Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action

In the present study, upon showing sexual dimorphism in dimethyl fumarate (DMF) efficacy to moderate the clinical severity of experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats, cellular and molecular substrate of this dimorphism was explored. In rats of both sexes, DMF administration from the day of immunization attenuated EAE severity, but this effect was more prominent in males leading to loss of the sexual dimorphism observed in vehicle-administered controls. Consistently, in male rats, DMF was more efficient in diminishing the number of CD4+ T lymphocytes infiltrating spinal cord (SC) and their reactivation, the number of IL-17+ T lymphocytes and particularly cellularity of their highly pathogenic IFN-gamma+GM-CSF+IL-17+ subset. This was linked with changes in SC CD11b+CD45+TCR alpha beta- microglia/proinflammatory monocyte progeny, substantiated in a more prominent increase in the frequency of anti-inflammatory phygocyting CD163+ cells and the cells expressing high surface levels of immunoregulatory CD83 molecule (associated with apoptotic cells phagocytosis and implicated in downregulation of CD4+ T lymphocyte reactivation) among CD11b+CD45+TCR alpha beta- cells in male rat SC. These changes were associated with greater increase in the nuclear factor (erythroid-derived 2)-like 2 expression in male rats administered with DMF. In accordance with the previous findings, DMF diminished reactive nitrogen and oxygen species generation and consistently, SC level of advanced oxidation protein products, to the greater extent in male rats. Overall, our study indicates sex-specificity in the sensitivity of DMF cellular and molecular targets and encourages sex-based clinical research to define significance of sex for action of therapeutic agents moderating autoimmune neuroinflammation-/oxidative stress-related nervous tissue damage

Atherogenic dyslipidemia and oxidative stress: a new look

Although results from in vitro studies and clinical trials demonstrate strong associations between oxidative stress and cardiovascular risk, to date still no convincing data are available to suggest that treatment with antioxidants might reduce vascular events. Oxidative modifications of low-density lipoproteins (LDL) represent an early stage of atherosclerosis, and small, dense LDL are more susceptible to oxidation than larger, more buoyant particles. Oxidized LDL are independent predictors of subclinical and clinical atherosclerosis. Recent studies suggested that novel therapeutic strategies may take into account the removal of such particles from circulation. Future research is required to explore the potential synergistic impact of markers of oxidative stress and atherogenic dyslipidemia, particularly small dense LDL, on cardiovascular risk

HDL cholesterol and stroke risk: The Multi-Ethnic Study of Atherosclerosis

BACKGROUND AND PURPOSE: Accurate identification of risk factors for stroke is important for public health promotion and disease prevention. HDL cholesterol is a potential risk factor, yet its role in stroke risk is unclear, as is whether HDL cholesterol content or particle number might be a better indicator of stroke risk. Furthermore, the degree to which ethnicity moderates the risk is unknown. As such, the current study examines the associations between incident stroke and both HDL cholesterol concentration and particle number, and assesses the moderating role of race and ethnicity. METHODS: The sample is a racially diverse cohort of US adults between the ages of 45 - 84 years enrolled in the Multi-Ethnic Study of Atherosclerosis between 2000 - 2002 and followed until December 2011. The associations among cholesterol content and stroke risk, particle number and stroke risk, and the interaction with race were explored. RESULTS: The incidence of stroke was 2.6%. HDL cholesterol concentration (mmol/L) (Hazard Ratio (HR) = 0.56; 95% Confidence Interval (CI): 0.312 - 0.988) and number of large HDL particles (μmol/L) (HR = 0.52, CI: 0.278 - 0.956) were associated with lower stroke risk. When interactions with race were evaluated, the relationship between both HDL variables and stroke were significant in Blacks, but not other races. CONCLUSIONS: Higher HDL cholesterol and a higher concentration of large particles are associated with lower risk of stroke in Blacks. Further research is needed to elucidate the mechanisms by which HDL subfractions may differentially affect stroke outcome in different races/ethnicities