Docosahexaenoic Acid Coordinating with Sodium Selenite Promotes Paraptosis in Colorectal Cancer Cells by Disrupting the Redox Homeostasis and Activating the MAPK Pathway.

Tumor cells are characterized by a delicate balance between elevated oxidative stress and enhanced antioxidant capacity. This intricate equilibrium, maintained within a threshold known as redox homeostasis, offers a unique perspective for cancer treatment by modulating reactive oxygen species (ROS) levels beyond cellular tolerability, thereby disrupting this balance. However, currently used chemotherapy drugs require larger doses to increase ROS levels beyond the redox homeostasis threshold, which may cause serious side effects. How to disrupt redox homeostasis in cancer cells more effectively remains a challenge. In this study, we found that sodium selenite and docosahexaenoic acid (DHA), a polyunsaturated fatty acid extracted from marine fish, synergistically induced cytotoxic effects in colorectal cancer (CRC) cells. Physiological doses of DHA simultaneously upregulated oxidation and antioxidant levels within the threshold range without affecting cell viability. However, it rendered the cells more susceptible to reaching the upper limit of the threshold of redox homeostasis, facilitating the elevation of ROS levels beyond the threshold by combining with low doses of sodium selenite, thereby disrupting redox homeostasis and inducing MAPK-mediated paraptosis. This study highlights the synergistic anticancer effects of sodium selenite and DHA, which induce paraptosis by disrupting redox homeostasis in tumor cells. These findings offer a novel strategy for more targeted and less toxic cancer therapies for colorectal cancer treatment.

Hepatic AMPK signaling dynamic activation in response to REDOX balance are sentinel biomarkers of exercise and antioxidant intervention to improve blood glucose control.

Antioxidant intervention is considered to inhibit reactive oxygen species (ROS) and alleviate hyperglycemia. Paradoxically, moderate exercise can produce ROS to improve diabetes. The exact redox mechanism of these two different approaches remains largely unclear. Here, by comparing exercise and antioxidant intervention on type 2 diabetic rats, we found moderate exercise upregulated compensatory antioxidant capability and reached a higher level of redox balance in the liver. In contrast, antioxidant intervention achieved a low-level redox balance by inhibiting oxidative stress. Both of these two interventions could promote glucose catabolism and inhibit gluconeogenesis through activation of hepatic AMP-activated protein kinase (AMPK) signaling; therefore, ameliorating diabetes. During exercise, different levels of ROS generated by exercise have differential regulations on the activity and expression of hepatic AMPK. Moderate exercise-derived ROS promoted hepatic AMPK glutathionylation activation. However, excessive exercise increased oxidative damage and inhibited the activity and expression of AMPK. Overall, our results illustrate that both exercise and antioxidant intervention improve blood glucose control in diabetes by promoting redox balance, despite different levels of redox state(s). These results indicate that the AMPK signaling activation, combined with oxidative damage markers, could act as sentinel biomarkers, reflecting the threshold of redox balance that is linked to effective glucose control in diabetes. These findings provide theoretical evidence for the precise management of diabetes by antioxidants and exercise.

Molecules known as reactive oxygen species or ROS play vital roles in healthy cells. However, ROS can act as a double-edged sword: if their levels become too high, they can be harmful and interfere with many physiological processes. Indeed, diabetes, high blood pressure and many other chronic diseases are associated with imbalances in the levels of ROS in the body. To counter high ROS levels, cells have antioxidant mechanisms that reduce the excess ROS in the cell and keep the 'redox' (from reduction and oxidation) balance of the cell. Exercise and antioxidant nutritional supplements have attracted much attention as drug-free interventions for diabetes. Both strategies alter the levels of ROS in the body, with exercise increasing the levels of ROS, and antioxidant supplements reducing them. Individuals with diabetes and other metabolic health issues have different ROS levels depending on the severity of the disease, age, genetics and other factors, leading to different redox states in their cells. Thus, approaches that can accurately evaluate the redox balance status of individuals are necessary for clinicians to identify what types of exercise and antioxidant supplements are beneficial and which treatments are most appropriate for each patient. Wu, Zhao, Yan, Gao et al. examined the effects of exercise and antioxidant supplements on rats with diabetes, with the aim of identifying molecules ­ also known as biomarkers ­ that reflect the bodies' redox balance. They found that moderate exercise increased the levels of ROS in the liver, which, in turn, compensated by increasing the production of antioxidants to protect against the higher levels of ROS. This resulted in a healthy 'high-level' redox balance, in which both ROS and antioxidants levels were high in the rats. On the other hand, giving the rats antioxidant supplements decreased their levels of ROS, leading to a healthy low-level redox balance with low levels of ROS. These findings indicate that regular moderate exercise may be appropriate for people with pre-diabetes symptoms to restore a healthy redox balance. This is because the compensatory antioxidant mechanisms that kick in during exercise may be enough to counteract the excessive levels of ROS in these people. For patients with mild diabetes, exercise, antioxidant supplements, or a combination of both may be appropriate treatment, depending on their levels of ROS. Finally, patients with severe diabetes, who already have high levels of ROS, may benefit from antioxidant supplements to help reduce their excessive levels of ROS. In the future, the biomarkers identified by Wu, Zhao, Yan, Gao et al. may be used to monitor and assess the change in the redox balance status of various populations and guide personalized interventions to maintain health. Additionally, these findings provide a new strategy for precision prevention and treatment of diabetes and other metabolic diseases.