Oral cancer is one of the most common cancers worldwide, with high mortality rates. According to the International Agency for Research on Cancer, there were an estimated 377,000 new cases of lip and oral cavity cancers in 2020, with nearly 177,000 deaths worldwide.¹ Despite advances in oncology therapy, mortality rates for oral cancer remain high over the past few decades. A majority of oral cancer patients do not have access to timely, quality diagnosis, and treatment, especially in rural areas, resulting in poor survival rates. The overall 5-year survival rate of diagnosed oral cancer patients is around 50% and has varied by race and area,² whereas survival rates as high as 65% have been reported in developed countries; in some rural areas, they can be as low as 15% depending on the affected part of the oral cavity. The 2020 Cancer Statistics Report from India estimated that 66.6% of patients suffering from head and neck cancer were diagnosed at the locally advanced stage.³ In short, patient survival rates and prognosis are severely compromised when oral cancer patients are diagnosed at more advanced stages^4,5 so that enhancing early diagnosis could mean a significant rise in positive survival outcomes.^6,7

The production and secretion of saliva is an essential function of the salivary glands. Saliva is a complicated liquid with different functions, including moistening, digestion, mineralization, lubrication, and mucosal protection. This review focuses on the mechanism and neural regulation of salivary secretion, and saliva is secreted in response to various stimuli, including odor, taste, vision, and mastication. The chemical and physical properties of saliva change dynamically during physiological and pathophysiological processes. Moreover, the central nervous system modulates salivary secretion and function via various neurotransmitters and neuroreceptors. Smell, vision, and taste have been investigated for the connection between salivation and brain function. The immune and endocrine functions of the salivary glands have been explored recently. Salivary glands play an essential role in innate and adaptive immunity and protection. Various immune cells such as B cells, T cells, macrophages, and dendritic cells, as well as immunoglobins like IgA and IgG have been found in salivary glands. Evidence supports the synthesis of corticosterone, testosterone, and melatonin in salivary glands. Saliva contains many potential biomarkers derived from epithelial cells, gingival crevicular fluid, and serum. High level of matrix metalloproteinases and cytokines are potential markers for oral carcinoma, infectious disease in the oral cavity, and systemic disease. Further research is required to monitor and predict potential salivary biomarkers for health and disease in clinical practice and precision medicine.

Synovitis is a key factor in temporomandibular joint osteoarthritis (TMJOA) and could be an early sign of the disease. Notably, synovitis and its macrophage component represent a target of interest for developing treatments. Dental pulp stem cells (DPSCs) are derived from the neural crest, coincidentally with maxillofacial tissues, thus attracting significant interest in situ maxillofacial regenerative medicine. However, there is a relative scarcity of studies investigating the role of DPSCs in the temporomandibular joint (TMJ) synovial macrophage. This study aimed to evaluate the regulatory and reparative capabilities of DPSCs on synovitis in TMJOA rat models and to elucidate their specific mechanisms of action on synovial macrophages. In vivo, three groups were established: the control group, which had neither induction nor treatment; the OA group, consisting of rats with OA but without any treatment; and the DPSCs treatment group, where rats with OA received DPSCs therapy. Progressive TMJOA was induced in rats via intra-articular injection of complete Freund’s adjuvant and sodium iodoacetate. After 2 weeks, DPSCs were injected into the joint cavity as a therapeutic intervention. Meanwhile, normal saline was injected into the joints of rats in both the control and OA groups. Four weeks after treatment, histological analysis was performed to evaluate the repair of synovitis. In addition, an in vitro co-culture system, consisting of macrophages and DPSCs. Each group was assessed using techniques, including mRFP-GFP-LC3 lentivirus transfection, Mito-Tracker Red and Lyso-Tracker Green staining, transmission electron microscopy, and Western blot analysis. Furthermore, apoptotic primary neutrophils were co-cultured with polarized macrophages to observe the phagocytic ability of macrophages towards apoptotic primary neutrophils under different treatments in vitro. In the rat model, compared with the OA group, the DPSCs group exhibited reduced cell infiltration and collagen deposition, along with elevated levels of anti-inflammatory CD206 and decreased levels of inflammatory CD86, and enhanced the ability of macrophages to phagocytize apoptotic cells in vivo and in vitro. Notably, DPSCs exhibited enhanced efficacy in upregulating autophagosome expression, promoting co-localization with mitochondria and lysosomes, and modulating the expression of mitochondrial mitophagy proteins. Furthermore, inhibition of mitophagy in M1 macrophages partially attenuated the M2 polarization effect and phagocytosis induced by DPSCs. DPSCs significantly mitigate synovitis in TMJOA rats by enhancing M2 polarization and efferocytic functions of macrophages. This study underscores the potential of DPSCs as a therapeutic strategy for TMJOA by modulating synovial macrophage functions through the regulation of mitophagy.