Proanthocyanidins Ameliorate LPS-Inhibited Osteogenesis of PDLSCs by Restoring Lysine Lactylation.

Periodontitis is a bacteria-induced inflammatory disease characterized by the progressive destruction of periodontal supporting tissues. Periodontal ligament stem cells (PDLSCs) are capable of differentiating into osteoblasts, which is an important stem cell source for endogenous periodontal tissue regeneration. Lysine lactylation (Kla) is a novel post-translational modification of proteins that is recently thought to be associated with osteogenic differentiation. Here, we found that lactylation levels are reduced both in the periodontal tissue of rats with periodontitis and lipopolysaccharide (LPS)-stimulated human PDLSCs. Proanthocyanidins were able to promote the osteogenesis of inflamed PDLSCs by restoring lactylation levels. Mechanistically, proanthocyanidins increased lactate production and restored the lactylation levels of PDLSCs, which recovered osteogenesis of inflamed PDLSCs via the Wnt/ß-catenin pathway. These results provide evidence on how epigenetic regulation by pharmacological agents influence the osteogenic phenotype of stem cells and the process of periodontal tissue repair. Our current study highlights the valuable potential of natural product proanthocyanidins in the regenerative engineering of periodontal tissues.

Preparation and characterization of hydroxyapatite nanoparticles carrying insulin and gallic acid for insulin oral delivery.

Although nanoparticles carriers for oral delivery of insulin have been researched for many years, this method still fails to solve issues with toxicity, biocompatibility, and degradability in the organism. We therefore developed an innovative conjugation system to solve this problem. Nano hydroxyapatite (HAP) particles were used as the core, then polyethylene glycol (PEG) was wrapped onto the surface of hydroxyapatite, and, finally, insulin (INS) and gallic acid (GA) were conjugated with PEG. PEG functionalized HAP was increased the hydrophilicity of the nanoparticles, also protected them from degradation in the gastrointestinal (GI) tract. Most importantly, the in vivo absorption of nanoparticles in rat small intestines revealed that HAP-PEG-GA-INS was absorbed by the small intestine epithelium. The blood glucose of the type 1 diabetes (T1D) rats that were given intragastrically HAP-PEG-GA-INS showed an obvious downward trend. Overall, we synthesized a safe, non-toxic, and effective oral insulin delivery system.

Controlled release of manganese and magnesium ions by microsphere-encapsulated hydrogel enhances cancer immunotherapy.

Despite the considerable potential of immune checkpoint blockade (ICB) therapy in treating various cancer types, it faces several challenges, of which the constrained objective response rate and relatively short duration of response observed in patients with cancer are the most important. This study introduces an injectable temperature-sensitive hydrogel, Pluronic F-127 (PF-127)@MnCl2/ alginate microspheres (ALG-MS)@MgCl2, that enhances the therapeutic efficacy of programmed cell death-ligand 1 (PD-L1) in cancer cells. The hydrogel material used in this study facilitated the rapid release of a significant amount of manganese ions (Mn2+) and the gradual and sustained release of magnesium ions (Mg2+) within the tumor microenvironment. This staged release profile promotes an immune microenvironment conducive to the cytotoxicity of CD8+ T cells and natural killer cells, thereby enhancing the efficacy of ICB therapy. Furthermore, the PF-127@MnCl2/ALG-MS@MgCl2 composite hydrogel exhibits the ability to convert drug-resistant tumor ("cold tumor") with a low PD-L1 response to a "hot tumor" with a high PD-L1 response. In summary, the PF-127@MnCl2/ALG-MS@MgCl2 hydrogel manipulates the immune microenvironment through the precise discharge of Mg2+ and Mn2+, thus, augmenting the efficacy of ICB therapy.

Cervical Cancer HeLa Cell Autocrine Apoptosis Induced by Coimmobilized IFN-γ plus TNF-α Biomaterials.

Using external methods to induce the death of cancer cells is recognized as one of the main strategies for cancer treatment. Research indicated that TNF-α is frequently used in tumor biotherapy while IFN-γ can directly inhibit tumor cell proliferation. In our study, TNF-α and IFN-γ were coimmobilized on polystyrene material (PSt) or Fe3O4-oleic acid nanoparticles (NPs). Then the structural change of these two proteins can be observed. Meanwhile, the expressions of both TNF-α and IFN-α increased significantly, as determined by gene microarray analysis; however, in the presence of TNF-α plus IFN-α inhibitors, TNF-α and IFN-α did not increase in HeLa cells induced by coimmobilized IFN-γ plus TNF-α. Our results indicate that such change can stimilate HeLa cells to secrete more TNF-α and IFN-α, by which the apoptosis of HeLa cells could be further induced. This study is the first report of autocrine-induced apoptosis of HeLa cells. In addition, we performed ELISA, RT-PCR, flow cytometry, and Western blot analyses, as well as a series of analytical tests at the animal level. our data also indicate that the PSt-coimmobilized IFN-γ plus TNF-α has apparent effects for cancer treatment in vivo, which is of great significance for translation into clinical medicine.

Severity of enterovirus A71 infection in a human SCARB2 knock-in mouse model is dependent on infectious strain and route.

Enterovirus A71 (EV-A71) is a major etiological agent of human hand, foot and mouth disease, and it can cause severe neurological complications. Although several genotypes of EV-A71 strains are prevalent in different regions of the world, the genotype C4 has circulated in mainland China for more than 20 years. The pathogenicity of different EV-A71 clinical isolates varies and needs to be explored. In this study, hSCARB2 knock-in mice (N = 181) with a wide range of ages were tested for their susceptibility to two EV-A71 strains with the subgenotypes C4 and C2, and two infection routes (intracranial and venous) were compared. The clinical manifestations and pathology and their relationship to the measured viral loads in different tissues were monitored. We observed that 3 weeks is a crucial age, as mice younger than 3-week-old that were infected became extremely ill. However, mice older than 3 weeks displayed diverse clinical symptoms. Significant differences were observed in the pathogenicity of the two strains with respect to clinical signs, disease incidence, survival rate, and body weight change. We concluded that hSCARB2 knock-in mice are a sensitive model for investigating the clinical outcomes resulting from infection by different EV-A71 strains. The intracranial infection model appears to be suitable for evaluating EV-A71 neurovirulence, whereas the venous infection model is appropriate for studying the pathogenicity of EV-A71.

[Safety and efficacy comparison between rapamycin-eluting stent with biodegradable polymer or permanent polymer in patients with coronary artery disease].

OBJECTIVE: To evaluate the safety and efficacy of rapamycin-eluting stent with biodegradable polymer (EXCEL) or permanent polymer (Cypher) in patients with coronary artery disease (CAD). METHODS: In this prospective, non-random and comparative study, 60 patients with CAD were divided into EXCEL group (n = 32) and Cypher group (n = 28). The coronary angiography (CAG) and stenting procedure were identical. The safety and efficacy of EXCEL stent was evaluated by major adverse cardiac events (MACE), restenosis rate and percent diameter stenosis rate as well as late luminal loss (LLL) at six months post stenting. RESULTS: During follow-up (mean: 6.04 +/- 2.12 months), there was no MACE in the two groups. Quantitative coronary angiography (QCA) data at 6.0 +/- 2.1 months post stenting were available in 27 patients (84.38%) in EXCEL group and 10 patients (35.71%) in Cypher group. Restenosis rate was zero in both groups. Percent diameter stenosis rate (5.98% +/- 5.52% vs. 5.21% +/- 6.3%) and LLL (-0.02 +/- 0.09 mm vs. -0.01 +/- 0.07 mm) were similar between the 2 groups. CONCLUSIONS: EXCEL stent was safe for the treatment of CAD and comparable as Cypher stent in preventing MACE and restenosis at 6 months post stenting.