Chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET), play key roles in drug discovery and development.

The aim of this study was to explore the intracellular mechanisms underlying the cardiovascular toxicity of air particulate matter (PM) with an aerodynamic diameter of less than 2.5 µm (PM2.5) in a human umbilical vein cell line, EA.hy926. We found that PM2.5 exposure triggered reactive oxygen species (ROS) generation, resulting in a significant decrease in cell viability. Data from Western blots showed that PM2.5 induced phosphorylation of Jun N-terminal kinase (JNK), extracellular signal regulatory kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and protein kinase B (AKT), and activation of nuclear factor kappa B (NF-κB). We further observed a significant increase in expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in a time- and dose-dependent manner. Moreover, the adhesion of monocytic THP-1 cells to EA.hy926 cells was greatly enhanced in the presence of PM2.5 . However, N-acetylcysteine (NAC), a scavenger of ROS, prevented the increase of ROS generation, attenuated the phosphorylation of the above kinases, and decreased the NF-κB activation as well as the expression of ICAM-1 and VCAM-1. Furthermore, ERK inhibitor (U0126), AKT inhibitor (LY294002) and NF-κB inhibitor (BAY11-7082) significantly down-regulated PM2.5 -induced ICAM-1 and VCAM-1 expression as well as adhesion of THP-1 cells, but not JNK inhibitor (SP600125) and p38 MAPK inhibitor (SB203580), indicating that ERK/AKT/NF-κB is involved in the signaling pathway that leads to PM2.5 -induced ICAM-1 and VCAM-1 expression. These findings suggest PM2.5 -induced ROS may function as signaling molecules triggering ICAM-1 and VCAM-1 expressions through activating the ERK/AKT/NF-κB-dependent pathway, and further promoting monocyte adhesion to endothelial cells.

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Objectives: Exposure to airborne particle (PM 2.5 ) is a risk factor for intracranial atherosclerosis (ICA). Because of the established role of systemic inflammation and oxidative stress by PM 2.5 , we determined whether these processes account for PM 2.5 -mediated ICA, and also whether omega-3 fatty acid (O3FA) dietary supplementation could attenuate them.Methods: Adult Sprague-Dawley rats were exposed to filtered air (FA) or PM 2.5 and fed either a normal chow diet (NCD) or a high-cholesterol diet (HCD), administered with or without O3FA (5 mg/kg/day by gavage) for 12 weeks. The lumen and thickness of the middle cerebral artery (MCA) were assessed. Serum tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin-1β (IL-1β), and interferon gamma (IFN-γ) were detected by ELISA. Reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) activity, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity, mRNA levels of Nrf2, HO-1, NQO-1, and protein level of NOX subunit gp91 were quantified to determine the oxidative profile of brain vessels.Results: PM 2.5 increased (P < .05) ICA, especially in the HCD group; elevated serum TNF-α, IL-6, IL-1β, and IFN-γ; increased cerebrovascular ROS, MDA, NOX activity, and gp91 protein levels;and decreased cerebrovascular SOD activity. Nrf2, HO-1, and NQO-1 mRNA levels were upregulated (P < .05) by PM 2.5 exposure, especially in the HCD group. O3FA attenuated (P < .05) PM 2.5 -induced systemic inflammation, vascular oxidative injury, and ICA.Conclusions: PM 2.5 exposure induced systemic inflammation, cerebrovascular oxidative injury, and ICA in rats with HCD. O3FA prevented ICA development, and may therefore exert a protective effect against the atherogenic potential of PM 2.5 . K E Y W O R D Shigh-cholesterol diet, intracranial atherosclerosis, omega-3 fatty acid, PM 2.5 , prevention