The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis

Alveolar bone is a unique osseous tissue due to the proximity of dental plaque biofilms. Periodontal health and homeostasis are mediated by a balanced host immune response to these polymicrobial biofilms. Dysbiotic shifts within dental plaque biofilms can drive a proinflammatory immune response state in the periodontal epithelial and gingival connective tissues, which leads to paracrine signaling to subjacent bone cells. Sustained chronic periodontal inflammation disrupts "coupled" osteoclast-osteoblast actions, which ultimately result in alveolar bone destruction. This chapter will provide an overview of alveolar bone physiology and will highlight why the oral microbiota is a critical regulator of alveolar bone remodeling. The ecology of dental plaque biofilms will be discussed in the context that periodontitis is a polymicrobial disruption of host homeostasis. The pathogenesis of periodontal bone loss will be explained from both a historical and current perspective, providing the opportunity to revisit the role of fibrosis in alveolar bone destruction. Periodontal immune cell interactions with bone cells will be reviewed based on our current understanding of osteoimmunological mechanisms influencing alveolar bone remodeling. Lastly, probiotic and prebiotic interventions in the oral microbiota will be evaluated as potential noninvasive therapies to support alveolar bone homeostasis and prevent periodontal bone loss.

Maintaining homeostatic control of periodontal bone tissue.

The protective effect of tetrahedral framework nucleic acids on periodontium under inflammatory conditions.

Palmitic acid (PA) is the most common saturated long-chain fatty acid in food that causes cell apoptosis However, little is known about the molecular mechanisms of PA toxicity In this study, we explore the effects of PA on proliferation and apoptosis in human osteoblast-like Saos-2 cells and uncover the signaling pathways involved in the process Our study showed that endoplasmic reticulum (ER) stress and autophagy are involved in PA-induced Saos-2 cell apoptosis We found that PA inhibited the viability of Saos-2 cells in a dose- and time-dependent manner At the same time, PA induced the expression of ER stress marker genes (glucose-regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)), altered autophagy-related gene expression (microtubule-associated protein 1 light chain 3 (LC3), ATG5, p62, and Beclin), promoted apoptosis-related gene expression (Caspase 3 and BAX), and affected autophagic flux Inhibiting ER stress with 4-PBA diminished the PA-induced cell apoptosis, activated autophagy, and increased the expression of Caspase 3 and BAX Inhibiting autophagy with 3-MA attenuated the PA and ER stress-induced cell apoptosis and the apoptosis-related gene expression (Caspase 3 and BAX), but seemed to have no obvious effects on ER stress, although the CHOP expression was downregulated Taken together, our results suggest that PA-induced Saos-2 cell apoptosis is activated via ER stress and autophagy, and the activation of autophagy depends on the ER stress during this process

/pdf/palmitic-acid-induces-human-osteoblast-like-saos-2-cell-1193xfmo5g.pdf

Palmitic acid induces human osteoblast-like Saos-2 cell apoptosis via endoplasmic reticulum stress and autophagy.

The endoplasmic reticulum is responsible for much of a cell's protein synthesis and folding, but it also has an important role in sensing cellular stress. Recently, it has been shown that the endoplasmic reticulum mediates a specific set of intracellular signalling pathways in response to the accumulation of unfolded or misfolded proteins, and these pathways are collectively known as the unfolded-protein response. New observations suggest that the unfolded-protein response can initiate inflammation, and the coupling of these responses in specialized cells and tissues is now thought to be fundamental in the pathogenesis of inflammatory diseases. The knowledge gained from this emerging field will aid in the development of therapies for modulating cellular stress and inflammation.

From endoplasmic reticulum stress to the inflammatory response.

Background and Objective
Endoplasmic reticulum (ER) stress is the cell response that activates the unfolded protein response (UPR) pathway in a variety of conditions, such as inflammation and bone metabolism. The UPR may be associated with the pathogenesis of periodontal disease because the disease is inflammatory in nature, and alveolar bone resorption is a characteristic feature of the disease. However, the relationship between ER stress and alveolar bone resorption observed in periodontal disease remains elusive.

Material and Methods
C57BL/6 mice were orally administered Porphyromonas gingivalis, a representative periodontopathic bacterium, in the presence or absence of a chemical chaperone, 4-phenylbutyrate (4-PBA). The gene expression of UPR-related molecules and cytokines in gingival tissues were analyzed using real-time polymerase chain reaction, and alveolar bone resorption and osteoclast numbers were evaluated histologically. The in vitro effect of 4-PBA on the differentiation of mouse bone marrow cells induced by receptor activator of nuclear factor-κB ligand in the presence of macrophage colony-stimulating factor was analyzed.

Results
The gene expression levels of UPR-related molecules and proinflammatory cytokines and alveolar bone resorption were significantly increased in P. gingivalis-administered mice. UPR-related gene expression and alveolar bone resorption were significantly suppressed by the administration of 4-PBA. However, no effect of 4-PBA was observed for proinflammatory cytokine expression in gingival tissues. Osteoclastic differentiation of bone marrow cells was also suppressed by 4-PBA with a concomitant reduction in the gene expression of cathepsin K and tartrate-resistant alkaline phosphatase genes.

Conclusion
ER stress induced by oral administration of P. gingivalis is involved in alveolar bone resorption independent of inflammatory cytokines in mice.

Endoplasmic reticulum stress response and bone loss in experimental periodontitis in mice.

Background and Objective

T and B cells are known to be involved in the disease process of periodontitis However, the role of natural killer T cells in the pathogenesis of periodontitis has not been clarified



Materials and Methods

To examine the role of these cells, C57BL/6J (wild-type), CD1d−/− and α-galactosylceramide (αGC)-stimulated wild-type mice were orally infected with Porphyromonas gingivalis strain W83



Results

Apart from CD1d−/− mice, the level of alveolar bone resorption was elevated by the infection and was further accelerated in αGC-stimulated mice The infection induced elevated levels of serum amyloid A and P gingivalis-specific IgG in the sera, although the degree of elevation was much smaller in the CD1d−/− mice Infection-induced RANKL elevation was only observed in αGC-stimulated mice Although the cytokines produced by splenocytes were mainly T-helper 1 type in wild-type mice, those in αGC-stimulated mice were predominantly T-helper 2 type In the liver, the infection demonstrated no effect on the gene expression for interferon-γ, interleukin-4 and RANKL except αGC-stimulated mice in which the infection upregulated the gene expressions



Conclusion

This study is the first to show that natural killer T cells upregulated systemic and local inflammatory responses induced by oral infection with P gingivalis, thereby contributing to the progression of alveolar bone resorption

Natural killer T cells mediate alveolar bone resorption and a systemic inflammatory response in response to oral infection of mice with Porphyromonas gingivalis.

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Endoplasmic reticulum stress response and bone loss in experimental periodontitis in mice.

Natural killer T cells mediate alveolar bone resorption and a systemic inflammatory response in response to oral infection of mice with Porphyromonas gingivalis.