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BackgroundAtherosclerosis is a multifaceted inflammatory disease involving cells in the vascular wall (eg, endothelial cells [ECs]), as well as circulating and resident immunogenic cells (eg, monocytes/macrophages). Acting as a ligand for liver X receptor (LXR), but an inhibitor of SREBP2 (sterol regulatory element-binding protein 2), 25-hydroxycholesterol, and its catalyzing enzyme cholesterol-25-hydroxylase (Ch25h) are important in regulating cellular inflammatory status and cholesterol biosynthesis in both ECs and monocytes/macrophages.MethodsBioinformatic analyses were used to investigate RNA-sequencing data to identify cholesterol oxidation and efflux genes regulated by Krüppel-like factor 4 (KLF4). In vitro experiments involving cultured ECs and macrophages and in vivo methods involving mice with Ch25h ablation were then used to explore the atheroprotective role of KLF4-Ch25h/LXR.ResultsVasoprotective stimuli increased the expression of Ch25h and LXR via KLF4. The KLF4-Ch25h/LXR homeostatic axis functions through suppressing inflammation, evidenced by the reduction of inflammasome activity in ECs and the promotion of M1 to M2 phenotypic transition in macrophages. The increased atherosclerosis in apolipoprotein E-/-/Ch25h-/- mice further demonstrates the beneficial role of the KLF4-Ch25h/LXR axis in vascular function and disease.ConclusionsKLF4 transactivates Ch25h and LXR, thereby promoting the synergistic effects between ECs and macrophages to protect against atherosclerosis susceptibility.

The common theme of my 5-year PhD research is to channel progress in spin physics and nano-bio-materials into meaningful improvements in the theoretical studies, methodological developments, and advanced applications of magnetic resonance (MR) to: 1) MR Molecular Imaging: to detect lesions (especially cancers) at early stages through imaging the existence and locations of physiologically important biomarkers; and2) MR Nano Medicine: to cure diseases (especially cancers) by targeted therapy through nanodrugs and hyperthermia.The research activities had encompassed a balanced approach to develop a rigorous theoretical understanding on sensitively imaging magnetic nanoparticles by active- feedback spin dynamics of selective self-excitation and fixed-point dynamics on one hand and sound methodology with biomedical applicability to early pancreatic cancers and brain tumors detection on the other. Computer simulations, phantom experiments of superparamagnetic nanoparticles, and in vivo experiments of orthotopic pancreatic cancer and brain tumor mouse models had been used to validate the applicability and efficacy of our proposed methods.The major research projects and achievements with my coworkers under the supervision of Prof. Yung-Ya Lin include:1) Developed original MR method, "Active-Feedback Fixed-Point Imaging", for early cancer detection, with both quantum and classical formulation of the spin dynamics. 2) Demonstrated 3-5 times of enhancement in the contrast-to-noise ratio (CNR) of early pancreatic cancers which were targeted and labeled by CA19-9 conjugated magnetic nanoparticles by our "Spin Avalanche Amplification" method, based on statistics from 7 orthotopic pancreatic cancer mouse models.3) Demonstrated 4-10 times of enhancement in the CNR of early GBM (glioblastoma multiforme, the most common and aggressive form of brain cancers) by our "Active-Feedback Fixed-Point Imaging" method, based on statistics from 20 orthotopic GBM mouse models. 4) Developed novel