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We sought to investigate the impact of CpG oligodeoxynucleotides (CpG-ODN) administration on the lung and gut microbiota in asthmatic mice, specifically focusing on changes in composition, diversity, and abundance, and to elucidate the microbial mechanisms underlying the therapeutic effects of CpG-ODN and identify potential beneficial bacteria indicative of its efficacy. HE staining were used to analyze inflammation in lung, colon and small intestine tissues. High-throughput sequencing technology targeting 16S rRNA was employed to analyze the composition, diversity, and correlation of microbiome in the lung, colon and small intestine of control, model and CpG-ODN administration groups. (1) Histopathologically, both lung and intestinal tissue in asthmatic mice exhibited significant structural damage and inflammatory response, whereas the structure of both lung and intestinal tissue approached normal levels, accompanied by a notable improvement in the inflammatory response after CpG-ODN treatment. (2) In the specific microbiota composition analysis, bacterial dysbiosis observed in the asthmatic mice, accompanied by enrichment of Proteobacteria found to cause lung and intestinal epithelial damage and inflammatory reaction. After CpG-ODN administration, bacterial dysbiosis was improved, and a notable enrichment of beneficial bacteria, indicating a novel microecology. Meanwhile Oscillospira and Clostridium were identified as two biomarkers of the CpG-ODN treatment. (3) Heatmap analysis revealed significant correlations among lung, small intestine, and colon microbiota. CpG-ODN treatment can ameliorate OVA-induced asthma in mice. One side, preserving the structural integrity of the lung and intestine, safeguarding the mucosal physical barrier, the other side, improving the dysbiosis of lung and gut microbiota in asthmatic mice. Beneficial bacteria and metabolites take up microecological advantages, regulate immune cells and participate in the mucosal immune response to protect the immune barrier. Meanwhile, Oscillospira and Clostridium as biomarkers for CpG-ODN treatment, has reference significance for exploring precise Fecal microbiota transplantation treatment for asthma.

Unmethylated cytosine-guanine dinucleotide-containing oligodeoxynucleotides (CpG ODNs), which are synthetic agonists of Toll-like receptor 9 (TLR9), activate humoral and cellular immunity and are being developed as vaccine adjuvants to prevent or treat cancers, infectious diseases, and allergies. Free CpG ODNs have been used in many clinical trials implemented to verify their effects. However, recent research has reported that self-assembled CpG ODNs, protein/peptide-CpG ODN conjugates, and nanomaterial-CpG ODN complexes demonstrate higher adjuvant effects than free CpG ODNs, owing to their improved uptake efficiency into cells expressing TLR9. Moreover, protein/peptide-CpG ODN conjugates and nanomaterial-CpG ODN complexes are able to deliver CpG ODNs and antigens (or allergens) to the same types of cells, which enables a higher degree of prophylaxis or therapeutic effect. In this review, the author describes recent trends in the research and development of CpG ODN nanomedicines containing self-assembled CpG ODNs, protein/peptide-CpG ODN conjugates, and nanomaterial-CpG ODN complexes, focusing mainly on the results of preclinical and clinical studies.

Inhibitory oligodeoxynucleotides (ODNs) are short single-stranded DNA, which capable of folding into complex structures, enabling them to bind to a large variety of targets. With appropriate modifications, the inhibitory oligodeoxynucleotides exhibited many features of long half-life time, simple production, low toxicity and immunogenicity. In recent years, inhibitory oligodeoxynucleotides have received considerable attention for their potential therapeutic applications in immune-mediated inflammatory diseases (IMIDs). Inhibitory oligodeoxynucleotides could be divided into three categories according to its mechanisms and targets, including antisense ODNs (AS-ODNs), DNA aptamers and immunosuppressive ODNs (iSup ODNs). As a synthetic tool with immunomodulatory activity, it can target RNAs or proteins in a specific way, resulting in the reduction, increase or recovery of protein expression, and then regulate the state of immune activation. More importantly, inhibitory oligodeoxynucleotides have been used to treat immune-mediated inflammatory diseases, including inflammatory disorders and autoimmune diseases. Several inhibitory oligodeoxynucleotide drugs have been developed and approved on the market already. These drugs vary in their chemical structures, action mechanisms and cellular targets, but all of them could be capable of inhibiting excessive inflammatory responses. This review summarized their chemical modifications, action mechanisms and applications of the three kinds of inhibitory oligodeoxynucleotidesin the precise treatment of immune-mediated inflammatory diseases.

Synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs trigger cells that express Toll-like receptor 9 (including human plasmacytoid dendritic cells and B cells) to mount an innate immune response characterized by the production of Th1 and proinflammatory cytokines. When used as vaccine adjuvants, CpG ODNs improve the function of professional antigen-presenting cells and boost the generation of humoral and cellular vaccine-specific immune responses. These effects are optimized by maintaining ODNs and vaccine in close proximity. The adjuvant properties of CpG ODNs are observed when administered either systemically or mucosally, and persist in immunocompromised hosts. Preclinical studies indicate that CpG ODNs improve the activity of vaccines targeting infectious diseases and cancer. Clinical trials demonstrate that CpG ODNs have a good safety profile and increase the immunogenicity of coadministered vaccines.

Necrotic enteritis (NE), caused by Clostridium perfringens (C. perfringens), presents a challenge to the global broiler industry. Evidence suggests that Toll-like receptor (TLR) ligands can enhance the immune responses in chickens and protect them against infectious diseases. This study investigated the protective effects of TLR21 ligand class B CpG oligonucleotides (ODN) against NE in broiler chickens. On day 21 of age, chickens were injected with 50 or 100 [mu]g CpG intramuscularly, and one group was injected with 50 [mu]g CpG followed by a booster dose on day 22. Subsequently, birds were orally challenged with C. perfringens twice daily for three days, starting on day 22. On day 22, intestinal samples were collected for gene expression analysis. On day 25, all birds were euthanized, intestinal lesions were scored, and tissue samples were collected from the intestine for gene expression analysis, lymphocyte subset determination, and histomorphological analysis. Cecal contents were also collected for microbiome analysis. The results demonstrated that CpG pre-treatment, either at a single dose of 100 [mu]g or two doses of 50 [mu]g per bird, reduced lesion scores compared to the positive control. C. perfringens infection increased crypt depth in both the jejunum and ileum in the positive control group compared to both the CpG-treated group. At 22 days of age, CpG administration at doses of 100 [mu]g per bird enhanced expression of TLR21, interleukin (IL)-2, CXCL8, IL-10, and interferon (IFN)-[gamma] mRNA transcripts in both the jejunum and ileum. Additionally, at 25 days of age, the group pretreated with two doses of 50 [mu]g of CpG per bird showed increased expression of all cytokines in both the jejunum and ileum compared to the control groups. The percentage of intestinal lymphocytes was not affected by CpG pre-treatment. However, CpG pretreatment at doses of 100 [mu]g resulted in a higher abundance of the members of families Lactobacillaceae and Bacteroidaceae, which are crucial for maintaining gut health. In conclusion, our findings suggest that pretreatment of chickens with intramuscular administration of CpG may be effective in maintaining gut health during C. perfringens infection.

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.

Background Precise genome editing is essential for both basic and translational research. The recently developed CRISPR/Cas9 system can specifically cleave a designated site of target gene to create a DNA double-strand break, which triggers cellular DNA repair mechanism of either inaccurate non-homologous end joining, or site-specific homologous recombination. Unfortunately, homology-directed repair (HDR) is challenging due to its very low efficiency. Herein, we focused on improving the efficiency of HDR using a combination of CRISPR/Cas9, eGFP, DNA ligase IV inhibitor SCR7, and single-stranded oligodeoxynucleotides (ssODN) in human cancer cells. Results When Cas9, gRNA and eGFP were assembled into a co-expression vector, the disruption rate more than doubled following GFP-positive cell sorting in transfected cells compared to those unsorted cells. Using ssODNs as templates, SCR7 treatment increased targeted insertion efficiency threefold in transfected cells compared to those without SCR7 treatment. Moreover, this combinatorial approach greatly improved the efficiency of HDR and targeted gene mutation correction at both the GFP-silent mutation and the β-catenin Ser45 deletion mutation cells. Conclusion The data of this study suggests that a combination of co-expression vector, ssODN, and ligase IV inhibitor can markedly improve the CRISPR/Cas9-directed gene editing, which should have significant application in targeted gene editing and genetic disease therapy.

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.

Background Cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) (K3)—a novel synthetic single-stranded DNA immune adjuvant for cancer immunotherapy—induces a potential Th1-type immune response against cancer cells. We conducted a phase I study of CpG ODN (K3) in patients with lung cancer to assess its safety and patients’ immune responses. Methods The primary endpoint was the proportion of dose-limiting toxicities (DLTs) at each dose level. Secondary endpoints included safety profile, an immune response, including dynamic changes in immune cell and cytokine production, and progression-free survival (PFS). In a 3 + 3 dose-escalation design, the dosage levels for CpG ODN (K3) were 5 or 10 mg/body via subcutaneous injection and 0.2 mg/kg via intravenous administration on days 1, 8, 15, and 29. Results Nine patients (eight non-small-cell lung cancer; one small-cell lung cancer) were enrolled. We found no DLTs at any dose level and observed no serious treatment-related adverse events. The median observation period after registration was 55 days (range: 46–181 days). Serum IFN-α2 levels, but not inflammatory cytokines, increased in six patients after the third administration of CpG ODN (K3) (mean value: from 2.67 pg/mL to 3.61 pg/mL after 24 hours). Serum IFN-γ (mean value, from 9.07 pg/mL to 12.7 pg/m after 24 hours) and CXCL10 levels (mean value, from 351 pg/mL to 676 pg/mL after 24 hours) also increased in eight patients after the third administration. During the treatment course, the percentage of T-bet-expressing CD8 + T cells gradually increased (mean, 49.8% at baseline and 59.1% at day 29, p  = 0.0273). Interestingly, both T-bet-expressing effector memory (mean, 52.7% at baseline and 63.7% at day 29, p  = 0.0195) and terminally differentiated effector memory (mean, 82.3% at baseline and 90.0% at day 29, p  = 0.0039) CD8 + T cells significantly increased. The median PFS was 398 days. Conclusions This is the first clinical study showing that CpG ODN (K3) activated innate immunity and elicited Th1-type adaptive immune response and cytotoxic activity in cancer patients. CpG ODN (K3) was well tolerated at the dose settings tested, although the maximum tolerated dose was not determined. Trial registration UMIN-CTR number 000023276. Registered 1 September 2016, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000026649