (PROTACs) have emerged as an attractive pharmaceutical development approach due to their catalytic ability to degrade numerous undruggable disease-causing proteins. Despite the remarkable progress, many aspects of traditional PROTACs still remain elusive.

Cell-Trappable BODIPY-NBD Dyad for Imaging of Basal and Stress-Induced HS in Live Biosystems.

HS is a gaseous signaling molecule that is involved in many physiological and pathological processes. In general, the level of intracellular HS (<1 μM) is much lower than that of GSH (∼1-10 mM), leading to the remaining challenge of selective detection and differentiation of endogenous HS in live biosystems. To this end, we quantitatively demonstrate that the thiolysis of NBD amine has much higher selectivity for HS over GSH than that of the reduction of aryl azide.

Circular Antisense Oligonucleotides for Specific RNase-H-Mediated microRNA Inhibition with Reduced Off-Target Effects and Nonspecific Immunostimulation.

Antisense microRNA oligodeoxynucleotides (AMOs) are powerful tools to regulate microRNA functions. Unfortunately, severe off-target effects are sometimes observed. Due to the special topological and enzymatic properties of circular oligodeoxynucleotides (c-ODNs), we rationally designed and developed circular AMOs, which effectively inhibited microRNA functions with high target specificity and low off-target effects.

Feasibility of cRGD conjugation at 5'-antisense strand of siRNA by phosphodiester linkage extension.

Small interfering RNAs (siRNAs) are widely studied for their highly specific gene silencing activity. However, obstacles remain to the clinical application of siRNAs. Attaching conjugates to siRNAs can improve their stability and broaden their application, and most functional conjugates of siRNAs locate at the 3'-terminus of the sense or antisense strand.

Redox manipulation of enzyme activity through physiologically active molecule.

The effective utility of physiologically active molecules is crucial in numerous biological processes. However, the regulation of enzyme functions through active substances remains challenging at present. Here, glutathione (GSH), produced in cells, was used to modulate the catalytic activity of thrombin without external stimulus.

Efficient Inhibition of SARS-CoV-2 Using Chimeric Antisense Oligonucleotides through RNase L Activation*.

There is an urgent need to develop antiviral drugs and alleviate the current COVID-19 pandemic. Herein we report the design and construction of chimeric oligonucleotides comprising a 2'-OMe-modified antisense oligonucleotide and a 5'-phosphorylated 2'-5' poly(A) (4A ) to degrade envelope and spike RNAs of SARS-CoV-2. The oligonucleotide was used for searching and recognizing target viral RNA sequence, and the conjugated 4A was used for guided RNase L activation to sequence-specifically degrade viral RNAs.

Multimerized self-assembled caged siRNA nanoparticles for photomodulation of RNAi-induced gene silencing.

We rationally designed and developed caged siRNA nanoparticles (Multi-Chol-siRNA) self-assembled with cholesterol-modified multimerized caged siRNAs for photomodulation of siRNA gene silencing activity. Strong resistance to serum nuclease and RNase A was observed for these cholesterol-modified caged siRNA nanoparticles due to the formation of nanostructures with high intensity of siRNA. These caged Multi-Chol-siRNA self-assembled nanoparticles were successfully used to achieve photochemical regulation of both exogenous GFP and endogenous Eg5 gene expressions with a GFP/RFP transient transfection system and Eg5-associated assays, respectively.

Chemical Modification and Transformation Strategies of Guide RNAs in CRISPR-Cas9 Gene Editing Systems.

The CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9 (CRISPR-associated protein 9) is a most powerful tool and has been widely used in gene editing and gene regulation since its discovery. However, wild-type CRISPR-Cas9 suffers from off-target effects and low editing efficiency. To overcome these limitations, engineered Cas9 proteins have been extensively investigated.

Optical Control of a CRISPR/Cas9 System for Gene Editing by Using Photolabile crRNA.

Currently CRISPR/Cas9 is a widely used efficient tool for gene editing. Precise control over the CRISPR/Cas9 system with high temporal and spatial resolution is essential for studying gene regulation and editing. Here, we synthesized a novel light-controlled crRNA by coupling vitamin E and a photolabile linker at the 5' terminus to inactivate the CRISPR/Cas9 system.

Photoregulation of Gene Expression with Ligand-Modified Caged siRNAs through Host/Guest Interaction.

Small interfering RNA (siRNA) can effectively silence target genes through Argonate 2 (Ago2)-induced RNA interference (RNAi). It is very important to control siRNA activity in both spatial and temporal modes. Among different masking strategies, photocaging can be used to regulate gene expression through light irradiation with spatiotemporal and dose-dependent resolution.