The daily rhythm of mammalian energy metabolism is subject to the circadian clock system, which is made up of the molecular clock machinery residing in nearly all cells throughout the body. The clock genes have been revealed not only to form the molecular clock but also to function as a mediator that regulates both circadian and metabolic functions. While the circadian signals generated by clock genes produce metabolic rhythms, clock gene function is tightly coupled to fundamental metabolic processes such as glucose and lipid metabolism. Therefore, defects in the clock genes not only result in the dysregulation of physiological rhythms but also induce metabolic disorders including diabetes and obesity. Among the clock genes, Dec1 (Bhlhe40/Stra13/Sharp2), Dec2 (Bhlhe41/Sharp1), and Bmal1 (Mop3/Arntl) have been shown to be particularly relevant to the regulation of energy metabolism at the cellular, tissue, and organismal levels. This paper reviews our current knowledge of the roles of Dec1, Dec2, and Bmal1 in coordinating the circadian and metabolic pathways.

Objectives: The receptor for advanced glycation end products (RAGE) is a newly recognized factor regulating cancer cell invasion and metastasis. Nevertheless, the involvement of RAGE in the development and progression of oral squamous cell carcinomas has not been elucidated. This study investigated the expression of RAGE in ten oral squamous cell carcinoma cell lines including primary and metastatic cell lines and its association with invasion and metastasis. Methods: Reverse transcriptase-polymerase chain reaction, antisense phosphorothioate (S)-oligodeoxynucleotide assay, preparation of antibody, immunohistochemical staining, immunoblot analysis, migration assay, in vitro invasion assay, and wound-healing assay were used. Results: RAGE protein expression of metastatic cancer cells treated with RAGE antisense S-oligodeoxynucleotide was significantly reduced compared to that of sense S-oligodeoxynucleotide-treated cells. The migration assay showed that invasive activity was significantly reduced in metastatic cancer cells treated with RAGE antisense S-oligodeoxynucleotide. Similarly, during invasion assays, numbers of invading cells were also reduced with the addition of RAGE antisense S-oligodeoxynucleotide-treated cells. A wound-healing assay showed that only a few RAGE antisense S-oligodeoxynucleotide-treated cancer cells migrated into the scraped area, whereas sense S-oligodeoxynucleotide-treated cells showed many budding nests in the scraped area of the metastatic cell lines. Immunohistochemically, oral squamous cell carcinoma cells in the tumour mesenchymal border were often immunopositive, whereas basal cells in the normal mucosa were scarcely positive. Conclusions: These results suggest that RAGE expression appears to be closely associated with the invasiveness of oral squamous cell carcinoma and represents a promising candidate for assessing the future therapeutic potential in treating patients with oral carcinoma.

Periodontitis is caused by overactive osteoclast activity that results in the loss of periodontal supporting tissue and mesenchymal stem cells (MSCs) are essential for periodontal regeneration. However, the hypoxic periodontal microenvironment during periodontitis induces the apoptosis of MSCs. Apoptotic bodies (ABs) are the major product of apoptotic cells and have been attracting increased attention as potential mediators for periodontitis treatment, thus we investigated the effects of ABs derived from MSCs on periodontitis. MSCs were derived from bone marrows of mice and were cultured under hypoxic conditions for 72 h, after which ABs were isolated from the culture supernatant using a multi-filtration system. The results demonstrate that ABs derived from MSCs inhibited osteoclast differentiation and alveolar bone resorption. miRNA array analysis showed that miR-223-3p is highly enriched in those ABs and is critical for their therapeutic effects. Targetscan and luciferase activity results confirmed that Itgb1 is targeted by miR-223-3p, which interferes with the function of osteoclasts. Additionally, DC-STAMP is a key regulator that mediates membrane infusion. ABs and pre-osteoclasts expressed high levels of DC-STAMP on their membranes, which mediates the engulfment of ABs by pre-osteoclasts. ABs with knock-down of DC-STAMP failed to be engulfed by pre-osteoclasts. Collectively, MSC-derived ABs are targeted to be engulfed by pre-osteoclasts via DC-STAMP, which rescued alveolar bone loss by transferring miR-223-3p to osteoclasts, which in turn led to the attenuation of their differentiation and bone resorption. These results suggest that MSC-derived ABs are promising therapeutic agents for the treatment of periodontitis.