ABCA1 x SCARB1

Atmospheric particulate matter (PM) is one of the main pollutants of air pollution, which adsorbs several harmful organic substances, heavy metals, bacteria, and viruses. Epidemiological research has demonstrated that PM_2.5 exposure might alter subclinical markers of atherosclerosis while the mechanism is unclear. In the current study, macrophages and foam cells that were differentiated from THP-1 cells were exposed to PM_2.5 (0, 25, 50, and 100 μg/mL). PM_2.5 exposure reduce the expression of miR-200b-3p and miR-424-5p, thereby regulating the Notch signaling pathway in macrophages and foam cells, which affects the expression of lipid metabolism-related genes (ABCA1, LDLR, SR-A, SR-BI and CD36) and aggravates the dysfunction of lipid metabolism and leads to atherosclerosis. The study provides new ideas for the prevention and treatment of atherosclerosis.

Acetaminophen is a commonly used antipyretic and analgesic during pregnancy. The placenta plays a crucial role in fetal development. In this study, we investigated the impact of different doses (100 or 400 mg/kg·d), courses (gestational day 12 or 10-12), and stages (gestational day 12 or 15-17) on placental development in mice. The results indicated that prenatal acetaminophen exposure (PAcE) leads to necrosis of trophoblast cells and disruption of septa. Additionally, the expression of placental cell proliferation genes was reduced, while the expression of apoptosis genes was elevated. Expression of glucose transporter genes (Glut1, Glut3), amino acid transporter gene (Lat2), and cholesterol uptake genes (Ldlr, Srb1) was increased, whereas the expression of cholesterol transport genes (Abca1, Abcg1) and fatty acid transporter genes (Cd36, Fatp1) was significantly reduced. These changes were more pronounced in the high-dose, single-course, third-trimester, and female placentas. Further analysis revealed that PAcE significantly suppressed the expression of the IGF1/2 signalling pathway. Correlation analysis suggested a strong association between IGF1/2 signalling pathway and placental genes. In summary, this study confirmed that PAcE induced changes in morphological and functional development. Dose, course, stage, and sex are important influencing factors. This study would provide a reference for the developmental toxicity of acetaminophen during pregnancy.

Atherosclerosis (AS) is a persistent inflammatory disorder marked by vulnerable plaques, which increase the likelihood of cardiovascular incidents. This study explored the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the development of vulnerable plaques triggered by hyperhomocysteinemia (HHcy), with a focus on lipid metabolism, and inflammation. Apolipoprotein E knockout (ApoE^-/-) mice were fed a methionine-rich diet to induce HHcy. PCSK9 inhibition via SBC-115076 significantly improved plaque stability. HHcy upregulated PCSK9 levels, and hinder cholesterol efflux by downregulating the ATP-binding cassette transporters ABCA1 and ABCG1. In contrast, no significant effects were noted on low-density lipoprotein receptor (LDLR), cluster of differentiation 36 (CD36), or scavenger receptor class B type I (SR-BI). Inhibition of PCSK9 led to the restoration of ABCA1 and ABCG1, thereby facilitating an increase in cholesterol efflux. Furthermore, PCSK9 inhibition reduced HHcy-induced increase of proinflammatory cytokines, including interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). In vitro, mouse peritoneal macrophages (MPMs) exposed to HHcy presented reduced ABCA1 and ABCG1, whereas LDLR, CD36, and SR-BI remained unaffected. PCSK9 knockout reversed these changes. Additionally, HHcy upregulated expression of proinflammatory cytokines, along with the activation of Toll-like receptor 4 (TLR4) /nuclear factor kappa B (NF-κB) pathway. PCSK9 inhibition reduced the production of these cytokines and mitigated the activation of the TLR4/NF-κB pathway, confirming its role in macrophage inflammation. These findings reveal that PCSK9 exacerbates HHcy-related AS by impairing cholesterol efflux and promoting inflammation. PCSK9 inhibitors may offer a dual therapeutic approach for stabilizing plaques and reducing cardiovascular risk in patients with HHcy.