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Xerostomia (dry mouth) is a significant age-related condition. Meanwhile, cordycepin, the natural therapeutic agent, has demonstrated an anti-aging effect. Therefore, the present study aimed to investigate the preventive effects of cordycepin on secretory function in an in vitro model of hydrogen peroxide (H 2 O 2 )-induced salivary hypofunction. After being exposed to H 2 O 2 , human submandibular gland (HSG) cells were treated with various concentrations of cordycepin (6.25-50 µM) for 24, 48, and 72h. To evaluate cell proliferation and reactive oxygen species (ROS) generation, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and 2, 7'-dichlorodihydrofluorescein diacetate assays were performed. The amylase activity was kinetically measured by 2-chloro- p -nitrophenol linked with maltotrioside. The expression of salivary, antioxidant and apoptotic markers at mRNA and protein levels were performed by reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence analysis, respectively. We demonstrated that cordycepin (6.25-25 µM) contributed to significant increases in expression of the salivary marker genes, alpha-amylase 1 (AMY1A) and aquaporin-5 (AQP5), and in amylase secretion without changes in cell viability. Under oxidative stress, HSG cells showed remarkable dysfunction. Cordycepin rescued the protective effects partially by decreasing ROS generation and restoring the expression of the salivary proteins, AMY and AQP5 via anti-oxidant and anti-apoptotic activity. In addition, the amount of amylase that was secreted from HSG cells cultured in cordycepin was increased. In conclusion, cordycepin demonstrated a protective effect on H 2 O 2 - induced HSG cells by decreasing ROS generation and upregulating the salivary function markers, AMY1A and AQP5 , at both the transcriptional and translational levels.

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Human oral squamous carcinoma is considered the most common oral cancer; it imposes multiple oral and dental consequences as a result of oral cancer treatment. We previously found that the nanoencapsulation of cordycepin (CS) could inhibit oral cancer cells. However, the mechanism of action was not understood. The aim of this study was to investigate the signaling pathway by which CS and encapsulated nanoparticles (NPs) activate the inhibition of cancer cell growth. We demonstrated that human oral cancer (HSC-4) cells underwent necroptosis when incubated with high concentrations of CS, but not when incubated with either low concentrations of CS or encapsulated CS NPs. High concentrations of CS-induced necroptosis of HSC-4 cells, demonstrated by a reduction in apoptotic ( BAX, Caspase-3, Caspase-8, and Caspase-9) and autophagic genes ( LC3, Atg5, and Atg12). However, low concentrations of CS significantly induced the expression of autophagic gene LC3. Interestingly, encapsulated CS NPs induced a significant increase in apoptotic genes ( P53, BAX, Caspase-3, Caspase-8, and Caspase-9), but a significant decrease in autophagic ( P62, Atg5, and Atg12) and necroptotic genes ( receptor-interacting serine/threonine-protein kinase 3 [RIPK3]) . We also found that encapsulated CS NPs enhanced the accumulation of cellular protein and decreased secreted supernatant protein levels. Moreover, encapsulated CS NPs had higher efficacy in terms of reactive oxygen species (ROS) generation-mediated inhibition of autophagy compared to nonencapsulated CS, suggesting that nanoencapsulation of CS can switch the program of HSC-4 cell death from necroptosis to apoptosis. In conclusion, HSC-4 cells have a defense strategy against CS-induced cell apoptosis, but this problem can be solved through the use of encapsulation combined with nanotechnology.

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