RESUMEN
Background: Severe headache or migraine is a neurological disease that seriously affects the quality of human life. Oxidative stress is considered a main factor in the pathogenesis of severe headache or migraine. The Composite Dietary Antioxidant Index (CDAI) is a score calculated using six dietary antioxidant components (including vitamins A, C, E, selenium, zinc, and carotenoid), which represents a person's level of dietary antioxidant ingredients. Based on the theory of oxidative stress, we speculated that CDAIs may be relevant to the risk of severe headache or migraine, as the relationship between the CDAI and severe headache or migraine is unclear. Hence, the purpose of this study was to explore the relationship between the CDAI and severe headache or migraine in participants. Methods: We performed a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) that were collected from 2001 to 2004. A total of 4,943 participants were included, of whom 1,232 experienced severe headaches or migraines. Participants' CDAIs were calculated based on their intake of six dietary antioxidants. We used logistic regression models, limited cubic spline analysis, and subgroup analysis to assess the association of CDAI with severe headache or migraine. Results: The multivariate logistic regression model (correcting for all potential covariates) revealed that the odds ratio (95% Confidence Interval [CI]) for the association between CDAI and severe headache or migraine was 0.97 (95% CI = 0.95-1.00, p = 0.048). Compared with individuals with low CDAIs in Quartile (Q)1, the adjusted Odds Ratio between the CDAI and severe headache or migraine in Q2, Q3, and Q4 were 0.84 (95% CI = 0.69-1.01, p = 0.07), 0.77 (95% CI = 0.63-0.96, p = 0.017), and 0.73 (95% CI = 0.56-0.95, p = 0.02), respectively. Restricted cubic spline regression analysis showed an L-shaped relationship between the CDAI and severe headache or migraine. Conclusion: Our findings indicate that higher CDAI was associated with a lower risk of severe headache or migraine.
RESUMEN
Triggering ferroptosis, an iron-dependent form of cell death, has recently emerged as an approach for treating cancer. A better understanding of the role and regulation of ferroptosis is needed to realize the potential of this therapeutic strategy. Here, we observed extensive activation of ferroptosis in hepatoma cells and human hepatocellular carcinoma (HCC) cases. Patients with low to moderate activation of ferroptosis in tumors had the highest risk of recurrence compared to patients with no or high ferroptosis. Upon encountering ferroptotic liver cancer cells, aggregated macrophages efficiently secreted proinflammatory IL1ß to trigger neutrophil-mediated sinusoidal vascular remodeling, thereby creating favorable conditions for aggressive tumor growth and lung metastasis. Mechanistically, hyaluronan fragments released by cancer cells acted via an NF-κB-dependent pathway to upregulate IL1ß precursors and the NLRP3 inflammasome in macrophages, and oxidized phospholipids secreted by ferroptotic cells activated the NLRP3 inflammasome to release functional IL1ß. Depleting either macrophages or neutrophils or neutralizing IL1ß in vivo effectively abrogated ferroptosis-mediated liver cancer growth and lung metastasis. More importantly, the ferroptosis-elicited inflammatory cellular network served as a negative feedback mechanism that led to therapeutic resistance to sorafenib in HCC. Targeting the ferroptosis-induced inflammatory axis significantly improved the therapeutic efficacy of sorafenib in vivo. Together, this study identified a role for ferroptosis in promoting HCC by triggering a macrophage/IL1ß/neutrophil/vasculature axis. SIGNIFICANCE: Ferroptosis induces a favorable tumor microenvironment and supports liver cancer progression by stimulating an inflammatory cellular network that can be targeted to suppress metastasis and improve the efficacy of sorafenib.