Optimization of Synthetic High-Density Lipoprotein Nanostructures for Treatment of Inflammatory Diseases

Biomimetic synthetic high-density lipoproteins (sHDLs) are nanoparticles that mimic the physical, chemical, and biological activity of endogenous HDL. A number of sHDL products have been investigated for the treatment of cardiovascular diseases (CVD) for the past three decades. sHDL is composed of apolipoprotein A-I (apoA-I) or apoA-I mimetic peptide complexed with phospholipids to form a discoidal nanoparticle. Infusions of sHDL in animals and humans have been shown to increase circulating HDL levels, improve plasma cholesterol efflux capacity, inhibit inflammation, and improve endothelial function. Phospholipid composition of sHDL appears to have a significant impact on its function by defining the plasma stability of and cholesterol and LPS binding to the nanoparticle. Thus, we proposed to optimize sHDL phospholipid composition to tailor nanoparticle functionality toward a specific therapeutic indication, such as atherosclerosis and sepsis. In the first chapter, we optimized sHDL for the treatment of sepsis by comparing different fluidities of sHDL based on various fatty acid chain lengths and saturation of phospholipid compositions (POPC, DMPC, DPPC, and DSPC). We hypothesized that sHDL with a fluid liquid crystalline phase would improve anti-inflammatory activities by accelerating the efflux of exogenous molecules and improving accessibility to phospholipids for potential signal transductions compared to sHDL in a rigid gel phase. We demonstrated that treating cells with 22A-DMPC, sHDL with a fluid liquid crystalline phase, resulted in the most effective inhibition of NF-κB signaling, TLR4 signaling through regulation of TLR4 recruitment into lipid rafts, and upregulation of activating transcription factor 3 (ATF-3) expression in vitro. Furthermore, 22A-DMPC effectively reduced mortality and protected organs in mice challenged with lethal doses of lipopolysaccharide (LPS) in a model of sepsis. In conclusion, we demonstrated that differences in sHDL phospholipid composition can impact sHDL’s anti-inflammatory signaling and the effectiveness of sepsis therapy. In the second study, we determined how phospholipid and peptide components of sHDL impacted the nanoparticle’s pharmacokinetic and pharmacodynamic properties. We synthesized two different sets of sHDL with either identical phospholipids with variable peptide sequences of different plasma stability or identical peptide sequences with variable fatty acid chain length and saturation. We observed that proteolytically stabilized 22A-P-sHDL increased nanoparticle half-life by 2-fold compared to less stable 22A-sHDL. Nevertheless, increased half-life did not translate to higher cholesterol mobilization. In contrast, varying phospholipids significantly impacted the nanoparticle’s pharmacokinetic profile whereby 22A-DSPC sHDL resulted in the longest half-life (6.0 h) compared to 22A-POPC sHDL (1.0 h). In addition, due to its increased half-life, 22A-DSPC sHDL notably impacted the nanoparticle’s cholesterol mobilization capability, resulting in a 6.5-fold increase compared to 22A-POPC sHDL. Thus, we observed that the phospholipid component of sHDL plays a critical role in cholesterol mobilization in vivo. In the final study, we formulated a new biomimetic nanomicelle called MiNano that is structurally similar to sHDL with a hydrophobic core, a hydrophilic exterior, and a particle size of 12 – 14 nm. We discovered that MiNano resulted in a similar functionality to sHDL, but with much more efficient suppression of the inflammatory response in vitro. Also, MiNano displayed robust inhibition of inflammatory cytokines in an LPS-induced endotoxin mice model. In summary, this thesis thoroughly investigates the importance of the phospholipid component of sHDL and MiNano in the regulation of inflammation and cholesterol mobilization, allowing us to optimize nanoparticle composition for the treatment of sepsis and atherosclerosis.PHDPharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/153385/1/kimsangy_1.pd

High‐Density Lipoprotein in Lupus: Disease Biomarkers and Potential Therapeutic Strategy

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152788/1/art41059_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152788/2/art41059.pd

Inverse Estimation Method of Material Randomness Using Observation

This study proposes a method for inversely estimating the spatial distribution characteristic of a material’s elastic modulus using the measured value of the observation data and the distance between the measurement points. The structural factors in the structural system possess temporal and spatial randomness. One of the representative structural factors, the material’s elastic modulus, possesses temporal and spatial randomness in the stiffness of the plate structure. The structural factors with randomness are typically modeled as having a certain probability distribution (probability density function) and a probability characteristic (mean and standard deviation). However, this method does not consider spatial randomness. Even if considered, the existing method presents limitations because it does not know the randomness of the actual material. To overcome the limitations, we propose a method to numerically define the spatial randomness of the material’s elastic modulus and confirm factors such as response variability and response variance.EC/H2020/841592/EU/Ultra-Lightweight Concrete for 3D printing technologies/Ultra-LightCon-3

Estimated Prevalence of Glaucoma in South Korea Using the National Claims Database

Purpose. To estimate the prevalence of glaucoma and costs associated with glaucoma care in South Korea between 2008 and 2013 using the Korean national claims database. Design. Retrospective cross-sectional study from a national claims database. Methods. Patients who were diagnosed with glaucoma between 2008 and 2013 were retrospectively identified in the national claims database using glaucoma diagnostic codes. For each year, the prevalence of glaucoma and direct medical costs associated with glaucoma care were estimated. Result. The prevalence of glaucoma in patients ≥40 years of age increased from 0.79% in 2008 to 1.05% in 2013. The number of patients with glaucoma increased by 54% between 2008 and 2013 (9% average annual increase). The prevalence of glaucoma increased with age and was higher in males than in females. The cost to care for glaucoma patients increased from $16.5 million in 2008 to$29.2 million in 2013, which translated into an 81% increase over the 6 years examined (12.7% average annual increase). Conclusion. The estimated prevalence and socioeconomic burden of glaucoma have steadily increased each year in South Korea. Nevertheless, many glaucoma patients remain undiagnosed in the present study using national claims database

Spontaneous Rupture of the Extensor Pollicis Longus Tendon in a Tailor

A spontaneous rupture of the extensor pollicis longus (EPL) tendon is associated with rheumatoid arthritis, fractures of the wrist, systemic or local steroids and repetitive, and excessive abnormal motion of the wrist joint. The authors encountered a case of a spontaneous rupture of the EPL tendon. The patient had no predisposing factors including trauma or steroid injection. Although the patient had a positive rheumatoid factor, he did not demonstrate other clinical or radiological findings of rheumatoid arthritis. During surgery, the EPL tendon was found to be ruptured at the extensor retinaculum (third compartment). Reconstruction of the extensor tendon using the palmaris longus tendon was performed. At the 18-month follow-up, the patient showed satisfactory extension of the thumb and 40° extension and flexion at the wrist

Basal Cell Nevus Syndrome Showing Several Histologic Types of Basal Cell Carcinoma

Basal cell nevus syndrome (BCNS), or Gorlin Syndrome, is an autosomal dominant disorder, characterized by multiple developmental abnormalities and associated with germline mutations in the PTCH gene. Patients show multiple and early onset basal cell carcinomas (BCCs) in skin, odontogeniccysts in the jaw, pits on palms and soles, medulloblastoma, hypertelorism, and calcification of the falx cerebri. Clinical features of BCCs in these patients are indistinguishable from ordinary BCCs. However, some patients show variable histologic findings in subtypes of BCCs, and only one case associated with several histologic types of BCCs in the syndrome has been reported in Korea. We present a case of BCNS characterized by multiple BCCs, odontogenic keratocysts, multiple palmar pits, and calcified falx cerebri. Histopathologic findings of BCCs showed several patterns, which were nodular, superficial, and pigmented types