Recent trends of NFκB decoy oligodeoxynucleotide-based nanotherapeutics in lung diseases

Mehta, Meenu; Paudel, Keshav Raj; Shukla, Shakti D.; Allam, Venkata Sita Rama Raju; Kannaujiya, Vinod K.; Panth, Nisha; Das, Amlan; Parihar, Vipan K.; Chakraborty, Amlan; Ali, Khadem; Jha, Niraj Kumar; Xenaki, Dia; Su, Qian; Wich, Peter; Adams, Jon; Hansbro, Philip M.; Chellappan, Dinesh Kumar; Oliver, Brian G.; Dua, Kamal

doi:10.1016/j.jconrel.2021.08.010

Cited by 24 publications

(11 citation statements)

References 160 publications

(183 reference statements)

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“…Decoy ODNs harboring the consensus DNA recognition motif of a target transcription factor compete with the binding sites in the promoter regions of target genes for the binding of that transcription factor, thereby also significantly reducing the expression levels of downstream genes. Several studies have investigated the application of NF-κB decoy ODNs in the treatment of inflammatory disorders 18 , 19 , highlighting the feasibility of employing RBP-J decoy ODNs for the treatment of diseases resulting from the aberrant activation of Notch signaling.…”

Section: Introductionmentioning

confidence: 99%

Exosome-mediated delivery of RBP-J decoy oligodeoxynucleotides ameliorates hepatic fibrosis in mice

He¹,

Li²,

Li³

et al. 2022

Theranostics

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Rationale: Macrophages play multi-dimensional roles in hepatic fibrosis. Studies have implicated Notch signaling mediated by the transcription factor RBP-J in macrophage activation and plasticity. Additionally, we have previously shown that myeloid-specific disruption of RBP-J can ameliorate hepatic fibrosis in mice. Accordingly, we next asked whether blocking Notch signaling in macrophages could serve as a therapeutic strategy to treat hepatic fibrosis. In this study, we used a combination of transcription factor decoy oligodeoxynucleotides (ODNs) and exosomes to test this possibility. Methods: Hairpin-type decoy oligodeoxynucleotides (ODNs) were designed for the transcription factor RBP-J. The effects of RBP-J decoy ODNs on Notch signaling were evaluated by western blot, quantitative RT-PCR, luciferase reporter assays, and electrophoretic mobility shift assays. ODNs were loaded into HEK293T-derived exosomes by electroporation. A hepatic fibrosis mouse model was established by the intraperitoneal injection of carbon tetrachloride or bile duct ligation. Mice with hepatic fibrosis were administered exosomes loaded with RBP-J decoy ODNs via tail vein injection. The in vivo distribution of exosomes was analyzed by fluorescence labeling and imaging. Liver histology was examined using hematoxylin and eosin, Sirius red, and Masson staining, as well as immunohistochemical staining for Col1α1 and αSMA. Results: We found that RBP-J decoy ODNs could be efficiently loaded into exosomes and inhibit the activation of Notch signaling. Furthermore, exosomes administered via the tail vein were found to be primarily taken up by hepatic macrophages in mice with liver fibrosis. Importantly, RBP-J decoy ODNs delivered by exosomes could efficiently inhibit Notch signaling in macrophages and ameliorate hepatic fibrosis in mice. Conclusions: Combined, our data showed that the infusion of exosomes loaded with RBP-J decoy ODNs represents a promising therapeutic strategy for the treatment of hepatic fibrosis.

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Section: Introductionmentioning

confidence: 99%

Exosome-mediated delivery of RBP-J decoy oligodeoxynucleotides ameliorates hepatic fibrosis in mice

He¹,

Li²,

Li³

et al. 2022

Theranostics

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“…However, one of the major limitations of this approach is the rapid degradation of phosphodiester ODN by intracellular nucleases, which further emphasizes the importance of PLGA as a vector (Ahn et al 2002; Park et al 2003). Previous studies concluded that PLGA NSs were a promising delivery system for a double-stranded decoy ODN to NF-κB (Tahara et al 2011; Mehta et al 2021). Such a system allows sustained ODN release together with an inhibition of the transcriptional activity of NF-κB in activated macrophages at significantly lower concentrations compared with naked ODN (De Rosa et al 2005).…”

Section: Discussionmentioning

confidence: 99%

NF-κB Decoy ODN-Loaded Poly lactic-co-glycolic Acid Nanospheres Inhibit Alveolar Ridge Resorption

Huang

Ishida

et al. 2022

Preprint

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Residual ridge resorption combined with dimensional loss resulting from tooth extraction has a prolonged correlation with early excessive inflammation. Nuclear factor-kappa B (NF-κB) decoy oligodeoxynucleotide (ODN) is a member of a group of double-stranded DNA capable of downregulating the expression of downstream genes of the NF-κB pathway. The healing action of its embellished effect combined with poly(lactic-co-glycolic acid) (PLGA) nanospheres on tooth extraction socket still remains unknown. Hence, the aim of this study was to investigate the therapeutic effect of NF-κB decoy ODN-loaded PLGA nanospheres (PLGA-NfD) transfected into extraction sockets in Wistar/ST rats. Micro-computed tomography and trabecular bone analysis following treatment with PLGA-NfD demonstrated inhibition of vertical alveolar bone loss with increased bone volume, smoother trabecular bone surface, thicker trabecular bone, larger trabecular number and separation, and fewer bone porosities. Histomorphometric and reverse transcription-quantitative polymerase chain reaction analysis revealed reduced tartrate-resistant acid phosphatase-expressing osteoclasts, interleukin-1β, tumor necrosis factor-α, receptor activator of NF-κB ligand, turnover rate and increased transforming growth factor-β1 immunopositive reactions and relative gene expressions. These data demonstrate that local delivery of PLGA-NfD could be used as a substantial suppressor of inflammation during the healing process in a tooth extraction socket, with the potential of accelerated new bone formation.

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“…Another issue of using the modern anti-asthmatic drugs is limited to their efficacy as they are effective only if administered particularly at the time when maintaining the chronotherapy, as the onset of symptoms and exacerbation varies between the patients (Paudel et al 2021). Therefore, a better understanding of the mechanistic pathways (Mehta et al 2020a, b) and investigating alternate novel mechanisms involved in the pathogenesis of asthma are highly needed to develop alternate therapies and new methods of advance drug delivery (example: liquid crystalline nanoparticles, decoy oligonucleotide, extracellular vesicles, and polysaccharides) with minimal side effects and enhanced efficacy (Chan et al 2021a;Manandhar et al 2022;Mehta et al 2021b;Prasher et al 2021).…”

Section: Introductionmentioning

confidence: 99%

Nutraceuticals and mitochondrial oxidative stress: bridging the gap in the management of bronchial asthma

Allam

Paudel

Gupta

et al. 2022

Environ Sci Pollut Res

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Asthma is a chronic inflammatory disease primarily characterized by inflammation and reversible bronchoconstriction. It is currently one of the leading causes of morbidity and mortality in the world. Oxidative stress further complicates the pathology of the disease. The current treatment strategies for asthma mainly involve the use of anti-inflammatory agents and bronchodilators. However, long-term usage of such medications is associated with severe adverse effects and complications. Hence, there is an urgent need to develop newer, novel, and safe treatment modalities for the management of asthma. This has therefore prompted further investigations and detailed research to identify and develop novel therapeutic interventions from potent untapped resources. This review focuses on the significance of oxidative stressors that are primarily derived from both mitochondrial and non-mitochondrial sources in initiating the clinical features of asthma. The review also discusses the biological scavenging system of the body and factors that may lead to its malfunction which could result in altered states. Furthermore, the review provides a detailed insight into the therapeutic role of nutraceuticals as an effective strategy to attenuate the deleterious effects of oxidative stress and may be used in the mitigation of the cardinal features of bronchial asthma.

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Recent trends of NFκB decoy oligodeoxynucleotide-based nanotherapeutics in lung diseases

Cited by 24 publications

References 160 publications

Exosome-mediated delivery of RBP-J decoy oligodeoxynucleotides ameliorates hepatic fibrosis in mice

Exosome-mediated delivery of RBP-J decoy oligodeoxynucleotides ameliorates hepatic fibrosis in mice

NF-κB Decoy ODN-Loaded Poly lactic-co-glycolic Acid Nanospheres Inhibit Alveolar Ridge Resorption

Nutraceuticals and mitochondrial oxidative stress: bridging the gap in the management of bronchial asthma

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