2 ',4 '-Dihydroxy-6 '-methoxy-3 ',5 '-dimethylchalcone inhibits apoptosis of MIN6 cells via improving mitochondrial function

State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, PR China.
Pharmazie (Impact Factor: 1.05). 09/2012; 67(9):798-803. DOI: 10.1691/ph.2012.1848
Source: PubMed


Mitochondrial dysfunction due to oxidative stress and concomitant beta-cell apoptosis may play a key role in type 2 diabetes. Inhibiting beta-cell apoptosis through ameliorating oxidative mitochondrial dysfunction with specific natural products may have preventive or therapeutic potential. In this study, the anti-apoptotic effect of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC), a isolated chalcone from the buds of Cleistocalyx operculatus, on H2O2 induced MIN6 cells damage was investigated. Exposure to H2O2 at 250 microM for 3 h, the viability of MIN6 cells was significantly decreased and the apoptosis apparently occurred. A pre-treatment with DMC at the concentrations of 12.5-25 microM, before H2O2 addition, reduced nucleus fragmentation, decreased endogenous reactive oxygen species (ROS) production, and improved mitochondrial potential (MMP), and consequently, inhibited apoptosis. Furthermore, decreased activities of caspase-3 and caspase-9 were observed. These results clearly demonstrated DMC protected MIN6 cells against apoptosis due to its highly protective effect on mitochondria, and thus, it has great potential as a candidate drug for the diabetes care.

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    ABSTRACT: 2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC), a compound isolated and purified from the dried flower buds of Cleistocalyx operculatus (Roxb.) Merr. et Perry (Myrtaceae), was investigated for its glucose control benefits using in vitro methods. DMC showed strong noncompetitive (IC(50) of 43 μM) inhibition of pancreatic α-amylase; it was, however, ineffective against intestinal α-glucosidase. In addition, DMC exhibited remarkable glucose transport inhibition effects in both simulated fasting and fed states in Caco-2 cell monolayers (P < 0.05). Besides, exposure of MIN6 cells to 250 μM H(2)O(2) for 1 h caused a significant viability loss and insulin secretion reduction. Pretreatment of MIN6 cells with DMC for 2 h protected against the H(2)O(2)-induced decrease in glucose-stimulated insulin secretion in a dose-dependent manner and also enhanced the impaired basal insulin secretion. Such effects highlight the therapeutic potential of DMC in the management of hyperglycemia.
    Journal of Agricultural and Food Chemistry 09/2012; 60(42). DOI:10.1021/jf303078r · 2.91 Impact Factor
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    ABSTRACT: This study is to report the study of protective effects of myricitrin against oxidative stress-induced apoptosis of vascular endothelial cells and the investigation of the possible mechanisms of action of myricitrin. The model of H2O2-induced apoptosis of vascular endothelial cells was used to determine the protective effects of myricitrin. The levels of LDH, MDA and the activities of SOD, NO were measured using the respective kits. The H2O2-induced apoptosis of vascular endothelial cells was detected using MTT reduction, TUNEL assay, JC-1 and ROS staining. The activation of Caspase-3 was also measured by fluorometry. The expression of apoptosis-related proteins was determined with Western blotting assay. Myricitrin had significant protective effects against H2O2-induced apoptosis of vascular endothelial cells in a time- and dose-dependent manner. The results show that myricitrin could attenuate H2O2-induced decrease in the activities of SOD (P < 0.01). Myricitrin could decrease the levels of LDH, MDA and increase cell viability and the mitochondrial membrane potential (P < 0.01). Myricitrin had protective effects in a dose-dependent manner between 32 micromol x L(-1) to 64 micromol x L(-1). Myricitrin pretreatment could attenuate H2O2-induced increase of p-ERK. Moreover, myricitrin pretreatment could up-regulate the expression of the anti-apoptotic protein Bcl-2, down-regulate the expression of the pro-apoptotic protein Bax, and decrease the expression of Caspase-3, 9. In conclusion, myricitrin had significant protective effects against H2O2-induced apoptosis of vascular endothelial cells. Myricitrin can enhance the activities of anti-oxidative enzymes and decrease the production of free radicals. The possible mechanisms of action of myricitrin are due to myricitrin-mediated inhibition of phosphorylation of the apoptosis signaling pathways-related kinase ERK, up-regulation of the expression of the anti-apoptotic protein, and down-regulation of the expression of the pro-apoptotic protein.
    Yao xue xue bao = Acta pharmaceutica Sinica 04/2013; 48(4):615-20.
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    ABSTRACT: In order to better understand the antioxidant behavior of a series of polyphenolic 2'-hydroxychalcones, we describe the results of several chemical and biological studies, in vitro and in vivo. Single crystal X-ray methods elucidated their molecular structures and important intermolecular interactions such as H-bonding and molecular stacking in the crystal structures that contribute to our knowledge in explaining antioxidant activity. The results of experiments using the 1,1-diphenyl-2-dipicrylhydrazyl (DPPH) UV-vis spectroscopic method indicate that a hydroxyl group in position 5' induces the highest antioxidant activity. Consequently, 2,2',5'-trihydroxychalcone was selected for further study in vitro towards ROS scavenging in L-6 myoblasts and THP-1 human monocytes, where it shows an excellent antioxidant activity in a concentration range lower than that reported by most studies of related molecules. In addition, this chalcone shows a very selective activity: it inhibits the proliferation of leukemic cells, but it does not affect the normal L-6 myoblasts and human fibroblasts. In studying 2,2',5'-trihydroxychalcone's effect on weight gain and serum glucose and insulin levels in Zucker fatty (fa(-)/fa(-)) rats we found that supplementing the diet with a 10 mg/kg dose of this chalcone (3 times weekly) blunted the increase in glucose that co-occurs with weight gain over the 6-week treatment period. It is concluded that 2,2',5'-trihydroxychalcone has the potential to serve as a protective agent for some debilitating diseases.
    Biochimie 07/2013; 95(10):1954-1963. DOI:10.1016/j.biochi.2013.07.002 · 2.96 Impact Factor
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