Marein

Natural chalcones as dual inhibitors of HDACs and NF-kappaB.[Pubmed:22710558]

Oncol Rep. 2012 Sep;28(3):797-805.

Histone deacetylase enzymes (HDACs) are emerging as a promising biological target for cancer and inflammation. Using a fluorescence assay, we tested the in vitro HDAC inhibitory activity of twenty-one natural chalcones, a widespread group of natural products with well-known anti-inflammatory and antitumor effects. Since HDACs regulate the expression of the transcription factor NF-kappaB, we also evaluated the inhibitory potential of the compounds on NF-kappaB activation. Only four chalcones, isoliquiritigenin (no. 10), butein (no. 12), homobutein (no. 15) and the glycoside Marein (no. 21) showed HDAC inhibitory activity with IC50 values of 60-190 microM, whereas a number of compounds inhibited TNFalpha-induced NF-kappaB activation with IC50 values in the range of 8-41 microM. Interestingly, three chalcones (nos. 10, 12 and 15) inhibited both TNFalpha-induced NF-kappaB activity and total HDAC activity of classes I, II and IV. Molecular modeling and docking studies were performed to shed light into dual activity and to draw structure-activity relationships among chalcones (nos. 1-21). To the best of our knowledge this is the first study that provides evidence for HDACs as potential drug targets for natural chalcones. The dual inhibitory potential of the selected chalcones on NF-kappaB and HDACs was investigated for the first time. This study demonstrates that chalcones can serve as lead compounds in the development of dual inhibitors against both targets in the treatment of inflammation and cancer.

Protective effects of marein on high glucose-induced glucose metabolic disorder in HepG2 cells.[Pubmed:27387397]

Phytomedicine. 2016 Aug 15;23(9):891-900.

BACKGROUND: Our previous study has shown that Coreopsis tinctoria increases insulin sensitivity and regulates hepatic metabolism in high-fat diet (HFD)-induced insulin resistance rats. However, it is unclear whether or not Marein, a major compound of C. tinctoria, could improve insulin resistance. Here we investigate the effect and mechanism of action of Marein on improving insulin resistance in HepG2 cells. METHODS: We investigated the protective effects of Marein in high glucose-induced human liver carcinoma cell HepG2. In kinase inhibitor studies, genistein, LY294002, STO-609 and compound C were added to HepG2 cells 1h before the addition of Marein. Transfection with siRNA was used to knock down LKB1, and 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2-deoxyglucose (2-NBDG), an effective tracer, was used to detect glucose uptake. RESULTS: The results showed for the first time that Marein significantly stimulates the phosphorylation of AMP-activated protein kinase (AMPK) and the Akt substrate of 160kDa (AS160) and enhanced the translocation of glucose transporter 1 (GLUT1) to the plasma membrane. Further study indicated that genistein (an insulin receptor tyrosine kinase inhibitor) altered the effect of Marein on glucose uptake, and both LY294002 (a phosphatidylinositol 3-kinase inhibitor) and compound C (an AMP-activated protein kinase inhibitor) significantly decreased Marein-stimulated 2-NBDG uptake. Additionally, Marein-stimulated glucose uptake was blocked in the presence of STO-609, a CaMKK inhibitor; however, Marein-stimulated AMPK phosphorylation was not blocked by LKB1 siRNA in HepG2 cells. Marein also inhibited the phosphorylation of insulin receptor substrate (IRS-1) at Ser 612, but inhibited GSK-3beta phosphorylation and increased glycogen synthesis. Moreover, Marein significantly decreased the expression levels of FoxO1, G6Pase and PEPCK. CONCLUSIONS: Consequently, Marein improved insulin resistance induced by high glucose in HepG2 cells through CaMKK/AMPK/GLUT1 to promote glucose uptake, through IRS/Akt/GSK-3beta to increase glycogen synthesis, and through Akt/FoxO1 to decrease gluconeogenesis. Marein could be a promising leading compound for the development of hypoglycemic agent or developed as an adjuvant drug for diabetes mellitus.

Marein protects against methylglyoxal-induced apoptosis by activating the AMPK pathway in PC12 cells.[Pubmed:27596733]

Free Radic Res. 2016;50(11):1173-1187.

Diabetic encephalopathy, which is characterized by cognitive decline and dementia, commonly occurs in patients with long-standing diabetes. Previous studies have suggested that methylglyoxal (MG), an endogenous toxic compound, plays an important role in diabetic complications such as cognitive impairment. MG induces neuronal apoptosis. To clarify whether Marein, a major compound from the hypoglycemic plant Coreopsis tinctoria, prevents PC12 cell damage induced by MG, we cultured PC12 cells in the presence of MG and Marein. Marein attenuated MG-induced changes in the mitochondrial membrane potential (DeltaPsim), mitochondrial permeability transition pores (mPTPs), intracellular Ca(2+ )levels, the production of reactive oxygen species (ROS), glutathione (GSH)/glutathione disulfide (GSSG) and adenosine triphosphate (ATP), and the increase in the percentage of apoptotic cells. Marein also increased glyoxalase I (Glo1) activity, phospho-AMPKalpha (Thr172) and Bcl-2 expression and diminished the activation of Bax, caspase-3 and inhibitor of caspase-activated deoxyribonuclease (ICAD). Importantly, pretreatment of cells with Marein diminished the compound C-induced inactivation of p-AMPK. Molecular docking simulation showed that Marein interacted with the gamma subunit of AMPK. In conclusion, we found for the first time that the neuroprotective effect of Marein is due to a reduction of damage to mitochondria function and activation of the AMPK signal pathway. These results indicate that Marein may be a potent compound for preventing/counteracting diabetic encephalopathy.

Rapid Identification and Comparison of Compounds with Antioxidant Activity in Coreopsis tinctoria Herbal Tea by High-Performance Thin-Layer Chromatography Coupled with DPPH Bioautography and Densitometry.[Pubmed:27516219]

J Food Sci. 2016 Sep;81(9):C2218-23.

A simple and efficient method based on high-performance thin-layer chromatography coupled with 2,2-diphenyl-1-picrylhydrazyl (DPPH) bioautography (HPTLC-DPPH) was established for the screening and comparison of antioxidants in different parts of Coreopsis tinctoria herbal tea from different origins and other related herbal tea materials, which used Chrysanthemum morifolium cv. "Gongju" and "Hangju" in this study. Scanning densitometry after DPPH derivatization was applied for the determination of antioxidant capacities of isolated compounds in each sample. It is considered that ethanol extracts of C. tinctoria had stronger antioxidant activity and more characteristic bands than those of 2 compared samples, C. morifolium cv. "Gongju" and "Hangju." Chemometric analysis results showed that the combination of hierarchical clustering analysis and principal component analysis based on determined antioxidant capacities could be used for the discrimination of different parts of C. tinctoria and C. morifolium. Results showed that 7 compounds made up the major contributions of antioxidant activity in C. tinctoria, including okanin, isookanin, Marein, flavanoMarein, 5,7,3',5'-tetrahydroxyflavanone-7-O-glucoside, 3,5-dicaffeoylquinic acid, and chlorogenic acid. Therefore, 7 compounds were identified as major antioxidant biomarkers for quality control of C. tinctoria. Results demonstrated that the established method could be applied for the identification of C. tinctoria, and were beneficial for the bioactivity-based quality control of C. tinctoria.