Dihydrostilbenes and flavonoids from whole plants of Jacobaea vulgaris.

The isolation of previously undescribed 12 compounds from the MeOH extract of Jacobaea vulgaris whole plants is disclosed, comprising 11 dihydrostilbenes (1-11) and one flavanone (12), and eight known compounds (six flavonoids, one dihydrostilbene, and one caffeoylquinic acid). Structural elucidation employed spectroscopic methods, including 1D and 2D NMR spectroscopy, HRESIMS, and ECD calculations. Evaluation of the compounds' effects on PCSK9 and LDLR mRNA expression revealed that compounds 1 and 3 downregulated PCSK9 mRNA while increasing LDLR mRNA expression, suggesting potential cholesterol-lowering properties.

Stereochemical assignment of clerodane-type diterpenes from the fruits of Casearia grewiifolia and their ability to inhibit PCSK9 expression.

More than 20 natural products have been reported to modulate PCSK9-mediated cholesterol regulation, and small-molecule-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors continue to be developed and identified. Here, twelve undescribed clerodane-type diterpenes (1-9 and 12-14) and two known compounds were isolated from the chloroform-soluble extract of the dried fruits of Casearia grewiifolia Vent. using a PCSK9 mRNA expression monitoring assay. Among the undescribed compounds, the stereochemistry of two diastereomeric grewiifolins A and B (1 and 2) were extensively elucidated using 2D Nuclear Overhauser Effect Spectroscopy (NOESY) experiments, excitation-sculptured indirect detection experiments (EXSIDE), interproton distance analyses, and computational calculations that included quantum chemical shift calculations combined with DP4+ analysis. All isolates were assessed for their inhibitory activity against PCSK9 and IDOL mRNA expression. Among the compounds tested, compound 3 inhibited PCSK9 and IDOL mRNA expression.

Acyclic Triterpenoids from Alpinia katsumadai Seeds with Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Secretion Inhibitory Activity.

Cholesterol is one of the primary causes of cardiovascular disease. Investigating and developing potential drugs to effectively treat hypercholesterolemia are therefore of critical importance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been developed to lower the levels of low-density lipoprotein cholesterol in patients with hypercholesterolemia. In this study, we aimed to identify compounds that inhibit the PCSK9 mRNA expression and secretion. The bioassay-guided investigation of Alpinia katsumadai seeds utilizing a PCSK9 mRNA expression monitoring assay yielded the isolation and identification of seven new compounds. Among these were three acyclic triterpenoids (1-3), an acyclic sesquiterpenoid (5), one arylpentanoid (6), and two diarylheptanoids (7 and 8), alongside 10 known compounds. The structures of these compounds were determined using nuclear magnetic resonance (NMR) spectroscopy, vibrational circular dichroism (VCD), and electronic circular dichroism (ECD). The absolute configurations of compounds 1 and 2 were identified by comparing the calculated and experimental VCD data as the ECD method was unable to distinguish the diastereomers. All the isolated compounds were evaluated for their regulatory effects on the low-density lipoprotein receptor (LDLR) and PCSK9 mRNA expression, as well as PCSK9 secretion. Of the tested compounds, two of the acyclic triterpenoids (1 and 2) demonstrated potent effects in downregulating PCSK9 at both the mRNA and protein levels, compared with the positive control (berberine chloride). Additionally, compound 1 inhibited PCSK9 secretion to a level comparable to that of berberine chloride. This study identifies compounds that inhibit PCSK9 mRNA expression and secretion, offering significant contributions to the development of novel drugs for the effective treatment of hypercholesterolemia..

Chemical constituents from Morus alba with proprotein convertase subtilisin/kexin type 9 expression and secretion inhibitory activity.

Six new flavanones, including sanggenol W (1), morusalnol D-F (2-4) and neovanone A and B (5 and6), and fourteen known compounds were isolated from the methanol extract of the dried root bark of Morus alba using various column chromatographic methods. Their structures were elucidated using spectroscopic methods. The isolated compounds were tested in vitro for LDLR, PCSK9 and IDOL mRNA regulatory activity, and it was found that betulinic acid (13) showed the most potent effect on downregulation of PCSK9 and upregulation of LDLR at both mRNA and protein levels, showing comparable results to berberine, the positive control. In addition, betulinic acid (13) inhibited PCSK9 secretion, indicating its role as a future PCSK9 synthesis inhibitor.

Isocoumarins and Benzoquinones with Their Proprotein Convertase Subtilisin/Kexin Type 9 Expression Inhibitory Activities from Dried Roots of Lysimachia vulgaris.

A phytochemical investigation of the n-hexane-soluble chemical constituents of Lysimachia vulgaris roots allowed for selection using a proprotein convertase subtilisin-kexin type 9 (PCSK9) mRNA expression monitoring assay in HepG2 cells. This led to the isolation of two previously undescribed isocoumarins of natural origin, 8'Z,11'Z-octadecadienyl-6,8-dihydroxyisocoumarin (1) and 3-pentadecyl-6,8-dihydroxyisocoumarin (2), along with 20 previously reported compounds (3-22). All of the structures were established using NMR spectroscopic data and MS analysis. Of the isolates, 1 and 3 were found to inhibit PCSK9, inducible degrader of the low-density lipoprotein receptor (IDOL), and SREBP2 mRNA expression. Further computational dockings of both 1 and 3 to C-ring of IDOL E3 ubiquitin ligase predicted the mechanism behind the inhibitory effect of these compounds on the enzyme.