ABSTRACT
DW1029M is a botanical extract consisting of Morus bark and Puerariae radix, produced by Dong-Wha Pharmaceutical, for nephroprotective drug development; it has been in phase II clinical trials in Korea. In our mechanistic investigations, we found that DW1029M inhibits advanced glycation end products (AGEs), rat lens aldose reductase (RLAR), and transforming growth factor (TGF)-ß1 signaling, all of which are implicated in diabetic complications such as diabetic nephropathy and diabetic retinopathy. DW1029M inhibits AGE formation via Fe(2+) chelation. The extract contains 13 active constituents that inhibit AGE formation, 8 active constituents that inhibit RLAR activity, and 1 inhibitor of TGF-ß1 signaling. Our results suggest DW1029M protects against diabetic nephropathy via blockade of AGE formation, RLAR activity, and TGF-ß1 signaling.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Glycation End Products, Advanced/antagonists & inhibitors , Morus , Plant Extracts/pharmacology , Pueraria , Signal Transduction/drug effects , Transforming Growth Factor beta1/antagonists & inhibitors , Aldehyde Reductase/drug effects , Aldehyde Reductase/metabolism , Animals , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/metabolism , Diabetic Nephropathies/prevention & control , Diabetic Retinopathy/prevention & control , Disease Models, Animal , Female , Glycation End Products, Advanced/drug effects , Glycation End Products, Advanced/metabolism , In Vitro Techniques , Lens, Crystalline/enzymology , Plant Extracts/therapeutic use , Rats , Rats, Sprague-Dawley , Streptozocin/adverse effects , Transforming Growth Factor beta1/drug effects , Transforming Growth Factor beta1/metabolismABSTRACT
Matrix metalloproteinases (MMPs) play an important role in tissue remodeling during normal physiological situations and pathological implications such as tumor invasion and metastasis. MMP inhibitors were screened from extracts of medicinal herbs by an enzymatic assay using the MMP-14 catalytic domain. Among samples tested, a methanol extract of the root of Dalbergia odorifera T. CHEN (Leguminosae) showed the strongest inhibitory activity. The inhibitory component was purified through fractionation methods and identified as fisetin, abundant in many fruits and vegetables. In addition to inhibition of MMP-14, fisetin inhibits MMP-1, MMP-3, MMP-7, and MMP-9, more efficiently than a naturally occurring MMP inhibitor tetracycline. Fisetin dose-dependently inhibits proliferation of fibrosarcoma HT-1080 cells and human umbilical vascular endothelial cells (HUVECs), MMP-14-mediated activation of proMMP-2 in HT-1080 cells, invasiveness of HT-1080 cells, and in vitro tube formation of HUVECs. Therefore, fisetin could be valuable as a chemopreventive agent against cancer and a lead compound for development of therapeutic MMP inhibitors.
Subject(s)
Flavonoids/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Matrix Metalloproteinase Inhibitors/pharmacology , Matrix Metalloproteinases/metabolism , Plant Extracts/pharmacology , Apolipoproteins E/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Chemoprevention , Dalbergia/chemistry , Dose-Response Relationship, Drug , Enzyme Precursors/genetics , Enzyme Precursors/metabolism , Flavonols , Gelatinases/genetics , Gelatinases/metabolism , Human Umbilical Vein Endothelial Cells/pathology , Humans , Neoplasm Invasiveness , Plant Roots/chemistryABSTRACT
Medicinal herbs are increasingly used in the search for safe and efficient drug candidates for hepatitis C virus infection. In this study, we have investigated the anti-HCV effect of compounds from Mori Cortex Radicis. During a screening for extracts with anti-HCV affinity from medicinal plants (173 species), the methanol extract of Mori Cortex Radicis was selected. Fractionation of the extract by monitoring antiviral activity with a replicon cell-based assay resulted in the isolation of five compounds, mulberroside C ( 1), moracin P ( 2), moracin O ( 3), moracin M ( 4) and mulberrofuran K ( 5) from the ethyl acetate-soluble fraction. Compounds 1 approximately 4 showed significant inhibitory activities. Compounds 2 and 3 showed potent inhibitory activity (IC (50) 35.6 microM, 80.8 microM, respectively) in the replicon cell assay, which was confirmed by NS3 helicase inhibitory activity (IC (50) 42.9 microM, 27.0 microM, respectively).
