Lei Wang

Periodontitis is the primary cause of tooth loss in adults and is associated with cardiovascular disorders and type 2 diabetes, etc., significantly impairing patients’ quality of life. Salvia miltiorrhiza(S. miltiorrhiza), a traditional Chinese medicine, possesses properties such as anti-inflammatory and antioxidative effects and has potential in the treatment of periodontitis; however, its mechanism of action remains unclear. The aim of this study was to investigate the therapeutic mechanism of S. miltiorrhiza in periodontitis using an integrated approach combining network pharmacology, molecular docking, molecular dynamics simulations, and experimental validation. The active components and target genes of Salvia miltiorrhiza were collected from the TCMSP and SwissTargetPrediction databases, while the target genes of periodontitis were obtained from the GeneCards, OMIM, Disgenet, and DrugBank databases. The intersection of these targets was identified using jvenn, followed by network visualization using STRING and Cytoscape 3.10.2 software. CytoNCA plug-ins were used to calculate node scores and identify hub genes. The DAVID database was used to conduct Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Molecular docking and molecular dynamics simulation were employed to evaluate the affinity and stability between key active compounds of S.miltiorrhiza and the hub genes. A RAW264.7 cell model induced by Pg-LPS (Porphyromonas gingivalis-lipopolysaccharide) was established. A CCK-8 assay was used to determine the effects of S.miltiorrhiza on the viability of RAW264.7 cells, thereby screening for appropriate drug concentrations. The Griess method was used to test the effect of S. miltiorrhiza on nitric oxide (NO) in cells. The mRNA expression levels of inflammation-related factors were detected by RT-qPCR. A total of 65 compounds from S. miltiorrhiza and 132 corresponding target genes were identified, along with 1900 periodontitis-related target genes. The intersection of these targets revealed 60 common targets. PPI network analysis revealed that S. miltiorrhiza may alleviate periodontitis by modulating key genes, including IL-6, BCL2, STAT3, TNF, TP53, CASP3, and MMP9. Molecular docking indicated strong binding affinities between the bioactive compounds in S. miltiorrhiza and these critical targets. Functional enrichment analysis suggested that the anti-inflammatory action of S. miltiorrhiza in periodontitis may involve the regulation of pathways such as AGE-RAGE, TNF and PI3k/AKT1 pathways. The results of cell experiments revealed that S. miltiorrhiza could treat and prevent periodontitis by inhibiting NO production and regulating the mRNA expression of inflammatory factors, including IL-1β, TNF, IL-6, and IL-10. S. miltiorrhiza exerts therapeutic effects on periodontitis via multiple components, targets and pathways, which provides a sufficient theoretical and practical basis for the further study of S. miltiorrhiza in the treatment of periodontitis.

Purpose: In a previous study, we found that oligodeoxynucleotide (ODN) YW002 could induce the activity of alkaline phosphatase of early osteogenesis in human periodontal membrane stem cells, and downregulate the synthesis of nitric oxide in RAW 264.7 cells in the late inflammatory stage, laying the experimental foundation for the subsequent application of ODN YW002 in periodontitis. However, free ODN does not easily adhere to cells and is easily hydrolyzed by nuclease, so the immune effect of ODN is greatly reduced. Therefore, the nano-drug delivery system provides a method for efficient delivery and uptake of ODN. Methods: We synthesized a polyethyleneimine (PEI) modified chondroitin sulfate (CS) derivative (PEI-CS) via Michael addition to deliver ODN YW002. We aimed to evaluate whether PEI-CS could effectively deliver YW002 to RAW 264.7 cells and if it can regulate inflammation in vitro. PEI-CS/YW002 nanocomplexes were locally injected into a mouse periodontitis model, and the therapeutic effects were evaluated by microcomputed tomography (micro-CT) and hematoxylin–eosin (H&E) staining. Results: The results indicated that PEI-CS had good biocompatibility and could form a stable nanocomplex with YW002 at a mass ratio of 4 : 1. Moreover, PEI-CS could deliver YW002 into RAW 246.7 cells and markedly decreased the expression levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α. Histological evaluation and micro-CT scanning showed that PEI-CS/YW002 nanocomplexes effectively inhibited periodontitis and reduced alveolar bone resorption in mice. Conclusion: Our study has underscored the potential of PEI-CS/YW002 nanocomplexes as promising agents for the prevention and treatment of periodontitis due to their potent anti-inflammatory effects.

In the original publication, there was a mistake in Figure 3 as published

Objective: This study aimed to investigate the regulatory effect of N-isopropylacrylamide-modified polyethyleneimine (PEN)-delivered oligodeoxynucleotide (ODN) MT01 on bone regeneration in vitro and in vivo.Methods: A polyethylenimine (PEI) derivative, PEN, was constructed through Michael addition and employed as a carrier for ODN MT01 transfection. PEN/MT01 nanocomposites were characterized using agarose gel retardation assay, size distribution, zeta potential and transmission electron microscopy. The Cell Counting Kit-8 (CCK-8) assay was used to detect the effect of PEN on cell viability. Alkaline phosphatase (ALP) staining was used to detect the osteogenic differentiation ability of PEN/MT01 nanocomposite. Real-time quantitative PCR (q RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the regulatory effects of PEN/MT01 nanocomposite on osteogenic differentiation gene expression. Rat model was observed using the skull defect method and verified using micro-computed tomography (CT), serum biochemical indices, hematoxylin and eosin (H&E) staining and Immunohistochemistry (IHC).Results: PEN had good biological properties and could deliver MT01 well to achieve efficient transmission of MT01. PEN/MT01 nanocomposites were effectively transfected into MC3T3-E1 cells at a ratio of 6.0. CCK-8 assay displayed that PEN had no cytotoxicity to MC3T3-E1 cells. Additionally, PEN/MT01 nanocomposites could promote the expression of osteogenic genes. In vivo results revealed that PEN/MT01 nanocomposites could promote bone regeneration more effectively than the other groups.Conclusion: PEN has good biocompatibility and low toxicity, which is a good carrier for ODN MT01. PEN-delivered MT01 can be potentially employed as a useful approach to achieving bone regeneration.

Periodontitis is a long-term inflammatory illness and a leading contributor to tooth loss in humans. Due to the influence of the anatomic parameters of teeth, such as root bifurcation lesions and the depth of the periodontal pocket, basic periodontal treatment on its own often does not completely obliterate flora microorganisms. As a consequence, topical medication has become a significant supplement in the treatment of chronic periodontitis. Berberine (BBR) has various pharmacological effects, such as hypoglycemic, antitumor, antiarrhythmic, anti-inflammatory, etc. The target of our project is to develop a safe and non-toxic carrier that can effectively release berberine, which can significantly reduce periodontal tissue inflammation, and to investigate whether berberine thermosensitive hydrogel can exert anti-inflammatory and osteogenic effects by modulating phosphatifylinositol-3-kinase/Protein Kinase B (PI3K/AKT) signaling pathway. Consequently, firstly berberine temperature-sensitive hydrogel was prepared, and its characterizations showed that the mixed solution gelated within 3 min under 37 °C with a hole diameter of 10–130 µm, and the accumulation of berberine release amounted to 89.99% at 21 days. CCK-8 and live-dead cell staining results indicated that this hydrogel was not biotoxic, and it is also presumed that the optimum concentration of berberine is 5 µM, which was selected for subsequent experiments. Real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB)results demonstrated that inflammatory factors, as well as protein levels, were significantly reduced in the berberine-loaded hydrogel group, and LY294002 (PI3K inhibitor) could enhance this effect (p < 0.05). In the berberine-loaded hydrogel group, osteogenesis-related factor levels and protein profiles were visibly increased, along with an increase in alkaline phosphatase expression, which was inhibited by LY294002 (p < 0.05). Therefore, berberine thermosensitive hydrogel may be an effective treatment for periodontitis, and it may exert anti-inflammatory and osteogenic effects through the PI3K/AKT signaling pathway.

Periodontitis is a chronic inflammatory disease that is considered to be the main cause of adult tooth loss. Diabetes mellitus (DM) has a bidirectional relationship with periodontitis. Interleukin-1β (IL-1β) is an important pre-inflammatory factor, which participates in the pathophysiological process of periodontitis and diabetes. The interleukin-1 receptor antagonist (IL-1ra) is a natural inhibitor of IL-1, and the balance between IL-1ra and IL-1β is one of the main factors affecting chronic periodontitis (CP) and diabetes. The purpose of this study is to develop a drug carrier that is safe and nontoxic and can effectively release IL-1ra, which can effectively slow down the inflammation of periodontal tissues with diabetes, and explore the possibility of lowering the blood sugar of this drug carrier. Therefore, in this experiment, a temperature-sensitive hydrogel loaded with IL-1ra was prepared and characterized, and its anti-inflammatory effect in high-sugar environments in vivo and in vitro was evaluated. The results showed that the hydrogel could gel after 5 min at 37 °C, the pore size was 5–70 μm, and the cumulative release of IL-1ra reached 83.23% on the 21st day. Real-time polymerase chain reaction (qRT-PCR) showed that the expression of IL-1β, Interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) inflammatory factors decreased after the treatment with IL-1ra-loaded thermosensitive hydrogel. Histological evaluation and micro-computed tomography (Micro-CT) showed that IL-1ra-loaded thermosensitive hydrogel could effectively inhibit periodontal inflammation and reduce alveolar bone absorption in rats with diabetic periodontitis. It is worth mentioning that this hydrogel also plays a role in relieving hyperglycemia. Therefore, the temperature-sensitive hydrogel loaded with IL-1ra may be an effective method to treat periodontitis with diabetes.

Periodontitis is a chronic infectious disease, the course and progression of which are determined by the interaction between microorganisms and the host. Interleukin 1β plays an important role in the destruction of periodontal tissues. Interleukin 1 receptor antagonist (IL-1ra) can inhibit the biological activity of IL-1β without triggering any intracellular signaling. This study aimed to prepare IL-1ra-loaded dextran/PLGA microspheres and evaluate the physical and chemical characteristics and anti-inflammatory properties. Results suggested that the microspheres can be easily prepared into a drug carrier with good biocompatibility and can effectively inhibit the gene expression of pro-inflammatory factors induced by IL-1β in human gingival fibroblasts. Hence, the microspheres are excellent candidate for periodontitis treatment.