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.

[Passive leg raising predicts volume responsiveness in patients with severe sepsis and septic shock].

OBJECTIVE: To evaluate the role of passive leg raising (PLR) test in predicting volume responsiveness in severe sepsis and septic shock patients. METHODS: Thirty severe sepsis and septic shock patients in intensive care unit (ICU) of Peking University Shenzhen Hospital were prospectively observed from February 2009 to January 2010. The hemodynamics including stroke volume (SV), cardiac output (CO) and systemic vascular resistance (SVR) were measured non invasively by ultrasonic cardiac output monitor (USCOM) device in the supine position, during PLR and after volume expansion (VE), and invasive arterial blood pressure and central venous pressure (CVP) were monitored consecutively. Responders were defined by the appearance of an increase in SV (ΔSV) ≥ 15% after VE. The role of PLR for predicting volume responsiveness was evaluated by receiver operating characteristic (ROC) curves. RESULTS: The CVP (cm H(2)O, 1 cm H(2)O=0.098 kPa) during PLR was increased compared with that at supine position in both responder group ( n =15) and non responder group ( n =15, 13.6 ± 6.6 vs. 12.1 ± 6.0, 11.9 ± 5.5 vs. 10.8 ± 5.2 , both P <0.01). ΔSV was higher in responder group than in non responder group during PLR [(16.6 ± 5.5)% vs. (3.8 ± 8.2)%, P=0.000].ΔSV during PLR was highly correlated to ΔSV after VE (r =0.681 , P =0.000).The area under the ROC curve (AUC) for PLR predicting volume responsiveness was 0.944 ± 0.039 ( P =0.000). The ΔSV>11% during PLR was found to predict volume responsiveness with a sensitivity of 86.7%, specificity of 93.3%, positive predictive value of 92.9% and negative predictive value of 87.5%. CONCLUSION: PLR can be used generally to predict volume responsiveness accurately in severe sepsis and septic shock patients, and it can be used to direct clinical practice.