Cubic liquid crystals containing propolis flavonoids as in situ thermo-sensitive hydrogel depots for periodontitis treatment: Preparation, pharmacodynamics and therapeutic mechanisms.

Propolis has a long ethnopharmacological history for oral periodontal diseases treatment. Propolis flavonoids are main active components for anti-inflammation and tissue protection. However, the intractable dissolution properties of propolis flavonoids and complex oral environment pose great challenges for periodontal delivery. In addition, the therapeutic mechanism as well as the therapeutic correlation of inflammation resolution and tissue regeneration remain unclear for propolis flavonoids. In this study, we constructed an in situ thermosensitive depot systems using total flavonoids from propolis-loaded cubic liquid crystals (TFP-CLC) hydrogel for periodontal delivery. TFP-CLC inhibited inflammatory cell infiltration, reactive oxygen species and the expression of inflammatory cytokines of NF-κB and IL-1ß. In addition, alveolar bone and collagen were significantly regenerated after TFP-CLC administration according to micro-CT and immunohistochemistry. Mechanism studies suggested that TFP-CLC alleviated inflammation and promoted alveolar bone repair via regulating TLR4/MyD88/NF-κB p65 and RANK/NF-κB signaling pathways, respectively. Correlation analysis further confirmed that the inflammatory resolution produced by TFP-CLC could accelerate periodontal tissue regeneration. In summary, TFP-CLC is a promising multifunctional in situ thermo-sensitive hydrogel depots for periodontitis treatment.

Amelioration of obesity and inflammation by polysaccharide from unripe fruits of raspberry via gut microbiota regulation.

Raspberry, a traditional medicine food homology species, has important benefits in patients with metabolic syndrome. However, the mechanism of raspberry polysaccharides (RP) on obesity remains unclear. In our study, we showed that RP intervention is negatively associated with body weight gain, hyperlipidemia, inflammation, and fat accumulation in obese mice. RP ameliorated HFD-induced gut microbiota dysbiosis, produced short-chain fatty acids, maintained intestinal barrier integrity, and prevented metabolic endotoxemia, manifested by decreased host lipopolysaccharide level, and increased colon expression of tight junction proteins. These effects might be related with driven by a SCFAs-producing bacterium and downregulation of TLR4/NF-κB signaling transduction. Notably, the abundance of Ruminococcaceae_UCG - 014, Lactobacillus taiwanensis, Bifidobacterium pseudolongum, and Turicibacter are markedly correlated with enhanced intestinal barrier function induced by RP treatment. Thus, we believe that RP could be as a potential health supplement or prebiotic for obesity therapy.

Flavonoid extract from propolis alleviates periodontitis by boosting periodontium regeneration and inflammation resolution via regulating TLR4/MyD88/NF-κB and RANK/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine, propolis has been used for treating oral diseases for centuries, widely. Flavonoid extract is the main active ingredient in propolis, which has attracted extensive attention in recent years. AIM OF THE STUDY: The objective and novelty of the current study aims to identify the mechanism of total flavonoid extract of propolis (TFP) for the treatment of periodontitis, and evaluate the therapeutic effect of TFP-loaded liquid crystal hydrogel (TFP-LLC) in rats with periodontitis. METHODS: In this study, we used lipopolysaccharide-stimulated periodontal ligament stem cells (PDLSCs) to construct in vitro inflammation model, and investigated the anti-inflammatory effect of TFP by expression levels of inflammatory factors. Osteogenic differentiation was assessed using alkaline phosphatase activity and alizarin red staining. Meanwhile, the expression of toll like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor-kappa B (NF-κB), receptor activator of NF-κB (RANK) etc, were quantitated to investigate the therapeutic mechanism of TFP. Finally, we constructed TFP-LLC using a self-emulsification method and administered it to rats with periodontitis via periodontal pocket injection to evaluate the therapeutic effects. The therapeutic index, microcomputed tomography (Micro-CT), H&E staining, TRAP staining, and Masson staining were used for this evaluation. RESULTS: TFP reduced the expression of TLR4, MyD88, NF-κB and inflammatory factor in lipopolysaccharide-stimulated PDLSCs. Meanwhile, TFP simultaneously regulating alkaline phosphatase, RANK, runt-associated transcription factor-2 and matrix metalloproteinase production to accelerate osteogenic differentiation and collagen secretion. In addition, TFP-LLC can stably anchor to the periodontal lesion site and sustainably release TFP. After four weeks of treatment with TFP-LLC, we observed a decrease in the levels of NF-κB and interleukin-1ß (IL-1ß) in the periodontal tissues of rats, as well as a significant reduction in inflammation in HE staining. Similarly, Micro CT results showed that TFP-LLC could significantly inhibit alveolar bone resorption, increase bone mineral density (BMD) and reduce trabecular bone space (Tb.Sp) in rats with periodontitis. CONCLUSION: Collectively, we have firstly verified the therapeutic effects and mechanisms of TFP in PDLSCs for periodontitis treatment. Our results indicate that TFP perform anti-inflammatory and tissue repair activities through TLR4/MyD88/NF-κB and RANK/NF-κB pathways in PDLSCs. Meanwhile, for the first time, we employed LLC delivery system to load TFP for periodontitis treatment. The results showed that TFP-LLC could be effectively retained in the periodontal pocket and exerted a crucial role in inflammation resolution and periodontal tissue regeneration.

Sorafenib-Loaded PLGA-TPGS Nanosystems Enhance Hepatocellular Carcinoma Therapy Through Reversing P-Glycoprotein-Mediated Multidrug Resistance.

Multidrug resistance (MDR) is a key determinant for hepatocellular carcinoma chemotherapy failure. P-glycoprotein is one of the main causes of MDR by causing drug efflux in tumor cells. In order to solve this thorny problem, we prepared a sorafenib-loaded polylactic acid-glycolic acid (PLGA) - D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) nanoparticles (SPTNs). SPTNs were successfully synthesized through an ultrasonic emulsion solvent evaporation method with a favourable encapsulation efficiency of 90.35%. SPTNs were almost spherical in shape with uniform particle size (215.70 ± 0.36 nm), narrow polydispersity index (0.27 ± 0.02) and negative surface charge (-26.01 ± 0.65 mV). In the cellular uptake assay, the intracellular coumarin-6 (C6) fluorescence of TPGS component-based PLGA nanoparticles (C6-PTNs) was 1.63-fold higher relative to that of PVA component-based PLGA nanoparticles (C6-PVNs). The half-maximal inhibitory concentration and apoptosis ratio of SPTNs against HepG2/MDR cells were 3.90 µM and 75.62%, respectively, which were notably higher than free SF and sorafenib-PLGA-PVA nanoparticles (SPVNs). The anti-drug efflux activities of SPTNs were assessed by the intracellular trafficking assay using verapamil as a P-gp inhibitor. SPTNs could effectively inhibit the drug efflux in tumor cells detected by flow cytometry, and suppressed relative MDR1 gene as well as P-glycoprotein expression in tumor cells. Attributed to the MDR reversion effect of SPTNs, the in vivo antitumor efficacy experiment showed that SPTNs significantly inhibited the tumor growth of HepG2/MDR xenograft-bearing nude mice, and obviously reduced the toxicity against liver and kidney compared with SF treatment. In summary, SPTNs, as highly efficient and safe antitumor nano delivery systems, showed promising potential for hepatocellular carcinoma therapy through reversing P-glycoprotein-mediated MDR. Graphical Abstract.

Pueraria flavones-loaded bile salt liposomes with improved intestinal absorption and oral bioavailability: in vitro and in vivo evaluation.

Pueraria flavone (PF), the main component of Pueraria lobata, is a traditional Chinese medicine used for the treatment of cardiovascular and cerebrovascular diseases; however, it exhibits low oral bioavailability because of its poor membrane permeability. In this study, PF-loaded sodium deoxycholate-decorated liposomes (SDC-Lips) were prepared using the reverse-phase evaporation method and optimised using the Box-Behnken design method. The morphology, particle size, zeta potential, and entrapment efficiency of these PF-loaded SDC-Lips were evaluated. The release behaviours of PF-loaded SDC-Lips in simulated gastric and intestinal fluids were consistent with the Weibull kinetic model. In situ intestinal perfusion studies showed that the absorption characteristics of free PF in rats were mainly passive diffusion and partly active transport, and the duodenum was the main absorption site. After encapsulated with SDC-Lips, the absorption of PF increased significantly. The in vivo pharmacokinetic parameters of area under the plasma concentration-time curve (AUC)(0 → 12 h) and AUC(0 → ∞) of PF-loaded SDC-Lips after intragastric administration were 1.34-fold and 1.543-fold, respectively. Overall, the PF-loaded SDC-Lips improved the oral absorption of PF by increasing its solubility and might be considered a promising formulation strategy for prolonging the biological activity time of PF.