Natural antisense transcript-targeted regulation of inducible nitric oxide synthase mRNA levels

Yoshigai, Emi; Hara, Tsunekatsu; Araki, Yoshinori; Tanaka, Yoshito; Oishi, Masaharu; Tokuhara, Katsuji; Kaibori, Masaki; Okumura, Tadayoshi; Kwon, A‐Hon; Nishizawa, Mikio

doi:10.1016/j.niox.2013.01.001

Cited by 27 publications

(32 citation statements)

References 35 publications

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“…2B). The iNOS asRNA interacts with and stabilizes the iNOS mRNA [17], [26]. Because the reduction of the iNOS asRNA levels leads to decreased iNOS mRNA stability, these results imply that FRLFE may also regulate the mRNA levels of iNOS at a posttranscriptional level.…”

Section: Resultsmentioning

confidence: 91%

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The Anti-Inflammatory Effects of Flavanol-Rich Lychee Fruit Extract in Rat Hepatocytes

et al. 2014

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Flavanol (flavan-3-ol)-rich lychee fruit extract (FRLFE) is a mixture of oligomerized polyphenols primarily derived from lychee fruit and is rich in flavanol monomers, dimers, and trimers. Supplementation with this functional food has been shown to suppress inflammation and tissue damage caused by high-intensity exercise training. However, it is unclear whether FRLFE has in vitro anti-inflammatory effects, such as suppressing the production of the proinflammatory cytokine tumor necrosis factor α (TNF-α) and the proinflammatory mediator nitric oxide (NO), which is synthesized by inducible nitric oxide synthase (iNOS). Here, we analyzed the effects of FRLFE and its constituents on the expression of inflammatory genes in interleukin 1β (IL-1β)-treated rat hepatocytes. FRLFE decreased the mRNA and protein expression of the iNOS gene, leading to the suppression of IL-1β-induced NO production. FRLFE also decreased the levels of the iNOS antisense transcript, which stabilizes iNOS mRNA. By contrast, unprocessed lychee fruit extract, which is rich in flavanol polymers, and flavanol monomers had little effect on NO production. When a construct harboring the iNOS promoter fused to the firefly luciferase gene was used, FRLFE decreased the luciferase activity in the presence of IL-1β, suggesting that FRLFE suppresses the promoter activity of the iNOS gene at the transcriptional level. Electrophoretic mobility shift assays indicated that FRLFE reduced the nuclear transport of a key regulator, nuclear factor κB (NF-κB). Furthermore, FRLFE inhibited the phosphorylation of NF-κB inhibitor α (IκB-α). FRLFE also reduced the mRNA levels of NF-κB target genes encoding cytokines and chemokines, such as TNF-α. Therefore, FRLFE inhibited NF-κB activation and nuclear translocation to suppress the expression of these inflammatory genes. Our results suggest that flavanols may be responsible for the anti-inflammatory and hepatoprotective effects of FRLFE and may be used to treat inflammatory diseases.

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Section: Resultsmentioning

confidence: 91%

“…These compounds suppress iNOS induction at the transcriptional level through transcription factors, including nuclear factor κB (NF-κB) [25]. These constituents posttranscriptionally suppress iNOS induction using a natural antisense transcript (asRNA) that interacts with and stabilizes the iNOS mRNA [17], [26].…”

Section: Introductionmentioning

confidence: 99%

The Anti-Inflammatory Effects of Flavanol-Rich Lychee Fruit Extract in Rat Hepatocytes

et al. 2014

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“…Single-stranded sense oligodeoxyribonucleotides corresponding to the iNOS mRNA sequence decrease iNOS mRNA levels by interfering with mRNA-asRNA interactions [21] . This method is referred to as natural antisense transcript-targeted regulation (NATRE) technology [22] . In contrast, when sense oligonucleotides corresponding to other mRNAs that are involved in inflammation (e.g., mRNAs encoding TNF-alpha, nuclear factor-kappaB p65 subunit, and several chemokines) were introduced into hepatocytes, their mRNA levels increased (discordant regulation) [23,24] .…”

Section: Inflammation and Infectionmentioning

confidence: 99%

“…Both sense oligodeoxyribonucleotides [11,[21][22][23][24] and antisense oligoribonucleotides (asRNA mimics) [6] have been successfully used to interfere with this interaction. The copy number of an asRNA is generally lower than that of an mRNA, although asRNAs have high specificity to their cognate mRNAs.…”

Section: Regulatory Rna Networkmentioning

confidence: 99%

“…Interaction sites for binding partners (mRNAs, microRNAs, or RNA-binding proteins) are blocked by sense oligonucleotides, asRNA mimics (oligoribonucleotides), or antimiRs (oligonucleotides complementary to microRNA seed regions) [6,11,21,22,25] . These oligonucleotides have the potential to be used for a therapeutic purpose.…”

Section: Drugs That Target Asrnas In Regulatory Rna Networkmentioning

confidence: 99%

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RNA Networks that Regulate mRNA Expression and their Potential as Drug Targets

Nishizawa

Kimura

2015

RNA Dis

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Natural antisense transcripts (asRNAs) transcribed from eukaryotic genes are primarily long transcripts that do not code for proteins. Transcriptome analyses have revealed that asRNAs exhibit diverse functional roles in the regulation of gene expression. In the case of inducible genes, asRNAs epigenetically affect their expression or post-transcriptionally affect stability and translatability of their mRNAs. Many low-copy-number asRNAs regulate the expression levels of mRNAs through cis-controlling elements in the mRNA in concert with trans-acting factors, such as RNA-binding proteins and microRNAs. Recently, a competitive endogenous RNA (ceRNA) hypothesis was postulated as the basis of a functional network, comprising mRNAs, asRNAs, and microRNAs. This network finely tunes mRNA expression by common microRNA-responsive elements being present among mRNAs and asRNAs, permitting the redirection of microRNAs between the two. Examples of the ceRNA-mediated cross-regulation of mRNA expression are observed in the phosphatase and tensin homolog mRNA network and the interferon-alpha1 mRNA network. In such regulatory RNA networks, an mRNA, its corresponding asRNAs (high specificity), microRNAs (low specificity), and RNA-binding proteins mutually interact. Both asRNAs and microRNAs are involved in the pathogenesis or pathophysiology of various diseases, such as cancer, inflammation, and infection. Simple disruption of an asRNA or a microRNA can often show off-target effects due to complicated interactions inside and outside the regulatory RNA networks. Therefore, drugs that target asRNAs should be developed to minimize off-target effects and to target interactions that are dysregulated in disease.

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Long noncoding RNAs and the regulation of innate immunity and host-virus interactions

Basavappa

Cherry

Henao‐Mejia

2019

Journal of Leukocyte Biology

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Immune responses are both pathogen and cell type-specific. The innate arm of immunity is characterized by rapid intracellular signaling cascades resulting in the production of hundreds of antimicrobial effectors that protect the host organism. Long noncoding RNAs have been shown to operate as potent modulators of both RNA and protein function throughout cell biology. Emerging data suggest that this is also true within innate immunity. LncRNAs have been shown to regulate both innate immune cell identity and the transcription of gene expression programs critical for innate immune responses. Here, we review the diverse roles of lncRNAs within innate defense with a specific emphasis on host-virus interactions.

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Natural antisense transcript-targeted regulation of inducible nitric oxide synthase mRNA levels

Cited by 27 publications

References 35 publications

The Anti-Inflammatory Effects of Flavanol-Rich Lychee Fruit Extract in Rat Hepatocytes

The Anti-Inflammatory Effects of Flavanol-Rich Lychee Fruit Extract in Rat Hepatocytes

RNA Networks that Regulate mRNA Expression and their Potential as Drug Targets

Long noncoding RNAs and the regulation of innate immunity and host-virus interactions

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