Mono- or Diphenylpyridazines Connected to <i>N</i>-(2,4-Difluorophenyl)-<i>N</i>‘-heptylurea as Acyl-CoA:Cholesterol Acyltransferase Inhibitors

Mono- and diphenylpyridazine ureido derivatives, structurally related to DuP 128, were synthesized and tested for their inhibitory activity against ACAT isolated from rat liver microsomes. Several compounds displayed ACAT inhibition in the micromolar range. The amino derivatives 4a−c were also tested against hACAT-1 and hACAT-2 isoforms. They retained the same trend shown in the previous assay. Modeling studies on representative terms were performed. Significant similarities between the geometrical features of the model DuP 128 and the most active pyridazine derivatives were observed

Biphenyl versus Phenylpyridazine Derivatives: The Role of the Heterocycle in a Series of Acyl-CoA:Cholesterol Acyl Transferase Inhibitors

A series of alkylamido- (1) and alkylaminobiphenyl (2) derivatives were synthesized as possible bioisosters of the reported ACAT inhibitors phenylpyridazine analogues (I). Both 1 and 2 were tested on the human ACAT-1 and ACAT-2 isoforms. The amino derivatives 2 were found to be inactive, contrary to the related pyridazine derivatives. By contrast, the ortho-substituted amides 1a and 1d showed an interesting activity. These results support the essential role of the pyridazine nucleus. Modeling studies were also performed

Flavonoids from <i>Lindera glauca</i> Blume as low-density lipoprotein oxidation inhibitors

<div><p>In order to identify antioxidant flavonoids from <i>Lindera glauca</i> Blume, we performed phytochemical analysis of <i>L</i>. <i>glauca</i> Blume heartwood and isolated eight flavonoids – lindeglaucol (<b>1</b>), lindeglaucone (<b>2</b>), cilicicone B (<b>3</b>), tamarixetin 3-<i>O</i>-α-L-rhamnoside (<b>4</b>), procyanidin A2 (<b>5</b>), cinnamtannin B1 (<b>6</b>), cinnamtannin D1 (<b>7</b>), and procyanidin A1 (<b>8</b>) – through repeated column chromatography over silica gel (SiO₂), octadecyl silica gel (ODS) and Sephadex LH-20. The chemical structures of compounds <b>1</b>–<b>8</b> were elucidated from spectroscopic data (NMR, IR and MS). The low-density lipoprotein oxidation inhibitory activities of the isolated compounds were evaluated <i>in vitro</i> by using the thiobarbituric acid reactive substances assay. Compounds <b>5</b>–<b>8</b> exhibited high inhibition activity, comparable to the positive control butyl hydroxyl toluene. Compounds <b>2</b> and <b>3</b> were slightly less active, while <b>1</b> and <b>4</b> expressed low activity.</p></div

LDL-Antioxidant Pterocarpans from Roots of <i>Glycine max</i> (L.) Merr.

The methanolic root extract of Glycine max (L.) Merr. was chromatographed, which yielded 10 flavonoids, including three isoflavones 1−3, five pterocarpans 4−8, one flavonol 9, and one anthocyanidin 10. All isolated compounds were examined for LDL-antioxidant activities using four different assay systems on the basis of Cu2+-mediated oxidation. Among them, seven compounds showed potent LDL-antioxidant activities in the thiobarbituric acid reactive substances (TBARS) assay, the lag time of conjugated diene formation, relative electrophoretic mobility (REM), and fragmentation of apoB-100 on copper-mediated LDL oxidation. Three pterocarpans 4, 6, and 7, never reported as LDL-antioxidant, showed potent activities with IC50 values of 19.8, 0.9, 45.0 μM, respectively, in comparison with probucol (IC50 = 5.6 μM) as positive control. Interestingly, coumestrol 6 (IC50 = 0.9 μM) showed 20 times more activity in the TBARS assay than genistein (IC50 = 30.1 μM) and daidzein (IC50 = 21.6 μM), representative antioxidants in soybean. Moreover, coumestrol 6 had an extended lag time of 190 min at 3.0 μM in measuring conjugated diene formation, while both genistein (120 min) and daidzein (93 min) lag times were extended to less than 120 min at the same concentration. Keywords: Glycine max (L.) Merr. roots; LDL-antioxidation; atherosclerosis; pterocarpan; coumestro

Relationship between Lp-PLA₂ activity from PBMCs or plasma ox-LDL and plasma Lp-PLA₂ activity according to plasma ox-LDL (below or above the median level of 48.715 U/L) in postmenopausal women.

<p>^§tested by log-transformed. Tested by Pearson correlation (<i>r₀</i>) or partial correlation analysis (<i>r₁, r₂</i>). <i>r</i>₀: correlation coefficient, unadjusted. <i>r₁</i>: correlation coefficient after adjusted for age, BMI, and alcohol consumption. <i>r₂</i>: correlation coefficient after adjusted for age, BMI, alcohol consumption, and LDL-cholesterol.</p

Oxidative stress markers, cytokines, and Lp-PLA₂ activity according to menopausal status.

<p>Mean ± SD. Tested by independent t-test or general linear model with the adjustment.</p>∮<p>tested by log-transformed. P₀: unadjusted, P₁: adjusted for age, BMI and alcohol consumption.</p

Clinical characteristics of the study participants according to menopausal status.

<p>Means ± SD. Tested by independent t-test or general linear model with the adjustment.</p>∮<p>tested by log-transformed P₀: unadjusted, P₁: adjusted for age, BMI, and alcohol consumption.</p

Lp-PLA₂ activity in plasma and supernatants from nonstimulated PBMC cultures and oxidative stress markers according to menopausal status and plasma ox-LDL levels (below or above the median level of 48.715 U/L).

<p>Data are means ± SD. ^§tested by log-transformed. P₀: unadjusted, tested by one-way ANOVA with Bonferroni method P₁: adjusted for BMI and alcohol consumption, tested by general linear model (GLM) analysis. P₂: adjusted for age, BMI, and alcohol consumption, tested by GLM analysis.</p

Soy Leaf Extract Containing Kaempferol Glycosides and Pheophorbides Improves Glucose Homeostasis by Enhancing Pancreatic β‑Cell Function and Suppressing Hepatic Lipid Accumulation in <i>db</i>/<i>db</i> Mice

This study investigated the molecular mechanisms underlying the antidiabetic effect of an ethanol extract of soy leaves (ESL) in <i>db</i>/<i>db</i> mice. Control groups (<i>db</i>/+ and <i>db</i>/<i>db</i>) were fed a normal diet (ND), whereas the <i>db</i>/<i>db</i>-ESL group was fed ND with 1% ESL for 8 weeks. Dietary ESL improved glucose tolerance and lowered plasma glucose, glycated hemoglobin, HOMA-IR, and triglyceride levels. The pancreatic insulin content of the <i>db</i>/<i>db</i>-ESL group was significantly greater than that of the <i>db</i>/<i>db</i> group. ESL supplementation altered pancreatic <i>IRS1</i>, <i>IRS2</i>, <i>Pdx1</i>, <i>Ngn3</i>, <i>Pax4</i>, <i>Ins1</i>, <i>Ins2</i>, and <i>FoxO1</i> expression. Furthermore, ESL suppressed lipid accumulation and increased glucokinase activity in the liver. ESL primarily contained kaempferol glycosides and pheophorbides. Kaempferol, an aglycone of kaempferol glycosides, improved β-cell proliferation through IRS2-related FoxO1 signaling, whereas pheophorbide <i>a</i>, a product of chlorophyll breakdown, improved insulin secretion and β-cell proliferation through IRS1-related signaling with protein kinase A in MIN6 cells. ESL effectively regulates glucose homeostasis by enhancing IRS-mediated β-cell insulin signaling and suppressing SREBP-1-mediated hepatic lipid accumulation in <i>db</i>/<i>db</i> mice