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Lipoproteins for Biomedical Applications: Medical Imaging and Drug Delivery
Published in Vladimir Torchilin, Handbook of Materials for Nanomedicine, 2020
Pratap C. Naha, Stephen E. Henrich, David P. Cormode, C. Shad Thaxton
Synthetic HDL mimetics for siRNA delivery have employed one of two core materials, gold nanoparticles or HDL-mimicking peptide-phospholipid scaffolds. First, bio-inspired HDL nanoparticles have been synthesized using a 5 nm gold nanoparticle core. The fabrication of these materials is carried out by functionalizing the surface of the 5 nm gold particle with apoA-1 and phospholipids. The resultant HDL NPs are size, surface chemistry, and functional mimics of native mature, spherical HDL, containing 2–4 copies of apoA-1 per particle and an outer phospholipid layer consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) [178]. These particles have been shown to interact strongly with SR-B1, as well as ABCA1 and ABCG1 to induce cholesterol efflux from immune cells (especially myeloid cells) [179, 180], neoplastic cells [179], and other cell types in vitro and in vivo. These particles have been shown to be effective for nucleic acid delivery, using both anti-sense DNA and siRNA. HDL NPs were able to efficiently absorb cholesterylated anti-sense DNA onto their surface and modulate gene expression in SR-B1 expressing cells in vivo [74].
Inorganic Chemical Pollutants
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
Genetically engineered disruption of cholesterol metabolism defines the two major models of atherosclerosis; apolipoprotein E-deficient (ApoE+) and LDL receptor (LDLR)-deficient mice develop two ApoE and other mice deficient in lipid-efflux proteins, such as the adenosine triphosphate (ATP)-binding cassette transporter 1 (ABCA1) and ATP-binding cassette transporter 1 (ABCAA1) and ATP-binding cassette subfamily G member 1 (ABCG1), have forged a mechanistic link between leukocyte and lipid biology. Trapped cholesterol in hematopoietic stem and progenitor cells (HSPCs) that lack the crucial cholesterol efflux machinery leads to the expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-3 common beta chain receptor on the plasma membrane contributes to excessive proliferation.247,248 In other words, cholesterol efflux suppress proliferation. Concurrently, lipid-rich splenic phagocytes release IL-23, which induces a cascade that eventually liberates HSPCs from their medullary niches.249 When HSPCs seed extramedullary sites, they encounter GM-CSF and IL-3.250 The net effect is HSPC proliferation, extramedullary hematopoiesis, leukocytosis, and accelerated atherosclerosis.
Endocrine disrupting toxicity of aryl organophosphate esters and mode of action
Published in Critical Reviews in Environmental Science and Technology, 2023
Wenxin Hu, Peng Gao, Lei Wang, Jianying Hu
LXR-antagonistic activities of TPHP and EHDPP were discovered by an LXR pull-down assay combined with nontarget high-resolution mass spectrometry screening in indoor dust. The potency of TPHP (IC50: 1477 nM for LXRα and 762 nM for LXRβ) was similar to that of the strong LXR positive antagonist SR9238 (IC50: 824.7 nM for LXRα and 446.4 nM for LXRβ), based on a two-hybrid yeast assay (Hu et al., 2019b). The LXR transcriptional activity after TPHP exposure was demonstrated by the downregulated expression of ABCA1 and ABCG1, and lysophosphatidylcholine acyltransferase 3 (Lpcat3), these genes are the downstream target genes of LXRs in macrophages (Hu et al., 2019b, 2020). Because ABCA1 and ABCG1 play critical roles in the efflux of excess cellular cholesterol in macrophages, their selective inactivation could cause an imbalance between the uptake and ABCA1- and ABCG1-mediated efflux of cholesterol, thus leading to the formation of foam cells. The effects of TPHP on cholesterol efflux and foam cell formation were also observed in RAW26.4 cells and peritoneal macrophages (Hu et al., 2019b). In an atherosclerotic mouse model (ApoE−/−), TPHP exposure at a concentration of 10 mg/kg for 3 months enlarged the area of atherosclerotic lesions in the en-face stained aorta and aortic roots by promoting foam cell formation, demonstrating that TPHP exposure induced AS via LXR pathway.
Well-posedness of a mathematical model of diabetic atherosclerosis with advanced glycation end-products
Published in Applicable Analysis, 2022
Although the pathophysiology of diabetic vascular disease is generally understood, there is no mathematical model to date that includes the effect of diabetes on plaque growth. In a recent work [39], we proposed a mathematical model for diabetic atherosclerosis, which include some key variables such as the concentrations of glucose, insulin, LDL and HDL and densities of foam cells, SMCs and macrophages. However, some important variables such as AGEs are missing in the model. The risk of diabetic cardiovascular complications after exposure to high glucose levels for a certain period of time is called ‘metabolic memory’ or ‘legacy effect’. One of the possible mechanisms of this effect is the formation of AGEs, which occurs when the blood glucose level is high. These compounds are not easily metabolized, accumulating in patients with a long history of inadequate blood glucose control. Such accumulation may accelerate the progression of vascular disease in diabetic patients [40,41]. In this paper, we have refined that model in [39] by including more comprehensive variables such as AGEs, oxidized LDL and HDL, MCP-1, T-cells [9,10,46] and PDGF [55]. In particular, the model in this paper includes the following effects of AGEs on diabetic atherosclerosis: High glucose level leads to the formation of AGEs, which in turn enhance glycation of LDC [27,49]; this effect is taken into account in Equations (2), (5) and (10).AGEs induces increased ROS and decreased eNOS expression as well as NO synthesis and increased ET-1 expression, leading to endothelial dysfunction [33–35]. This effect is reflected in Equation (9).AGEs may inhibit reverse cholesterol transport by reducing ABCA1 and ABCG1 [29,37]. This is taken into account in Equations (12) and (13).AGEs promotes the entrance of monocytes and macrophages into the subendothelial space, this effect is reflected in the boundary condition (25).