Search Results (16)

Orthodontic space closure following tooth extraction is often hindered by alveolar bone deficiency. This study investigates the therapeutic use of nuclear factor-kappa B (NF-κB) decoy oligodeoxynucleotides loaded with polylactic-co-glycolic acid nanospheres (PLGA-NfDs) to mitigate alveolar bone loss during orthodontic tooth movement (OTM) following the bilateral extraction of maxillary first molars in a controlled experiment involving forty rats of OTM model with ethics approved. The decreased tendency of the OTM distance and inclination angle with increased bone volume and improved trabecular bone structure indicated minimized alveolar bone destruction. Reverse transcription-quantitative polymerase chain reaction and histomorphometric analysis demonstrated the suppression of inflammation and bone resorption by downregulating the expression of tartrate-resistant acid phosphatase, tumor necrosis factor-α, interleukin-1β, cathepsin K, NF-κB p65, and receptor activator of NF-κB ligand while provoking periodontal regeneration by upregulating the expression of alkaline phosphatase, transforming growth factor-β1, osteopontin, and fibroblast growth factor-2. Importantly, relative gene expression over the maxillary second molar compression side in proximity to the alveolus highlighted the pharmacological effect of intra-socket PLGA-NfD administration, as evidenced by elevated osteocalcin expression, indicative of enhanced osteocytogenesis. These findings emphasize that locally administered PLGA-NfD serves as an effective inflammatory suppressor and yields periodontal regenerative responses following tooth extraction. Full article

Liposomes as carriers for CRISPR/Cas9 complexes represent an attractive approach for cardiovascular gene therapy. A critical barrier to this approach remains the efficient delivery of CRISPR-based genetic materials into cardiomyocytes. Echogenic liposomes (ELIP) containing a fluorescein isothiocyanate-labeled decoy oligodeoxynucleotide against nuclear factor kappa B (ELIP-NF-κB-FITC) were used both in vitro on mouse neonatal ventricular myocytes and in vivo on rat hearts to assess gene delivery efficacy with or without ultrasound. In vitro analysis was then repeated with ELIP containing Cas9-sg-IL1RL1 (interleukin 1 receptor-like 1) RNA to determine the efficiency of gene knockdown. ELIP-NF-κB-FITC without ultrasound showed limited gene delivery in vitro and in vivo, but ultrasound combined with ELIP notably improved penetration into heart cells and tissues. When ELIP was used to deliver Cas9-sg-IL1RL1 RNA, gene editing was successful and enhanced by ultrasound. This innovative approach shows promise for heart disease gene therapy using CRISPR technology. Full article

Liver damage caused by various factors results in fibrosis and inflammation, leading to cirrhosis and cancer. Fibrosis results in the accumulation of extracellular matrix components. The role of STAT proteins in mediating liver inflammation and fibrosis has been well documented; however, approved therapies targeting STAT3 inhibition against liver disease are lacking. This study investigated the anti-fibrotic and anti-inflammatory effects of STAT3 decoy oligodeoxynucleotides (ODN) in hepatocytes and liver fibrosis mouse models. STAT3 decoy ODN were delivered into cells using liposomes and hydrodynamic tail vein injection into 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice in which liver injury was induced. STAT3 target gene expression changes were verified using qPCR and Western blotting. Liver tissue fibrosis and bile duct proliferation were assessed in animal experiments using staining techniques, and macrophage and inflammatory cytokine distribution was verified using immunohistochemistry. STAT3 decoy ODN reduced fibrosis and inflammatory factors in liver cancer cell lines and DDC-induced liver injury mouse model. These results suggest that STAT3 decoy ODN may effectively treat liver fibrosis and must be clinically investigated. Full article

Background: Cartilage harvest and transplantation is a common surgery using costal, auricular, and septal cartilage for craniofacial reconstruction. However, absorption and warping of the cartilage grafts can occur due to inflammatory factors associated with wound healing. Transcription factor nuclear factor-κB (NF-κB) is activated by the various stimulation such as interleukin-1 (IL-1), and plays a central role in the transactivation of this inflammatory cytokine gene. Inhibition of NF-κB may have anti-inflammatory effects. The aim of this study was to explore the potential of an NF-κB decoy oligodeoxynucleotide (Decoy) as a chondroprotective agent. Materials and Methods: Safe and efficacious concentrations of Decoy were assessed using rabbit nasal septal chondrocytes (rNSChs) and assays for cytotoxicity, proteoglycan (PG) synthesis, and PG turnover were carried out. The efficacious concentration of Decoy determined from the rNSChs was then applied to human nasal septal cartilage (hNSC) in vitro and analyzed for PG turnover, the levels of inflammatory markers, and catabolic enzymes in explant-conditioned culture medium. Results: Over the range of Decoy conditions and concentrations, no inhibition of PG synthesis or cytotoxicity was observed. Decoy at 10 μM effectively inhibited PG degradation in the hNSC explant, prolonging PG half-life by 63% and decreasing matrix metalloprotease 3 (MMP-3) by 70.7% (p = 0.027). Conclusions: Decoy may be considered a novel chondroprotective therapeutic agent in cartilage transplantation due to its ability to inhibit cartilage degradation due to inflammation cytokines. Full article

The long-term patency of vein grafts is challenged by intimal hyperplasia. We sought to explore the intricate relationships between the transcription factor Egr-1, toll-like receptors (TLRs), and stem cell genes and also assessed oligodeoxynucleotide decoys (ODNs) as a strategy to prevent vein graft failures. A total of 42 New Zealand white rabbits were fed hyperlipidemic chow and classified into three groups. A double-stranded Egr-1 ODN was synthesized and infused in vein grafts prior to anastomosis with the common carotid artery. All vein grafts were retrieved at the conclusion of the predefined experimental period. Real-time quantitative polymerase chain reaction was performed to estimate expression patterns for several genes of interest. MYD88, TLR2-4, TLR8, NF-kB, TNF-α, IFNβ, and IFNγ; chemokines CCL4, CCL20, CCR2; numerous interleukins; and stem cell genes KFL4, NANOG, HOXA5, and HIF1α were universally downregulated in the ODN arm compared with the controls. By understanding these multifaceted interactions, our study offers actionable insights that may pave the way for innovative interventions in vascular reconstructions. Full article

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 oligodeoxynucleotides (ODNs) are double-stranded DNA sequences capable of downregulating the expression of downstream genes of the NF-κB pathway, which is recognized for regulating prototypical proinflammatory signals, physiological bone metabolism, pathologic bone destruction, and bone regeneration. The aim of this study was to investigate the therapeutic effect of NF-κB decoy ODNs on the extraction sockets of Wistar/ST rats when delivered by poly(lactic-co-glycolic acid) (PLGA) nanospheres. Microcomputed tomography and trabecular bone analysis following treatment with NF-κB decoy ODN-loaded PLGA nanospheres (PLGA-NfDs) 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 expression. These data demonstrate that local NF-κB decoy ODN transfection via PLGA-NfD can be used to effectively suppress inflammation in a tooth-extraction socket during the healing process, with the potential to accelerate new bone formation. Full article

Acne vulgaris has a pathogenesis that involves increased sebum production and perifollicular inflammation. Sterol regulatory element-binding protein-1 (SREBP-1) and peroxisome proliferator activated receptor-γ (PPAR-γ) are transcription factors that regulate numerous genes involved in lipid biosynthesis. To improve a new therapeutic approach, we designed the SREBP/PPAR decoy oligodeoxynucleotide (ODN), a synthetic short DNA containing complementary sequences for the SREBP and PPAR transcription factors. We aim to investigate the beneficial functions and the molecular mechanisms of the synthetic SREBP/PPAR decoy ODN in lipogenic models. C. acnes was intradermally injected with a 1.0 × 10⁷ colony forming unit/20 μL. The synthetic SREBP/PPAR decoy ODN or scrambled decoy ODN (10 μg) was transferred via the mouse tail vein injection. SZ95 cells were transfected with 2 μg of synthetic ODNs. After transfection, the SZ95 cells were cultured in serum-free medium containing 20 ng/μL of insulin-like growth factor-1 (IGF)-1 for 24 h. To investigate the expression of gene and signaling pathways, we performed Western blotting. The distribution of the chimeric decoy ODN was confirmed by EMSA. Lipid levels were assessed by Nile red and Oil Red O staining. The cytokine levels were measured by ELISA kit. This study showed that C. acnes-injected mice and IGF-1-stimulated SZ95 cells exhibited increased expression of SREBP-1 and PPAR-γ compared to the normal controls. In contrast, the administration of the SREBP/PPAR chimeric decoy ODN significantly suppressed the upregulation of lipogenic genes. Furthermore, the SREBP/PPAR decoy ODN decreased the plasma cytokines and cytokine levels of total protein. These results suggested that the SREBP/PPAR decoy ODN exerts its anti-lipogenic effects by regulating lipid metabolism and by inhibiting lipogenesis through the inactivation of the SREBP and PPAR pathways. Therefore, the synthetic SREBP/PPAR ODN demonstrates substantial therapeutic feasibility for the treatment of acne vulgaris. Full article

Renal fibrosis is a common process of various kidney diseases. Autophagy is an important cell biology process to maintain cellular homeostasis. In addition, autophagy is involved in the pathogenesis of various renal disease, including acute kidney injury, glomerular diseases, and renal fibrosis. However, the functional role of autophagy in renal fibrosis remains poorly unclear. The mammalian target of rapamycin (mTOR) plays a negative regulatory role in autophagy. Signal transducer and activator of transcription 3 (STAT3) is an important intracellular signaling that may regulate a variety of inflammatory responses. In addition, STAT3 regulates autophagy in various cell types. Thus, we synthesized the mTOR/STAT3 oligodeoxynucleotide (ODN) to regulate the autophagy. The aim of this study was to investigate the beneficial effect of mTOR/STAT3 ODN via the regulation of autophagy appearance on unilateral ureteral obstruction (UUO)-induced renal fibrosis. This study showed that UUO induced inflammation, tubular atrophy, and tubular interstitial fibrosis. However, mTOR/STAT3 ODN suppressed UUO-induced renal fibrosis and inflammation. The autophagy markers have no statistically significant relation, whereas mTOR/STAT3 ODN suppressed the apoptosis in tubular cells. These results suggest the possibility of mTOR/STAT3 ODN for preventing renal fibrosis. However, the role of mTOR/STAT3 ODN on autophagy regulation needs to be further investigated. Full article

Cardiovascular disease (CVD) is the main cause of global death, highlighting the fact that conventional therapeutic approaches for the treatment of CVD patients are insufficient, and there is a need to develop new therapeutic approaches. In recent years, decoy technology, decoy oligodeoxynucleotides (ODN), and decoy peptides show promising results for the future treatment of CVDs. Decoy ODN inhibits transcription by binding to the transcriptional factor, while decoy peptide neutralizes receptors by binding to the ligands. This review focused on studies that have investigated the effects of decoy ODN and decoy peptides on non-atherosclerotic CVD. Full article

Hyperlipidemia is a chronic disorder that plays an important role in the development of cardiovascular diseases, type II diabetes, atherosclerosis, hypertension, and non-alcoholic fatty liver disease. Hyperlipidemias have created a worldwide health crisis and impose a substantial burden not only on personal health but also on societies and economies. Transcription factors in the sterol regulatory element binding protein (SREBP) family are key regulators of the lipogenic genes in the liver. SREBPs regulate lipid homeostasis by controlling the expression of a range of enzymes required for the synthesis of endogenous cholesterol, fatty acids, triacylglycerol, and phospholipids. Thereby, SREBPs have been considered as targets for the treatment of metabolic diseases. The aim of this study was to investigate the beneficial functions and the possible underlying molecular mechanisms of SREBP decoy ODN, which is a novel inhibitor of SREBPs, in high-fat diet (HFD)-fed hyperlipidemic mice. Our studies using HFD-induced hyperlipidemia animal model revealed that SREBB decoy ODN inhibited the increased expression of fatty acid synthetic pathway, such as SREBP-1c, FAS, SCD-1, ACC1, and HMGCR. In addition, SREBP decoy ODN decreased pro-inflammatory cytokines, including TNF-α, IL-1β, IL-8, and IL-6 expression. These results suggest that SREBP decoy ODN exerts its anti-hyperlipidemia effects in HFD-induced hyperlipidemia mice by regulating their lipid metabolism and inhibiting lipogenesis through inactivation of the SREPB pathway. Full article

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting the proliferation and survival of tumor cells. As a ubiquitously-expressed transcription factor, STAT3 has commonly been considered an “undruggable” target for therapy; thus, much research has focused on targeting upstream pathways to reduce the expression or phosphorylation/activation of STAT3 in tumor cells. Recently, however, novel approaches have been developed to directly inhibit STAT3 in human cancers, in the hope of reducing the survival and proliferation of tumor cells. Several of these agents are nucleic acid-based, including the antisense molecule AZD9150, CpG-coupled STAT3 siRNA, G-quartet oligodeoxynucleotides (GQ-ODNs), and STAT3 decoys. While the AZD9150 and CpG-STAT3 siRNA interfere with STAT3 expression, STAT3 decoys and GQ-ODNs target constitutively activated STAT3 and modulate its ability to bind to target genes. Both STAT3 decoy and AZD9150 have advanced to clinical testing in humans. Here we will review the current understanding of the structures, mechanisms, and potential clinical utilities of the nucleic acid-based STAT3 inhibitors. Full article

Approximately 30% of pancreatic cancer patients harbor targetable mutations. However, there has been no therapy targeting these molecules clinically. Nucleic acid medicines show high specificity and can target RNAs. Nucleic acid medicine is expected to be the next-generation treatment next to small molecules and antibodies. There are several kinds of nucleic acid drugs, including antisense oligonucleotides, small interfering RNAs, microRNAs, aptamers, decoys, and CpG oligodeoxynucleotides. In this review, we provide an update on current research of nucleic acid-based therapies. Despite the challenging obstacles, we hope that nucleic acid drugs will have a significant impact on the treatment of pancreatic cancer. The combination of genetic diagnosis using next generation sequencing and targeted therapy may provide effective precision medicine for pancreatic cancer patients. Full article

Interleukin (IL)-32θ, a newly identified IL-32 isoform, has been reported to exert pro-inflammatory effects through the association with protein kinase C delta (PKCδ). In this study, we further examined the effects of IL-32θ on IL-13 and IL-13Rα2 expression and the related mechanism in THP-1 cells. Upon stimulating IL-32θ-expressing and non-expressing cells with phorbol 12-myristate 13-acetate (PMA), the previous microarray analysis showed that IL-13Rα2 and IL-13 mRNA expression were significantly decreased by IL-32θ. The protein expression of these factors was also confirmed to be down-regulated. The nuclear translocation of transcription factors STAT3 and STAT6, which are necessary for IL-13Rα2 and IL-13 promoter activities, was suppressed by IL-32θ. Additionally, a direct association was found between IL-32θ, PKCδ, and signal transducer and activator of transcription 3 (STAT3), but not STAT6, revealing that IL-32θ might act mainly through STAT3 and indirectly affect STAT6. Moreover, the interaction of IL-32θ with STAT3 requires PKCδ, since blocking PKCδ activity eliminated the interaction and consequently limited the inhibitory effect of IL-32θ on STAT3 activity. Interfering with STAT3 or STAT6 binding by decoy oligodeoxynucleotides (ODNs) identified that IL-32θ had additive effects with the STAT3 decoy ODN to suppress IL-13 and IL-13Rα2 mRNA expression. Taken together, our data demonstrate the intracellular interaction of IL-32θ, PKCδ, and STAT3 to regulate IL-13 and IL-13Rα2 synthesis, supporting the role of IL-32θ as an inflammatory modulator. Full article

Hepatic fibrosis is the wound-healing process of chronic hepatic disease that leads to the end-stage of hepatocellular carcinoma and demolition of hepatic structures. Epithelial–mesenchymal transition (EMT) has been identified to phenotypic conversion of the epithelium to mesenchymal phenotype that occurred during fibrosis. Smad decoy oligodeoxynucleotide (ODN) is a synthetic DNA fragment containing a complementary sequence of Smad transcription factor. Thus, this study evaluated the antifibrotic effects of Smad decoy ODN on carbon tetrachloride (CCl₄)-induced hepatic fibrosis in mice. As shown in histological results, CCl₄ treatment triggered hepatic fibrosis and increased Smad expression. On the contrary, Smad decoy ODN administration suppressed fibrogenesis and EMT process. The expression of Smad signaling and EMT-associated protein was markedly decreased in Smad decoy ODN-treated mice compared with CCl₄-injured mice. In conclusion, these data indicate the practicability of Smad decoy ODN administration for preventing hepatic fibrosis and EMT processes. Full article

Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of proteins that promote cellular proliferation and survival. Previous studies have demonstrated antitumor activity of CS3D in preclinical models of solid tumors. However, prior to entering human clinical trials, the efficiency of generating the CS3D molecule and its stability in biological fluids should be determined. CS3D is synthesized as a single-stranded ODN and must have its free ends ligated to generate the final cyclic form. In this study, we report a ligation efficiency of nearly 95 percent. The ligated CS3D demonstrated a half-life of 7.9 h in human serum, indicating adequate stability for intravenous delivery. These results provide requisite biochemical characterization of CS3D that will inform upcoming clinical trials. Full article