Associations of High-Density Lipoprotein Functionality with Coronary Plaque Characteristics in Diabetic Patients with Coronary Artery Disease: Integrated Backscatter Intravascular Ultrasound Analysis.

High-density lipoprotein (HDL) functionality has been reported to be associated with coronary artery disease (CAD). However, little is known about the impact of HDL functionality on coronary atherosclerosis. Thirty-eight type 2 diabetic patients with CAD who underwent percutaneous coronary intervention were examined.

Structural Development of Silicon-Containing Retinoids: Structure-Activity Relationship Study of the Hydrophobic Pharmacophore of Retinobenzoic Acids Using Silyl Functionalities.

We designed and synthesized a series of retinobenzoic acids bearing various silyl functionalities in order to explore in detail the structure-activity relationship (SAR) at the hydrophobic moiety of retinoids. Among the synthesized compounds, 24 c bearing a t-butyldimethylsilyl (TBS) group at the hydrophobic site exhibited potent retinoid activity comparable to that of the lead compound Am555S (4). Compound 24 c exhibited transcription-promoting activity towards all three subtypes of retinoic acid receptor (RAR), but showed the highest activity towards RARγ, in contrast to the high RARα-selectivity of Am80 (3) and Am555S (4).

Lithocholic Acid Derivatives as Potent Vitamin D Receptor Agonists.

Lithocholic acid () was identified as a second endogenous ligand of vitamin D receptor (VDR), though its activity is very weak. In this study, we designed novel lithocholic acid derivatives based on the crystal structure of VDR-ligand-binding domain (LBD) bound to . Among the synthesized compounds, bearing a 2-hydroxy-2-methylprop-1-yl group instead of the 3-hydroxy group at the 3α-position of showed dramatically increased activity in HL-60 cell differentiation assay, being at least 10 000 times more potent than lithocholic acid () and 3 times more potent than 1α,25-dihydroxyvitamin D ().

Development of Androgen-Antagonistic Coumarinamides with a Unique Aromatic Folded Pharmacophore.

First-generation nonsteroidal androgen receptor (AR) antagonists, such as flutamide () and bicalutamide (), are effective for most prostate cancer patients, but resistance often appears after several years due to the mutation of AR. Second-generation AR antagonists are effective against some of these castration-resistant prostate cancers, but their structural variety is still limited. In this study, we designed and synthesized 4-methyl-7-(-alkyl-arylcarboxamido)coumarins as AR antagonist candidates and evaluated their growth-inhibitory activity toward androgen-dependent SC-3 cells.

Anti-atherosclerotic effects of an improved apolipoprotein A-I mimetic peptide.

Background: Apolipoprotein (Apo)A-I is a major protein component of high-density lipoprotein (HDL) that causes cholesterol efflux from peripheral cells through ATP-binding cassette transporter A1 (ABCA1) and the generation of HDL. Furthermore, it has a possible protective function against atherosclerotic cardiovascular disease (ASCVD). We previously developed a novel ApoA-I mimetic peptide without phospholipids (Fukuoka University ApoA-I Mimetic Peptide, FAMP).

Development of novel lithocholic acid derivatives as vitamin D receptor agonists.

Lithocholic acid (2) was identified as the second endogenous ligand of vitamin D receptor (VDR), though its binding affinity to VDR and its vitamin D activity are very weak compared to those of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D (1). 3-Acylated lithocholic acids were reported to be slightly more potent than lithocholic acid (2) as VDR agonists. Here, aiming to develop more potent lithocholic acid derivatives, we synthesized several derivatives bearing a 3-sulfonate/carbonate or 3-amino/amide substituent, and examined their differentiation-inducing activity toward human promyelocytic leukemia HL-60 cells.

Comparison of Two Homogeneous LDL-Cholesterol Assays Using Fresh Hypertriglyceridemic Serum and Quantitative Ultracentrifugation Fractions.

Aim: The purpose of this study was to compare two homogeneous assays of low-density lipoprotein-cholesterol (LDL-C) with a modified beta quantification reference measurement for LDL-C (BQ-LDL), fractions of chylomicron (CM), very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) by quantitative ultracentrifugation in patients with hypertriglyceridemia.

Methods: Two homogeneous LDL-C assays (LDL-C(K), Kyowa Medex and LDL-C(S), Sekisui Medical) were used to measure 198 samples of fresh anonymized leftover sera with hypertriglyceridemia (≥ 150 mg/dL). Of these, 32 samples with discrepant LDL-C levels or hypertriglyceridemia (≥ 400 mg/dL) were used for further analysis.

Improved Ga-labeling method using ethanol addition: Application to the α-helical peptide DOTA-FAMP.

We examined the Ga labeling of the α-helical peptide, DOTA-FAMP, and evaluated conformational changes during radiolabeling. Ga-DOTA-FAMP is a positron emission tomography probe candidate for atherosclerotic plaques. The labeling yield achieved by Zhernosekov's method (using acetone for Ga purification) was compared with that achieved by the original and 2 modified Mueller's methods (using NaCl solution).

The ApoA-I mimetic peptide FAMP promotes recovery from hindlimb ischemia through a nitric oxide (NO)-related pathway.

Background/objective: HDL has various atheroprotective functions and improves endothelial function. Apolipoprotein A-I (apoA-I) is a major protein of HDL and plays a crucial role in HDL functions. We developed a novel apoA-I mimetic peptide, FAMP (Fukuoka University ApoA-I Mimetic Peptide).

Design and synthesis of 4-benzyl-1-(2H)-phthalazinone derivatives as novel androgen receptor antagonists.

The androgen receptor (AR) plays important roles in multiple physiological functions, including differentiation, growth, and maintenance of male reproductive organs, and also has effects on hair and skin. In this paper, we report the synthesis of nonsteroidal AR antagonists having a 4-benzyl-1-(2H)-phthalazinone skeleton. Among the synthesized compounds, 11c with two ortho-substituents on the phenyl group potently inhibited SC-3 cell proliferation (IC50: 0.

Impact of cigarette smoking cessation on high-density lipoprotein functionality.

Background: Smoking cessation reduces the risk of cardiovascular disease (CVD) and improves clinical outcomes in public health. We studied the effect of smoking cessation on high-density lipoprotein (HDL) functionality. METHODS AND RESULTS: We randomly treated 32 smokers with varenicline or a transdermal nicotine patch as part of a 12-week smoking cessation program (The VN-SEESAW Study).

Structural development of p-carborane-based potent non-secosteroidal vitamin D analogs.

Non-secosteroidal vitamin D receptor (VDR) ligands are promising candidates for many clinical applications. We recently developed novel non-secosteroidal VDR agonists based on p-carborane (an icosahedral carbon-containing boron cluster) as a hydrophobic core structure. Here, we report the design, synthesis and biological evaluation of carborane-based vitamin D analogs bearing various substituents at the diol moiety.

Design and synthesis of tetraol derivatives of 1,12-dicarba-closo-dodecaborane as non-secosteroidal vitamin D analogs.

Vitamin D receptor (VDR), a nuclear receptor for 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3, 1), is a promising target for multiple clinical applications. We recently developed non-secosteroidal VDR ligands based on a carbon-containing boron cluster, 1,12-dicarba-closo-dodecaborane (p-carborane), and examined the binding of one of them to VDR by means of crystallographic analysis. Here, we utilized that X-ray structure to design novel p-carborane-based tetraol-type vitamin D analogs, and we examined the biological activities of the synthesized compounds.

Improved survival rate after myocardial infarction using an inducible cholesterol efflux (iCE) peptide: FAMP.

Background: There have been no previous reports that apolipoprotein (apo) A-I mimetic peptide improves survival rate after myocardial infarction (MI).

Method And Results: Male C57Bl/6J mice were subjected to left coronary artery permanent ligation as a model of MI. We synthesized a novel 24-amino acid apoA-I mimetic peptide-type5 (FAMP5), which potently removes cholesterol via specific ATP-binding cassette transporter A1 (ABCA1).

Synthesis and structure-activity relationship of p-carborane-based non-secosteroidal vitamin D analogs.

1α,25-Dihydroxyvitamin D3 [1α,25(OH)₂D₃: 1] is a specific modulator of nuclear vitamin D receptor (VDR), and novel vitamin D analogs are therapeutic candidates for multiple clinical applications. We recently developed non-secosteroidal VDR agonists bearing a p-carborane cage (a carbon-containing boron cluster) as a hydrophobic core structure. These carborane derivatives are structurally quite different from classical secosteroidal vitamin D analogs.

Molecular diagnosis of mitochondrial respiratory chain disorders in Japan: focusing on mitochondrial DNA depletion syndrome.

Background: Although mitochondrial respiratory chain disorders (MRCD) are one of the most common congenital metabolic diseases, there is no cumulative data on enzymatic diagnosis and clinical manifestation for MRCD in Japan and Asia.

Methods: We evaluated 675 Japanese patients having profound lactic acidemia, or patients having symptoms or signs of multiple-organ origin simultaneously without lactic acidemia on respiratory chain enzyme activity assay and blue native polyacrylamide gel electrophoresis. Quantitative polymerase chain reaction was used to diagnose mitochondrial DNA depletion syndrome (MTDPS).

Therapeutic approaches to the regulation of metabolism of high-density lipoprotein. Novel HDL-directed pharmacological intervention and exercise.

High-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles transport cholesterol in plasma and play an important role in cellular cholesterol homeostasis, which influences cell function. The risk of coronary artery disease (CAD) associated with high levels of LDL-cholesterol (LDL-C) can be reduced by treatment with statins, which reduce LDL-C levels by inhibiting cellular cholesterol synthesis. However, patients who are treated with high doses of statins, especially secondary CAD prevention, regardless of their resulting LDL-C levels, are still at high risk of CAD.

Novel molecular imaging of atherosclerosis with gallium-68-labeled apolipoprotein A-I mimetic peptide and positron emission tomography.

Background:  High-density lipoprotein (HDL) plays a major role in reverse cholesterol transport. Many researchers have been working to enhance the biochemical function of HDL for use in therapy. Although HDL therapy using injections of apolipoprotein (apo)-A-I mimetics, apo A-I Milano or full-length apo A-I is dramatically effective, it is still unclear whether apo A-I or apo A-I mimetics actually enter atherosclerotic plaque and remove cholesterol from the lipid burden.

Structure-activity relationship study on benzoic acid part of diphenylamine-based retinoids.

Based on structure-activity relationship studies of the benzoic acid part of diphenylamine-based retinoids, the potent RXR agonist 4 was derivatized to obtain retinoid agonists, synergists, and an antagonist. Cinnamic acid derivatives 5 and phenylpropionic acid derivatives 6 showed retinoid agonistic and synergistic activities, respectively. The difference of the activities is considered to be due to differences in the flexibility of the carboxylic acid-containing substituent on the diphenylamine skeleton.

Reactivity of direct assays for low-density lipoprotein (LDL) cholesterol toward charge-modified LDL in hypercholesterolemia.

Background: The aim of the present study was to compare 2 direct measurements for low-density lipoprotein cholesterol (LDL-C) with the Friedewald calculation (LDL-C [F]) in serum and their relationship with size-and charge-based LDL subfractions in serum ultracentrifugation fractions in patients with hypercholesterolemia (HC).

Methods And Results: Serum samples from 283 HC patients who participated in a statin trial (the PATROL trial) were analyzed. Homogeneous assays for LDL-C were performed using reagents from Sekisui Medical (LDL-C [Se]) and Kyowa Medex (LDL-C [Ky]).

Novel vitamin D receptor ligands bearing a spherical hydrophobic core structure--comparison of bicyclic hydrocarbon derivatives with boron cluster derivatives.

Vitamin D receptor (VDR) is a nuclear receptor for 1α,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)), and is an attractive target for multiple clinical applications. We recently developed novel non-secosteroidal VDR ligands bearing a hydrophobic p-carborane cage, thereby establishing the utility of this spherical hydrophobic core structure for development of VDR ligands. Here, we synthesized two series of novel non-secosteroidal VDR ligands with different spherical hydrophobic cores, that is, bicyclo[2.

Boron cluster-based development of potent nonsecosteroidal vitamin D receptor ligands: direct observation of hydrophobic interaction between protein surface and carborane.

We report here the design and synthesis of a novel vitamin D receptor (VDR) agonist whose hydrophobic core structure is p-carborane (1,12-dicarba-closo-dodecaborane, an icosahedral carbon-containing boron cluster having remarkable thermal and chemical stability and a characteristically hydrophobic B-H surface). This carborane-based VDR ligand exhibited moderate vitamin D activity, comparable to that of the natural hormone, despite its simple and flexible structure. X-ray structure analysis provided direct evidence that the carborane cage binds to the hydrophobic surface of the ligand-binding pocket of the receptor, promoting transition to the active conformation.

Diphenylamine-based retinoid antagonists: regulation of RAR and RXR function depending on the N-substituent.

Based upon the structure-activity relationships of diphenylamine derivatives with retinoid synergistic activity (RXR agonists), novel diphenylamine derivatives with a long alkyl chain (9a and 9b) or a benzyl group (10a-f) as the N-substituent were designed and synthesized. All the synthesized compounds dose-dependently inhibited HL-60 cell differentiation induced by 3.3×10(-10)M Am80.