A declined salivary gland function is commonly observed in elderly people. Advanced glycation end products (AGEs) are believed to contribute to the pathogenesis of aging. Although physical exercise is shown to increase various organ functions in human and experimental models, it is not known whether it has a similar effect in the salivary glands. In the present study, we evaluated the AGEs burden in the salivary gland in the aging process and the protective effect of physical exercise on age-related salivary hypofunction. To accelerate the aging process, rats were peritoneally injected with D-galactose for 6 weeks. Young control rats and d-galactose-induced aging rats in the old group were not exercised. The rats in the physical exercise group ran on a treadmill (12 m/min, 60 min/day, 3 days/week for 6 weeks). The results showed that the salivary flow rate and total protein levels in the saliva of the d-galactose-induced aging rats were reduced compared to those of the young control rats. Circulating AGEs in serum and secreted AGEs in saliva increased with d-galactose-induced aging. AGEs also accumulated in the salivary glands of these aging rats. The salivary gland of aging rats showed increased reactive oxygen species (ROS) generation, loss of acinar cells, and apoptosis compared to young control mice. However, physical exercise suppressed all of these age-related salivary changes. Overall, physical exercise could provide a beneficial option for age-related salivary hypofunction.
Polydatin (resveratrol-3-O-β-mono-D-glucoside) is a polyphenol that can be easily accessed from peanuts, grapes, and red wine, and is known to have antiglycation, antioxidant, and anti-inflammatory effects. Diabetes mellitus is a very common disease, and diabetic complications are very common complications. The dry mouth symptom is one of the most common oral complaints in patients with diabetes mellitus. Diabetes mellitus is thought to promote hyposalivation. In this study, we aimed to investigate the improvement effect of polydatin on diabetes-induced hyposalivation in db/db mouse model of type 2 diabetes. We examined salivary flow rate, TUNEL assay, PAS staining, and immunohistochemical staining for AGEs, RAGE, HMGB1, 8-OHdG, and AQP5 to evaluate the efficacy of polydatin in the submandibular salivary gland. Diabetic db/db mice had a decreased salivary flow rate and salivary gland weight. The salivary gland of the vehicle-treated db/db mice showed an increased apoptotic cell injury. The AGEs were highly accumulated, and its receptor, RAGE expression was also enhanced. Expressions of HMGB1, an oxidative cell damage marker, and 8-OHdG, an oxidative DNA damage marker, increased greatly. However, polydatin ameliorated this hypofunction of the salivary gland and inhibited diabetes-related salivary cell injury. Furthermore, polydatin improved mucin accumulation, which is used as a damage marker for salivary gland acinar cells, and decreased expression of water channel AQP5 was improved by polydatin. In conclusion, polydatin has a potent protective effect on diabetes-related salivary gland hypofunction through its antioxidant and anti-glycation activities, and its AQP5 upregulation. This result suggests the possibility of the use of polydatin as a therapeutic drug to improve hyposalivation caused by diabetes.
Esculetin is an antioxidant and anti-inflammatory compound derived from coumarin. Oxidative stress can cause overproduction of reactive oxygen species (ROS), which can lead to the development of chronic kidney failure. In this study, human embryonic kidney 293 (HEK293) cells were treated with tert-butyl hydroperoxide (t-BHP) to determine the antioxidant effects of esculetin. HEK293 cells were treated with t-BHP to validate changes in cell viability, ROS production, and apoptosis, and then treated with esculetin to evaluate the changes. Changes in mRNA and protein levels were analyzed using a proteome kit, PCR, and Western blotting. Esculetin improved HEK293 cell viability and reduced apoptosis caused by t-BHP-induced oxidative stress. At the mRNA and protein levels, esculetin decreased pro-apoptotic factor expression as well as increased anti-apoptotic factor expression. The antioxidant efficacy of esculetin was validated when it inhibited the apoptosis caused by t-BHP-induced oxidative stress in HEK293 cells.
Esculetin is a natural lactone that is commonly derived from coumarins. According to previous experiments using human cancer cells, esculetin has potent antitumor activity; it also inhibits proliferation and induces the apoptosis of cancer cells. In the present study, the anti-proliferative effect of esculetin on the submandibular salivary gland tumor cell line, A253, was evaluated via in vitro and in vivo analyses. Furthermore, the anti-cancer effects of esculetin in A253 cells and a xenograft model of salivary gland tumors were determined using 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide and TUNEL assay, apoptosis protein array, quantitative polymerase chain reaction and western blot analysis. Esculetin (50-150 µM) was demonstrated to have an anti-proliferative effect in the A253 cell line in vitro; this observed effect was dependent on the dose and duration of treatment. Esculetin also increased the levels of Bax, cleaved caspase-3, cleaved-9 and cleaved poly (ADP-ribose) polymerase apoptosis-related proteins, and decreased the expression levels of the Bcl-2 anti-apoptotic protein. With respect to apoptosis regulation, esculetin significantly decreased the proliferation of tumor cells in a xenograft model (100 mg/kg/day) for 18 days. Overall, esculetin could be a potential oral anticancer drug against salivary gland cancer.
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