The important role of the inorganic nitrate cycle mediated by the oral salivary glands in systemic health

Homeostasis represents a dynamic equilibrium process of self-regulation employed by living organisms, which sustains the relative stability of the internal environment of an organism, thus allowing for the continuation of normal physiological functions under ever-changing external conditions. Through homeostatic regulation, organisms adapt to various physiological stimuli and combat pathogenic factors, thereby enhancing their chances of survival. When the delicate balance of homeostasis is disrupted, a cascade of abnormal changes occurs, manifesting as physical symptoms and behavioural abnormalities, commonly recognised as disease symptoms. Homeostatic medicine, rooted in the maintenance of homeostatic balance, includes a systematic investigation into the laws and mechanisms underlying homeostatic regulation at multiple levels, from the molecular and cellular environments to the organ, whole-body, and external environments. This comprehensive approach aims to promote human health, as well as prevent and treat diseases. Inorganic nitrate is widely present in everyday water and food sources and is essential for the survival of organisms. Its historical significance in various aspects of human life, including diet, medicine, and industry, spans over 2000 years in the records of our country. In recent years, extensive research has been conducted to explore the biological activities of nitrate as a natural dietary nutrient. Within the human body, inorganic nitrate undergoes partial reduction to nitrite and nitric oxide due to the action of oral bacteria in saliva. Nitrite is subsequently absorbed into the bloodstream via the intestinal mucosa, where it further reduces to nitric oxide-a process known as the nitrate-nitrite-NO pathway. This pathway plays a pivotal role in regulating bodily nitric oxide levels, and thus, maintaining overall homeostasis. In addition, sialin is a mammalian membrane nitrate transporter, facilitating the transportation of nitrate to salivary glands, where it is secreted into the oral cavity via saliva. The upregulation of sialin expression enhances nitrate influx into cells, establishing a positive nitratesialin feedback loop that protects salivary glands and other organs. Recent studies have revealed the involvement of sialin in various biological functions, further emphasising its significance in homeostatic regulation. Exogenous nitrate supplementation has demonstrated various beneficial effects on the body, including the regulation of vascular tone, antioxidant properties, improvement of muscle performance, gastrointestinal protection, inhibition of inflammatory factor release, modulation of glucose metabolism, and regulation of intestinal flora. The nitrate-sialin system, as a crucial component in maintaining whole-body homeostasis, holds significant promise. As awareness of the advantages of inorganic nitrate for human health deepens, nutritional supplements containing nitrate as the primary ingredient have become increasingly integrated into people's lives, with their positive effects reported by an increasing number of clinical studies. The effective use and safe management of oral inorganic nitrate represent key challenges in maximising its potential benefits to human health. In this context, this article provides a comprehensive overview of the historical discovery and current research status of inorganic nitrate, elucidating the potential challenges and strategies for future applications. This contribution aims to inspire new research avenues, positioning inorganic nitrate as a promising candidate for health promotion and disease prevention.