ABSTRACT
Lifestyle choices play a significant role in the etiology of atherosclerosis. Male Apoe-/- mice that develop spontaneous atherosclerotic lesions were fed 0%, 0.3%, and 0.4% mangosteen extracts, composed largely of α-mangostin (MG), for 17 weeks. Body weight gains were significantly decreased in both MG-treated groups compared to the control, but the general condition remained good throughout the study. The levels of total cholesterol (decreased very-low-density lipoprotein in lipoprotein profile) and triglycerides decreased significantly in the MG-treated mice in conjunction with decreased hepatic HMG-CoA synthase and Fatty acid transporter. Additionally, increased serum lipoprotein lipase activity and histopathology further showed a significant reduction in atherosclerotic lesions at both levels of MG exposure. Real-time PCR analysis for macrophage indicators showed a significant elevation in the levels of Cd163, an M2 macrophage marker, in the lesions of mice receiving 0.4% MG. However, the levels of Nos2, associated with M1 macrophages, showed no change. In addition, quantitative immunohistochemical analysis of macrophage subtypes showed a tendency for increased M2 populations (CD68âº/CD163âº) in the lesions of mice given 0.4% MG. In further analysis of the cytokine-polarizing macrophage subtypes, the levels of Interleukin13 (Il13), associated with M2 polarization, were significantly elevated in lesions exposed to 0.4% MG. Thus, MG could suppress the development of atherosclerosis in Apoe-/- mice, possibly through an M2 macrophage-mediated mechanism.
Subject(s)
Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Macrophages/metabolism , Xanthones/therapeutic use , Animals , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Atherosclerosis/blood , Atherosclerosis/genetics , Cholesterol/blood , Macrophages/drug effects , Male , Mice , Mice, Knockout , Plaque, Atherosclerotic/blood , Plaque, Atherosclerotic/drug therapy , Plaque, Atherosclerotic/genetics , Plaque, Atherosclerotic/metabolism , Xanthones/chemistryABSTRACT
Anti-androgens are used to treat prostate cancer. Here, we report that hydroxyxanthones from a plant extract act as anti-androgens in androgen receptor (AR)-positive prostate cancer LNCaP cells. Anti-androgenic activity of the ethanol extract from Garcinia subelliptica was observed in a luciferase assay using LNCaP/MMTV cells with a stably integrated mouse mammary tumor virus (MMTV) promoter. HPLC-based activity profiling followed by a chemical library-based assay strategy enabled the rapid identification of several active principles bearing a xanthone core substituted with hydroxyl and isoprenyl groups. Among the active compounds, 2-(1,1-dimethyl-allyl)-1,4,5,6-tetrahydroxyxanthone (subelliptenone F) was identified as a potent inhibitor of AR transcriptional activity. The structure-activity relationship of some substituents on the xanthone core was also determined using the chemical library-based bioassay. A quantitative RT-PCR analysis revealed that treatment with the compound resulted in a significant reduction in AR-induced gene (KLK3) expression. Hydroxyxanthone may be a possible candidate for the development of a new anti-androgenic molecule.
Subject(s)
Androgen Antagonists/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Garcinia/chemistry , Gene Expression Regulation, Neoplastic/drug effects , Prostatic Neoplasms/metabolism , Receptors, Androgen/metabolism , Xanthones/pharmacology , Androgen Antagonists/isolation & purification , Androgen Antagonists/therapeutic use , Animals , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/therapeutic use , Cell Line, Tumor , Gene Expression/drug effects , Humans , Kallikreins/genetics , Kallikreins/metabolism , Male , Mice , Phytotherapy , Prostate-Specific Antigen/genetics , Prostate-Specific Antigen/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Structure-Activity Relationship , Xanthones/isolation & purification , Xanthones/therapeutic useABSTRACT
We tested the peroxisome proliferator-activated receptor (PPAR)δ agonistic activity of a Garcinia mangostana pericarp extract to develop a treatment for the metabolic syndrome, and demonstrated γ-mangostin to be an active compound on the basis of a luciferase reporter gene assay. γ-Mangostin induced the expression of the uncoupling protein-3 (UCP-3) gene which is related to energy expenditure and fat metabolism in L6 cells. We showed that γ-mangostin is a dual agonist that activates both PPARδ and PPARα. γ-Mangostin also induced the expression of acyl-CoA synthase and carnitine palmitoyl-transferase 1A genes in HepG2 cells. These results suggest the potential of γ-mangostin as a preventive agent of the metabolic syndrome.
