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Fulltext Broad anti-pathogen potential of DEAD box RNA helicase eIF4A-targeting rocaglates

Obermann W, Azri MFD, Konopka L, Schmidt N, Magari F, Sherman J, et al.

Sci Rep, 2023 Jun 08;13(1):9297.
PMID: 37291191 DOI: 10.1038/s41598-023-35765-6

Inhibition of eukaryotic initiation factor 4A has been proposed as a strategy to fight pathogens. Rocaglates exhibit the highest specificities among eIF4A inhibitors, but their anti-pathogenic potential has not been comprehensively assessed across eukaryotes. In silico analysis of the substitution patterns of six eIF4A1 aa residues critical to rocaglate binding, uncovered 35 variants. Molecular docking of eIF4A:RNA:rocaglate complexes, and in vitro thermal shift assays with select recombinantly expressed eIF4A variants, revealed that sensitivity correlated with low inferred binding energies and high melting temperature shifts. In vitro testing with silvestrol validated predicted resistance in Caenorhabditis elegans and Leishmania amazonensis and predicted sensitivity in Aedes sp., Schistosoma mansoni, Trypanosoma brucei, Plasmodium falciparum, and Toxoplasma gondii. Our analysis further revealed the possibility of targeting important insect, plant, animal, and human pathogens with rocaglates. Finally, our findings might help design novel synthetic rocaglate derivatives or alternative eIF4A inhibitors to fight pathogens.

Matched MeSH terms: DEAD-box RNA Helicases/metabolism
Design, mechanism, delivery and therapeutics of canonical and Dicer-substrate siRNA

Raja MAG, Katas H, Amjad MW

Asian J Pharm Sci, 2019 Sep;14(5):497-510.
PMID: 32104477 DOI: 10.1016/j.ajps.2018.12.005

Upon the discovery of RNA interference (RNAi), canonical small interfering RNA (siRNA) has been recognized to trigger sequence-specific gene silencing. Despite the benefits of siRNAs as potential new drugs, there are obstacles still to be overcome, including off-target effects and immune stimulation. More recently, Dicer substrate siRNA (DsiRNA) has been introduced as an alternative to siRNA. Similarly, it also is proving to be potent and target-specific, while rendering less immune stimulation. DsiRNA is 25-30 nucleotides in length, and is further cleaved and processed by the Dicer enzyme. As with siRNA, it is crucial to design and develop a stable, safe, and efficient system for the delivery of DsiRNA into the cytoplasm of targeted cells. Several polymeric nanoparticle systems have been well established to load DsiRNA for in vitro and in vivo delivery, thereby overcoming a major hurdle in the therapeutic uses of DsiRNA. The present review focuses on a comparison of siRNA and DsiRNA on the basis of their design, mechanism, in vitro and in vivo delivery, and therapeutics.

Matched MeSH terms: DEAD-box RNA Helicases
Fulltext Derivation of an endogenous small RNA from double-stranded Sox4 sense and natural antisense transcripts in the mouse brain

Ling KH, Brautigan PJ, Moore S, Fraser R, Cheah PS, Raison JM, et al.

Genomics, 2016 Mar;107(2-3):88-99.
PMID: 26802803 DOI: 10.1016/j.ygeno.2016.01.006

Natural antisense transcripts (NATs) are involved in cellular development and regulatory processes. Multiple NATs at the Sox4 gene locus are spatiotemporally regulated throughout murine cerebral corticogenesis. In the study, we evaluated the potential functional role of Sox4 NATs at Sox4 gene locus. We demonstrated Sox4 sense and NATs formed dsRNA aggregates in the cytoplasm of brain cells. Over expression of Sox4 NATs in NIH/3T3 cells generally did not alter the level of Sox4 mRNA expression or protein translation. Upregulation of a Sox4 NAT known as Sox4ot1 led to the production of a novel small RNA, Sox4_sir3. Its biogenesis is Dicer1-dependent and has characteristics resemble piRNA. Expression of Sox4_sir3 was observed in the marginal and germinative zones of the developing and postnatal brains suggesting a potential role in regulating neurogenesis. We proposed that Sox4 sense-NATs serve as Dicer1-dependent templates to produce a novel endo-siRNA- or piRNA-like Sox4_sir3.

Matched MeSH terms: DEAD-box RNA Helicases/metabolism
Lutein improves cell viability and reduces Alu RNA accumulation in hydrogen peroxide challenged retinal pigment epithelial cells

Chong YS, Mai CW, Leong CO, Wong LC

Cutan Ocul Toxicol, 2018 Mar;37(1):52-60.
PMID: 28554225 DOI: 10.1080/15569527.2017.1335748

PURPOSE: Dysfunction of the microRNA (miRNA)-processing enzyme DICER1 and Alu RNA accumulation are linked to the pathogenesis of age-related macular degeneration (AMD). This study determined the optimal dose of lutein (LUT) and zeaxanthin (ZEA) to protect human retinal pigment epithelium (RPE) cells against hydrogen peroxide (H2O2). The effect of the optimal dose of LUT and ZEA as DICER1 and Alu RNA modulators in cultured human RPE cells challenged with H2O2 was investigated.
MATERIALS AND METHODS: ARPE-19 cells were pre-treated with LUT, ZEA, or both for 24 h before 200 μM H2O2 challenge. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. DICER1 and Alu RNA were quantified by western blotting and real-time polymerase chain reaction, respectively.
RESULTS: H2O2 increased cell Alu RNA expression and decreased cell viability of ARPE-19, but had no significant impact on the DICER1 protein level. LUT, alone and in combination with ZEA pre-treatment, prior to H2O2 challenge significantly improved cell viability of ARPE-19 and reduced the level of Alu RNA compared to the negative control.
CONCLUSIONS: These results support the use of LUT alone, and in combination with ZEA, in AMD prevention and treatment. This study is also the first to report LUT modulating effects on Alu RNA.

Matched MeSH terms: DEAD-box RNA Helicases/metabolism
Fulltext Dual-action of thermoresponsive gels containing DsiRNA-loaded gold nanoparticles for diabetic wound therapy: Characterization, in vitro safety and healing efficacy

Nor Azlan AYH, Katas H, Habideen NH, Mh Busra MF

Saudi Pharm J, 2020 Nov;28(11):1420-1430.
PMID: 33250649 DOI: 10.1016/j.jsps.2020.09.007

Diabetic wounds are difficult to treat due to multiple causes, including reduced blood flow and bacterial infections. Reduced blood flow is associated with overexpression of prostaglandin transporter (PGT) gene, induced by hyperglycaemia which causing poor vascularization and healing of the wound. Recently, gold nanoparticles (AuNPs) have been biosynthesized using cold and hot sclerotium of Lignosus rhinocerotis extracts (CLRE and HLRE, respectively) and capped with chitosan (CS) to produce biocompatible antibacterial nanocomposites. The AuNPs have shown to produce biostatic effects against selected gram positive and negative bacteria. Therefore, in this study, a dual therapy for diabetic wound consisting Dicer subtract small interfering RNA (DsiRNA) and AuNPs was developed to improve vascularization by inhibiting PGT gene expression and preventing bacterial infection, respectively. The nanocomposites were incorporated into thermoresponsive gel, made of pluronic and polyethylene glycol. The particle size of AuNPs synthesized using CLRE (AuNPs-CLRE) and HLRE (AuNPs-HLRE) was 202 ± 49 and 190 ± 31 nm, respectively with positive surface charge (+30 to + 45 mV). The thermoresponsive gels containing DsiRNA-AuNPs gelled at 32 ± 1 °C and released the active agents in sufficient amount with good texture and rheological profiles for topical application. DsiRNA-AuNPs and those incorporated into thermoresponsive pluronic gels demonstrated high cell viability, proliferation and cell migration rate via in vitro cultured cells of human dermal fibroblasts, indicating their non-cytotoxicity and wound healing properties. Taken together, the thermoresponsive gels are expected to be useful as a potential dressing that promotes healing of diabetic wounds.

Matched MeSH terms: DEAD-box RNA Helicases
Fulltext Brain Beta-Catenin Signalling During Stress and Depression

Teo CH, Soga T, Parhar IS

Neurosignals, 2018 02 22;26(1):31-42.
PMID: 29490303 DOI: 10.1159/000487764

Beta-catenin is a protein with dual functions in the cell, playing a role in both adhesion between cells as well as gene transcription via the canonical Wnt signalling pathway. In the canonical Wnt signalling pathway, beta-catenin again plays multiple roles. In the embryonic stage, the regulation of beta-catenin levels activates genes that govern cell proliferation and differentiation. In an adult organism, beta-catenin continues to regulate the cell cycle - as a result over-expression of beta-catenin may lead to cancer. In the brain, dysfunctions in Wnt signalling related to beta-catenin levels may also cause various pathological conditions like Alzheimer's disease, Parkinson's disease, and depression. Beta-catenin can be influenced by stressful conditions and increases in glucocorticoid levels. In addition, beta-catenin can be regulated by neurotransmitters such as serotonin and dopamine. Fluctuations in beta-catenin in brain regions under duress have been associated with depressive-like behaviours. It is theorized that the change in behaviour can be attributed to the regulation of Dicer by beta-catenin. Dicer, a protein that produces micro-RNAs in the cell, is a target gene for beta-catenin. Amongst the micro-RNA that it produces are those involved in stress resilience. In this way, beta-catenin has taken its place in the well-studied biochemistry of stress and depression, and future research into this interesting protein may yet yield fruitful results in that field.

Matched MeSH terms: DEAD-box RNA Helicases