A natural xanthone increases catalase activity but decreases NF-kappa B and lipid peroxidation in U-937 and HepG2 cell lines.

Mangiferin, a C-glycosyl xanthone, has shown anti-inflammatory, antioxidant, and anti-tumorigenic activities. In the present study, we investigated the molecular mechanism for the antioxidant property of mangiferin. Considering the role of nuclear transcription factor kappa B (NF-κB) in inflammation and tumorigenesis, we hypothesized that modulating its activity will be a viable therapeutic target in regulating the redox-sensitive ailments. Our results show that mangiferin blocks several inducers, such as tumor necrosis factor (TNF), lypopolysaccharide (LPS), phorbol-12-myristate-13-acetate (PMA) or hydrogen peroxide (H2O2) mediated NF-κB activation via inhibition of reactive oxygen species generation. In silico docking studies predicted strong binding energy of mangiferin to the active site of catalase (-9.13 kcal/mol), but not with other oxidases such as myeloperoxidase, glutathione peroxidase, or inducible nitric oxide synthase. Mangiferin increased activity of catalase by 44%, but had no effect on myeloperoxidase activity in vitro. Fluorescence spectroscopy further revealed the binding of mangiferin to catalase at the single site with binding constant and binding affinity of 3.1×10(-7) M(-1) and 1.046 respectively. Mangiferin also inhibits TNF-induced lipid peroxidation and thereby protects apoptosis. Hence, mangiferin with its ability to inhibit NF-κB and increase the catalase activity may prove to be a potent therapeutic.

Advanced glycation end products induce lipogenesis: regulation by natural xanthone through inhibition of ERK and NF-κB.

Advanced glycation end products (AGE) accumulate in diabetic patients and aged persons due to high amounts of 3- or 4-carbon derivatives of glucose. Understanding the mechanism of AGE-mediated signaling leading to these consequences, like oxidative stress, inflammation, apoptosis, etc. and its regulation would be a viable strategy to control diabetic complication and age-related diseases. We have detected the probable mechanism by which AGE increases lipogenesis, the cause of fatty liver in diabetic patients. AGE increased lipid accumulation in different cells as shown by Oil Red O staining. AGE-mediated regulation of several transcription factors was determined by gel shift assay. Antioxidants like NAC, PDTC, and vitamin C, except mangiferin, were unable to protect AGE-induced activation of SREBP and subsequent lipid accumulation. AGE increased the phosphorylation of ERK, and IKK and also DNA binding ability of SREBP, thereby its dependent gene transcription. AGE induces NF-κB which might suppress PPARγ activity, in turn reducing lipid breakdown and mobilization. Mangiferin not only inhibits AGE-mediated ROI generation that requires NF-κB activation, but also inhibits ERK and IKK activity, thereby suppression of SREBP activity and lipogenesis. Mangiferin has shown a double-edged sword effect to suppress AGE-mediated ailments by reducing ROI-mediated responses as antioxidant and inhibiting SREBP activation thereby lipogenesis, suggesting its potential efficacy against diabetes and obesity-related diseases.

Beta-D-glucoside protects against advanced glycation end products (AGEs)-mediated diabetic responses by suppressing ERK and inducing PPAR gamma DNA binding.

Accumulation of advanced glycation end products (AGEs), due to excessive amounts of 3- or 4-carbon sugars derived from glucose; cause multiple consequences in diabetic patients and older persons. The transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), is down regulated in the diabetic condition. Drugs targeting PPARγ were developed for diabetes therapy. We found that AGE inhibited PPARγ activity in different cell types induced by PPARγ activators, like troglitazone, rosiglitazone, oleamide, and anandamide. AGE induced translocation of PPARγ from nucleus to cytoplasm, increased on activation of ERK in cells. Antioxidants that inhibit AGE-induced NF-κB activation by preventing ROI generation were unable to protect AGE-mediated decrease in PPARγ activity. Only mangiferin, a ß-D-glucoside, prevented AGE-mediated decrease in PPARγ activity and inhibited phosphorylation of ERK and cytoplasmic translocation of PPARγ. Mangiferin interacts with PPARγ and enhanced its DNA binding activity as predicted by in silico and shown by in vitro DNA-binding activity. Overall, the data suggest that (i) mangiferin inhibited AGE-induced ERK activation thereby inhibited PPARγ phosphorylation and cytoplasmic translocation; (ii) mangiferin interacts with PPARγ and enhances its DNA-binding ability. With these dual effects, mangiferin can be a likely candidate for developing therapeutic drug against diabetes.