Distribution of the molecular species of phospholipids in human umbilical cord blood

The composition of phosphatidylcholine (PC) and sphingomyelin (SM) was studied in cord blood lipoproteins to determine whether equilibration of the molecular species of phospholipids among lipoproteins was comparable with that reported for adults. The molecular species distributions of PC in low density lipoprotein (LDL) differed from that of high density lipoprotein (HDL). Whereas LDL PC was richer in combinations of fatty acids with 16 and 18 carbon atoms than HDL, the HDL was markedly enriched in combinations of fatty acids with 18 and 20 carbon atoms. Sphingomyelins in LDL were richer in palmitic acid than HDL while HDL had a greater proportion of long chain sphingomyelin than LDL. The molecular species of PC and SM do not equilibrate in cord blood. The results for the SM distributions were similar to other reports for adult human lipoprotein. However, the marked differential distribution of PC among lipoproteins appears unique to cord blood. The mechanisms responsible for equilibrating PC among lipoproteins are less well developed in the neonate when compared with the adult.     

Analytic ultracentrifuge calibration and determination of lipoprotein-specific refractive increments

Accurate quantification of the major classes and subfractions of human serum lipoproteins is an important analytical need in the characterization and evaluation of therapy of lipid and lipoprotein abnormalities. For calibrating the analytic ultracentrifuge (AnUC), we routinely use a Beckman calibration wedge cell with parallel scribed lines 1 cm apart. Such a cell gives a rectangular pattern in the schlieren diagram, which determines magnification and also provides an area corresponding to an invariant refractive increment. We have independently validated this wedge calibration cell using a special boundary-forming cell in which 1.174% sucrose is overlayered with distilled water. Comparing wedge cell area with extrapolated zero time boundary area refractive increment gives agreement to within less than 1%, corresponding to a refractive increment error of ±0.00002 Δn. Complete calibration for AnUC analysis of lipoproteins also requires accurate determination of the specific refractive increments (SRI) of the major lipoprotein classes, namely low density lipoprotein (LDL) and high density lipoprotein (HDL). These are measured in the density in which they are analyzed, i.e., 1.061 g/ml for LDL and 1.200 g/ml for HDL. Five fresh serum samples were fractionated for total LDL and total HDL and their SRI determined. Total lipoprotein mass was determined using precise CHN elemental analysis and compositional analyses. The results yielded corrected SRI of 0.00142 and 0.00135 Δn/g/100 ml for LDL and HDL. Thus, our current values using 0.00154 and 0.00149 Δn/g/100 ml underestimate LDL and HDL by 9% and 11%. Corrections of all previous LDL and HDL AnUC data can be made using appropriate factors of 1.087 and 1.106. A preliminary part of this study was presented at the 74th Annual AOCS meeting, Chicago, 1983.     

Quantitation of baboon lipoproteins by high performance gel exclusion chromatography

High performance liquid chromatography with gel exclusion columns was used for quantitative measurement of plasma lipoproteins. A combination of columns TKS 4000 PW and 3000 PW gave good separation of very low (VLDL), low (LDL) and high (HDL) density lipoproteins. The area under each lipoprotein peak detected by absorbance at 280 nm was measured by digitizing and was expressed as cm². Purified lipoprotein standards isolated by ultracentrifugation were also chromatographed in increasing concentrations. The area under the lipoprotein standard peak was linearly related to the amount of total protein over a wide range. The areas of most of the measured plasma lipoproteins were within the linear range. The relationship between the area and the amount of protein for each standard was used to quantitate the amount of protein and was expressed as mg/dl plasma. This technique is simple and requires a small amount of plasma. The validated technique was applied to a large population of pedigreed baboons. An average plasma lipoprotein profile of feral baboons on the chow diet was characterized by a high level of HDL (90.9±30.7 mg/dl) with a lesser amount of LDL (29.1±13.2 mg/dl). VLDL was present in much lower concentration (8.6±2.6 mg/dl). Feeding a high cholesterol and high saturated fat (HCHF) diet raised both LDL (1.5-fold) and HDL levels (1.3-fold) without changing VLDL levels. Progeny of sires with low response to dietary cholesterol increased their HDL protein when challenged with HCHF diet without any change in their LDL or VLDL. Progeny of high-responding sires, however, had increases in both their HDL and LDL levels when challenged with HCHF diet. The survey of lipoprotein profiles of the pedigreed baboon colony disclosed a number of animals with interesting and unusual lipoprotein patterns.     

Properties of ultrasonically irradiated human serum lipoproteins

Human serum low density lipoprotein (LDL) and human serum high density lipoprotein (HDL) were treated with ultrasonic irradiation. The immunochemical properties, spectrophotometrical analysis and thiobarbituric acid test (TBA) value of ultrasonically irradiated lipoproteins were examined. The agar gel precipitin reaction of sonicated LDL disappeared as the irradiation time increased. The effects of ultrasonic irradiation upon human serum lipoproteins resulted in a loss of lipids from the sonicated lipoproteins and are increased in TBA value. TBA value of LDL increased in two steps.     

Low-Density Lipoproteins,High-Density Lipoproteins (HDL), and HDL-Associated Proteins Differentially Modulate Chronic Myelogenous Leukemia Cell Viability

Cellular lipid metabolism, lipoprotein interactions, and liver X receptor (LXR) activation have been implicated in the pathophysiology and treatment of cancer, although findings vary across cancer models and by lipoprotein profiles. In this study, we investigated the effects of human-derived low-density lipoproteins (LDL), high-density lipoproteins (HDL), and HDL-associated proteins apolipoprotein A1 (apoA1) and serum amyloid A (SAA) on markers of viability, cholesterol flux, and differentiation in K562 cells—a bone marrow-derived, stem-like erythroleukemia cell model of chronic myelogenous leukemia (CML). We further evaluated whether lipoprotein-mediated effects were altered by concomitant LXR activation. We observed that LDL promoted higher K562 cell viability in a dose- and time-dependent manner and increased cellular cholesterol concentrations, while LXR activation by the agonist TO901317 ablated these effects. LXR activation in the presence of HDL, apoA1 and SAA-rich HDL suppressed K562 cell viability, while robustly inducing mRNA expression of ATP-binding cassette transporter A1 (ABCA1). HDL and its associated proteins additionally suppressed mRNA expression of anti-apoptotic B-cell lymphoma-extra large (BCL-xL), and the erythroid lineage marker 5′-aminolevulinate synthase 2 (ALAS2), while SAA-rich HDL induced mRNA expression of the megakaryocytic lineage marker integrin subunit alpha 2b (ITGA2B). Together, these findings suggest that lipoproteins and LXR may impact the viability and characteristics of CML cells.     

Current Nanomedicine for Targeted Vascular Disease Treatment: Trends and Perspectives

Nanotechnology has been developed to deliver cargos effectively to the vascular system. Nanomedicine is a novel and effective approach for targeted vascular disease treatment including atherosclerosis, coronary artery disease, strokes, peripheral arterial disease, and cancer. It has been well known for some time that vascular disease patients have a higher cancer risk than the general population. During atherogenesis, the endothelial cells are activated to increase the expression of adhesion molecules such as Intercellular Adhesion Molecule 1 (ICAM-1), Vascular cell adhesion protein 1 (VCAM-1), E-selectin, and P-selectin. This biological activation of endothelial cells gives a targetability clue for nanoparticle strategies. Nanoparticle formation has a passive targeting pathway due to the increased adhesion molecule expression on the cell surface as well as increased cell activation. In addition, the VCAM-1-targeting peptide has been widely used to target the inflamed endothelial cells. Biomimetic nanoparticles using platelet and leukocyte membrane fragment strategies have been promising techniques for targeted vascular disease treatment. Cyclodextrin, a natural oligosaccharide with a hydrophobic cavity, increase the solubility of cholesterol crystals at the atherosclerotic plaque site and has been used to deliver the hydrophobic drug statin as a therapeutic in a targeted manner. In summary, nanoparticles decorated with various targeting molecules will be an effective and promising strategy for targeted vascular disease treatment.     

Lipoproteins modify the macrophage uptake of triacylglycerol emulsion and of zymosan particles by similar mechanisms

The uptake of lipids and formation of foam cells are key events in atherosclerosis and in eruptive xanthomata formation in primary hyperchylomicronemia. Here we have compared the influence of low density lipoprotein (LDL), oxidized LDL (oxLDL), high density lipoprotein (HDL), and delipidated HDL (apoHDL) on the uptake by macrophages of zymosan (an insoluble fraction of yeast cell walls) and of triglyceride-rich emulsion (EM) particles that resemble chylomicrons, but, like zymosan, are equally devoid of protein components. Zymosan internalization is known to occur through unspecific phagocytosis, whereas natural chylomicrons are taken up by several specific lipoprotein receptors. We found that phagocytosis is not promoted as much by oxLDL as by normal LDL. HDL-coated zymosan was found to be inert and apoHDL slightly enhanced phagocytosis. LDL and apoHDL promoted the uptake of EM while oxLDL and HDL significantly inhibited the uptake. Therefore, the data support that HDL, and not apoHDL, particles inhibit EM uptake. We concluded that by using lipoprotein-coated zymosan particles, we could demonstrate different biological effects of LDL, oxLDL, HDL, and apoHDL on macrophage phagocytosis and that this method could be useful to delineate components of the various lipoproteins important for the propagation or inhibition of the formation of foam cells.     

Synthesis and Development of Lipoprotein-Based Nanocarriers for Light-Activated Theranostics

The design and synthesis of new light-activated contrast agents for theranostics (therapy/diagnosis) has the potential to facilitate multifunctional and improved personalized medicine. The use of light as a remote activation strategy provides spatial and temporal control of drug effect and nanotechnology can play a key role in this process. Lipoproteins (LDL and HDL), which transport water-insoluble cholesteryl esters and triacylglycerols in nature, have evolved to efficiently ferry exogenous hydrophobic compounds in vivo. They are naturally biocompatible, maneuverable due to their small size (<30 nm), and can be loaded through various methods, and are therefore ideal vehicles to load and transport hydrophobic theranostic agents. This review examines the history and ongoing research activities regarding the design and synthesis of lipoprotein-based formulations, and their applications or potential applications as light-activated theranostic agents, with a main focus on photodynamic therapy. This field, while still in its infancy, will benefit from improved design and modulation of enhanced lipoprotein-based nanocarriers, with the ultimate goal of simultaneous imaging and photoactivation of therapeutic agents in a clinical setting.     

High density lipoproteins from bovine plasma and follicular fluid do not possess a high affinity for glycosaminoglycans

Possible interactions between glycosaminoglycans and high density lipoproteins (HDL) in plasma and follicular fluid were examined. Total lipoproteins (d<1.21 g/ml) were obtained from plasma of five Holstein cows by ultracentrifugation and fractionated by gel filtration. Every other fraction from the HDL peak or fractions corresponding to the base and ascending portion of the HDL peak were composited and applied to a heparin-Sepharose affinity chromatography column. Elution profiles from both composites showed a peak that did not bind to the column that contained HDL devoid of apolipoprotein-E as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and silver staining and immunoblot analysis. Elution of lipoproteins from the ascending portion of the HDL peak resulted in a second minor peak eluting at 0.35 M NaCl, which was low density lipoprotein (LDL) contamination. Lipoproteins (d<1.21g/ml) isolated from follicular fluid obtained from small, medium or large follicles also were subjected to heparin-Sepharose affinity chromatography. Two peaks were observed, one corresponding to the lipoprotein that did not bind to the column, the other eluted at 0.5M NaCl and accounted for less than 2% of the protein applied. The second peak did not contain apolipoprotein-E or LDL. Bovine follicular fluid glycosaminoglycans (GAG) were isolated and subjected to HDL-Sepharose affinity chromatography. Less than 2% of the total GAG bound to the HDL column. Therefore, HDL in bovine specimens did not interact appreciably with heparin or GAG isolated from follicular fluid.     

Lipoproteins of fetal and newborn calves and adult steer: A study of developmental changes

Serum lipoproteins in fetal and newborn calves were characterized and compared with those of adult animals. Fetal calf serum contains only low density (LDL) and high density (HDL) lipoproteins; the LDL is the major lipoprotein class. Fetal LDL are ca. 26.0 nm diameter and are morphologically unusual in that particles form linear aggregates or “chains” in which LDL have flattened, parallel sides. These particles contain only apolipoprotein B and are high in polar lipids. Fetal HDL consist of 8.2-nm, round particles which contain large amounts of chlesteryl ester thus suggesting an active lecithin: cholesterol acyltransferase system in the fetal state. The major protein in fetal HDL is apolipoprotein A−I (80%); however, another component with a molecular weight (MW) of ca. 9,000 is also present. Newborn calves show a 5-fold increase in HDL concentration. These particles are 9.0 nm spherical particles and they contain mainly apolipoprotein A−I although C-apolipoproteins are also present; the lipid and apolipoprotein composition of newborn HDL is similar to that of adults. Newborn calves possess very low density (VLDL) lipoproteins which have a mean diameter of 61 nm and are similar in size and composition to those of adult animals; their apolipoprotein composition is principally apolipoprotein B, although C-apolipoproteins and apolipoprotein A−I are also present. The LDL of neonatal and adult animals are similar in morphology, chemical composition and apolipoprotein content. In both instances, LDL are round particles ca. 19.0 nm diameter which contain less polar lipids than the fetal animal. Apolipoprotein B is the major protein in newborn LDL, but adult LDL additionally contains a protein of 27,000 MW which probably represents apolipoprotein A−I from overlapping α-migrating particles in this region. The altered morphology and composition of fetal LDL, together with the lack of VLDL, suggest that the LDL particles may be synthesized de novo. Preliminary data was presented at the American Oil Chemists' Society Meeting, 1979.     

A rapid method for separation of plasma low and high density lipoproteins for tocopherol and carotenoid analyses

Ultracentrifugation (UC) is the method most often employed for separation and quantification of lipoproteins. Because this procedure requires expensive laboratory equipment, a large volume of fresh sample and an inordinate amount of time, it may not be ideal for routine clinical/experimental use. The aim of the current study was to evaluate a method which combines selective precipitation (HDL-P) and immunoseparation (LDL-I) for the rapid and reliable isolation of high density lipoproteins (HDL) and low density lipoproteins (LDL) specifically for vitamin E and carotenoid determination within these fractions. Cholesterol and triacylglycerol concentrations within the HDL and LDL were also determined to enable expression of vitamin E and carotenoid concentrations per gram of lipid. Isolation of lipoproteins by UC was used as the reference method (HDL-UC/LDL-UC). There were no significant differences between methods for α-and γ-tocopherol in LDL and HDL. Carotenoids measured in HDL and LDL were comparable between the methods. The exception was higher lutein/zeaxanthin concentration in HDL-P and LDL-I compared to HDL-UC and LDL-UC, respectively. Additionally, lycopene concentration was significantly lower in LDL-I compared to LDL-UC. In comparing vitamin E and carotenoid values in lipoproteins separated from fresh and frozen plasma by the direct method, there was no difference in α-tocopherol or the majority of carotenoids measured. In conclusion, a combination of selective precipitation and immunoseparation of fresh or frozen plasma for subsequent α-and γ-tocopherol analyses provides an accurate and reliable alternative to lipoprotein separation by UC. Additionally, carotenoid concentrations in HDL separated by selective precipitation and analyses of α-and β-carotenes and β-cryptoxanthin in LDL separated by immunoseparation are also reliable, while lycopene and lutein/zeaxanthin concentrations in LDL-I are not readily comparable to LDL-UC.     

Inhibition of Endothelial Lipase Activity by Sphingomyelin in the Lipoproteins

Endothelial lipase (EL) is a major determinant of plasma HDL concentration, its activity being inversely proportional to HDL levels. Although it is known that it preferentially acts on HDL compared to LDL and VLDL, the basis for this specificity is not known. Here we tested the hypothesis that sphingomyelin, a major phospholipid in lipoproteins is a physiological inhibitor of EL, and that the preference of the enzyme for HDL may be due to low sphingomyelin/phosphatidylcholine (PtdCho) ratio in HDL, compared to other lipoproteins. Using recombinant human EL, we showed that sphingomyelin inhibits the hydrolysis of PtdCho in the liposomes in a concentration‐dependent manner. While the enzyme showed lower hydrolysis of LDL PtdCho, compared to HDL PtdCho, this difference disappeared after the degradation of lipoprotein sphingomyelin by bacterial sphingomyelinase. Analysis of molecular species of PtdCho hydrolyzed by EL in the lipoproteins showed that the enzyme preferentially hydrolyzed PtdCho containing polyunsaturated fatty acids (PUFA) such as 22:6, 20:5, 20:4 at the sn‐2 position, generating the corresponding PUFA‐lyso PtdCho. This specificity for PUFA‐PtdCho species was not observed after depletion of sphingomyelin by sphingomyelinase. These results show that sphingomyelin not only plays a role in regulating EL activity, but also influences its specificity towards PtdCho species.     

The effect of dietary lipid on the lipoprotein status of the mongolian gerbil

The Mongolian gerbil,Meriones unguiculatus, may be a suitable animal model for the investigation of dietary lipid effects on cholesterol metabolism. The effects of dietary cholesterol, and its possible interaction with the type of dietary fat, on the lipoprotein status of this animal have not been examined previously. In the present research, the effects of adding 0.5% cholesterol to diets high in saturated (19.5% beef tallow: 0.5% safflower oil) or polyunsaturated (20% safflower oil) fats on the lipoprotein status of the gerbil were determined after 11 and 22 days of feeding. Lipoproteins (VLDL, LDL and HDL) were separated by sequential ultracentrifugation. Their cholesterol, phospholipid and protein concentrations were determined colorimetrically. In the absence of 0.5% cholesterol, safflower oil lowered the concentration (mg/100 ml) of cholesterol in each of the VLDL, LDL and HDL relative to beef tallow (BT) without greatly influencing the cholesterol distribution amongst them. The HDL carried the majority of the serum cholesterol and the VLDL transported the smallest amount. However, inclusion of 0.5% dietary cholesterol resulted in a redistribution of cholesterol amongst the lipoproteins so that the VLDL and LDL became the major and the HDL the minor carriers. Dietary cholesterol also brought about a rise in the VLDL and LDL concentrations (mg/100 ml) of cholesterol, phospholipid and protein and altered the VLDL and LDL compositions. No such changes were observed in the HDL, indicating that the HDL are relatively resistant to any of the possible effects of cholesterol feeding measured in this experiment. The specific mechanisms responsible for the changes observed in the lipoprotein status of the gerbil remain to be elucidated. Presented in part at the Triennial Joint Meeting of the AIN/ASCN/CSNS, July 1982     

Subfractionation of Sf 4–105, Sf 4–20 and high density lipoproteins

Subfractionation of the total low density S_f 4–10⁵, the low density S_f 4–20 and high density plasma (or serum) lipoproteins has been accomplished using a cumulative flotation rate procedure. Fractionation employs nonlinear salt gradients and high performance swinging bucket rotors. Subfractionation of the total low density lipoproteins with minimal contamination allows and extremely accurate lipoprotein mass measurement of S_f > 400, total very low density lipoproteins and low density lipoproteins (LDL) by elemented CHN analysis. Physical and chemical data on LDL and high density lipoprotein (HDL) subfractions are in general agreement with earlier data. Lower molecular weight data are obtained for HDL subfractions than reported earlier; however this may be the result of the different fractionation procedures used. Presented in part at AOCS Meeting, New Orleans, April 1970.     

Studies on the transfer of tocopherol between lipoproteins

The net transfer of labeled α-tocopherol from donor to acceptor lipoproteins at physiological concentrations was investigated. Labeled lipoproteins were isolated i) followingin vitro addition of [3,4-³H]all rac-α-tocopherol to plasma, or ii) from plasma obtained 12–16 h after ingestion by normal subjects of an oral dose (100 mg each) of 2R,4′R,8′R-α-[5,7-(C²H₃)₂]tocopheryl acetate and 2S,4′R′,R-α-[5-C²H₃]tocopheryl acetate. A constant amount (on a protein basis) of labeled lipoprotein was incubated with an increasing amount of unlabeled acceptor lipoprotein for 2 h at 37°C. No discrimination between stereoisomers of α-tocopherol was detected. Labeled VLDL and labeled LDL (very low and low density lipoproteins, respectively) tended to retain their labeled tocopherol. Labeled high density lipoproteins (HDL) readily transferred the labeled tocopherol to VLDL (>60% transferred), while the transfer to LDL was dependent upon the ratio of labeled HDL/LDL with a lower net transfer at higher ratios. This dependency of the distribution of tocopherol upon the ratio of HDL/LDL was also observedin vivo. The tocopherol/mg HDL protein was measured in 11 subjects with varying HDL levels. As the %HDL in the plasma increased from 14 to 50%, the tocopherol/HDL protein also increased (r²=0.37,P<0.05).     

Liposomes: from a clinically established drug delivery system to a nanoparticle platform for theranostic nanomedicine

For decades, clinicians have used liposomes, self-assembled lipid vesicles, as nanoscale systems to deliver encapsulated anthracycline molecules for cancer treatment. The more recent proposition to combine liposomes with nanoparticles remains at the preclinical development stages; however, such hybrid constructs present great opportunities to engineer theranostic nanoscale delivery systems, which can combine simultaneous therapeutic and imaging functions. Many novel nanoparticles of varying chemical compositions are being developed in nanotechnology laboratories, but further chemical modification is often required to make these structures compatible with the biological milieu in vitro and in vivo. Such nanoparticles have shown promise as diagnostic and therapeutic tools and generally offer a large surface area that allows covalent and non-covalent surface functionalization with hydrophilic polymers, therapeutic moieties, and targeting ligands. In most cases, such surface manipulation diminishes the theranostic properties of nanoparticles and makes them less stable. From our perspective, liposomes offer structural features that can make nanoparticles biocompatible and present a clinically proven, versatile platform for further enhancement of the pharmacological and diagnostic efficacy of nanoparticles. In this Account, we describe two examples of liposome-nanoparticle hybrids developed as theranostics: liposome-quantum dot hybrids loaded with a cytotoxic drug (doxorubicin) and artificially enveloped adenoviruses. We incorporated quantum dots into lipid bilayers, which rendered them dispersible in physiological conditions. This overall vesicular structure allowed them to be loaded with doxorubicin molecules. These structures exhibited cytotoxic activity and labeled cells both in vitro and in vivo. In an alternative design, lipid bilayers assembled around non-enveloped viral nanoparticles and altered their infection tropism in vitro and in vivo with no chemical or genetic capsid modifications. Overall, we have attempted to illustrate how alternative strategies to incorporate nanoparticles into liposomal nanostructures can overcome some of the shortcomings of nanoparticles. Such hybrid structures could offer diagnostic and therapeutic combinations suitable for biomedical and even clinical applications.     

Glycosphingolipids of human plasma lipoproteins

The content and structure of glycosphingolipids (GSL) in human plasma lipoproteins were studies. The quantitative distribution of the neutral GSL(Glc-Cer, Gal-Glc-Cer, Gal-Gal-Glc-Cer, and GalNAc-Gal-Gal-Glc-Cer) and the principal ganglioside (AcNeu-Gal-Glc-Cer) within the different lipoprotein classes was similar to that of whole plasma. The total amounts (μmol glucose/100 ml plasma) of GSL in the plasma lipoproteins of three normal subjects were VLDL (very low density lipoproteins) (trace to 0.46), LDL (low density lipoproteins) (1.08–1.48), HDL₂ (high density lipoproteins₂) (0.62–0.85), and HDL₃ (high density lipoproteins₃) (trace to 0.28). In subjects with Lp(a) lipoproteins, HDL₂ rather than HDL₃ contained most of the GSL in HDL. When the data were corrected for differences in the plasma concentrations of the lipoproteins, the total amounts of GSL(nmol glucose/mg lipoprotein cholesterol) were VLDL(trace to 21.20), LDL(11.70–15.36), HDL₂(8.50–9.10), and HDL₃(3.12). No GSL were detected in lipoprotein deficient plasma. Mass spectrometry of the trimethylsilyl derivatives of the GSL in LDL showed major fragment ions characteristic of their individual structural components. The elevated plasma levels of the GSL(2–18 fold), in a homozygote for familial hypercholesterolemia, resided in LDL which contained an absolute increase (per mg lipoprotein cholesterol) of GSL. Most, if not all, of the plasma GSL are associated with plasma lipoproteins and may have an important role in their biological functions.     

Synthetic Guaiacol Derivatives as Promising Myeloperoxidase Inhibitors Targeting Atherosclerotic Cardiovascular Disease

Myeloperoxidase (MPO) is known to cause oxidative stress and inflammation leading to cardiovascular disease (CVD) complications. MPO-mediated oxidation of lipoproteins leads to dysfunctional entities altering the landscape of lipoprotein functionality. The specificity of guaiacol derivatives toward preventing MPO-mediated oxidation to limit MPO's harmful effects is unknown. Diligent in silico studies were accomplished for a portfolio of compounds with guaiacol as a building block. The compounds’ activity toward MPO inhibition was also validated. The role of these chemical entities in controlling MPO-mediated oxidation of lipoproteins (LDL and HDL) was shown to agree with our approach of developing powerful MPO inhibitors. The mechanism of MPO inhibition was demonstrated to be reversible in nature. This study reveals that there is great potential for guaiacol derivatives as therapeutics for CVD by modulating lipid profiles, reducing atherosclerotic plaque burden, and subsequently optimizing cardiovascular functions.     

Preparation and functional study of pH-sensitive amorphous calcium phosphate nanocarriers

Recently, multifunctional nanoparticles have shown great prospects in cancer treatment, which have the ability to simultaneously deliver the drug, image and target tumor cells. In this paper, we designed a luminescent nanoparticles platform based on hydrothermal hyaluronic acid/amorphous calcium phosphate (HA-FCNs/ACP) with multifunctional properties for drug delivery, bio-imaging, and targeting treatment. HA-FCNs/ACP shows an ability to load curcumin (Cur) with pH-sensitive responsive drug release behavior and excellent biocompatibility. HA-FCNs/ACP dispersed in the cytoplasm through the overexpressed CD44 receptor that is actively targeted into human lung cancer cells (A549 cells). Meanwhile, the viability of A549 cells was significantly inhibited in vitro. The prepared HA-FCNs and HA-FCNs/ACP both exhibit excellent targeted bioimaging performance on cancer cells. Hence, the as-prepared nanoparticles have promising applications in treating tumor disease.     

Increased amounts of cholesterol precursors in lipoproteins after ileal exclusion

Serum cholesterol precursor sterols reflect the activity of cholesterol synthesis. In this study, squalene, methyl sterol and lathosterol contents were studied in very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) of heterozygous familial hypercholesterolemia patients without and with ileal bypass. The contents of lathosterol and all methyl sterols (lanosterol, Δ^8,24-dimethylsterol, Δ⁸-dimetylsterol, Δ⁸-methostenol and methostenol), but not of squalene were increased in all lipoproteins by ileal bypass. The increase in the free methyl sterols was more marked than that in the esterified ones. The percentage esterification of the methyl sterols was highest in HDL and lowest in VLDL. Lipoprotein methyl sterol contents were positively correlated with each other and with cholesterol synthesis. The methyl sterols were slightly concentrated in LDL, and squalene strongly concentrated in VLDL. It is concluded that long-term stimulation of cholesterol synthesis increases the methyl sterols in all lipoproteins.