Decreased protein kinase C activation mediates inhibitory effect of norathyriol on serotonin-mediated endothelial permeability

Lee, Hong‐Zin; Lin, Wen-Chiao; Yeh, Feng-Tsgh; Lin, Chun‐Nan; Wu, Ching Hsiang

doi:10.1016/s0014-2999(98)00385-9

Cited by 19 publications

(8 citation statements)

References 38 publications

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“…1) 5) indicates an important role of mangiferinmetabolizing bacteria in the disposition of norathyriol and its subsequent metabolites in vivo, as well as in the pharmacological activities of mangiferin. Norathyriol also exerts antiinflammatory, 18,19) vasorelaxation 20) and antiplatelet 21) activities. Therefore, the biotransformation of mangiferin should be thoroughly investigated.…”

Section: -8)mentioning

confidence: 99%

Isolation of a Human Intestinal Bacterium That Transforms Mangiferin to Norathyriol and Inducibility of the Enzyme That Cleaves a C-Glucosyl Bond

Sanugul

Akao

et al. 2005

Biological & Pharmaceutical Bulletin

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C-Glucosides, which are widely distributed among plants, are more resistant towards acid, alkaline and enzyme hydrolysis than O-glucosides. Even prolonged exposure to acid does not cleave the glucosyl bond of C-glucosides, in which glucose is attached by a carbon-carbon bond to the aglycone, to give the aglycone. 1) However, intestinal bacteria from human feces can cleave C-glucosyl bonds in various C-glucosides such as mangiferin, abrusin 2Љ-O-b-D-apioside, aloeresin A, aloesin, barbaloin, bergenin, homoorientin, puerarin and safflor yellow B. 2-8)Mangiferin (2-b-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone), was originally isolated from Mangifera indica L. (Anacardiaceae). It is distributed among at least sixteen plant families including Anacardiaceae, Iridaceae and Gentianaceae. Studies in vitro have shown that mangiferin has antiviral activity against herpes simplex virus 9) as well as antioxidant, 10) and anti-HIV activity. 11) Mangiferin orally administered to rats or mice exerts biological antitumor, 11) antidiabetic, 12) antioxidant, 13) hepatoprotective 14) and immunomodulative 15) activities. However, the pharmacokinetic studies in rats given oral mangiferin have failed to detect mangiferin in plasma, 16) suggesting poor absorption. On the other hand, appreciable amounts of euxanthone (1,7-dihydroxyxanthone) and its glucuronides are excreted into the urine of rabbits given oral mangiferin, 17) indicating a unique metabolic transformation that involves elimination of a Cglucosyl chain and two phenolic hydroxyl groups. The transformation of mangiferin to norathyriol by human fecal flora in vitro ( Fig. 1) 5) indicates an important role of mangiferinmetabolizing bacteria in the disposition of norathyriol and its subsequent metabolites in vivo, as well as in the pharmacological activities of mangiferin. Norathyriol also exerts antiinflammatory, 18,19) vasorelaxation 20) and antiplatelet 21) activities. Therefore, the biotransformation of mangiferin should be thoroughly investigated.Here, we isolated and characterized a bacterium that transforms mangiferin to norathyriol. Furthermore, the novel enzyme that cleaved C-glucosyl was selectively inducible with mangiferin and apparently differs from a-and b-glucosidases. The C-glucosyl bond of C-glucosides generally tolerates acid and enzymatic hydrolysis. Many C-glucosides are cleaved by human intestinal bacteria. We isolated the specific bacterium involved in the metabolism of mangiferin (2-b b-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthone), C-glucosyl xanthone, from a mixture of human fecal bacteria. The anaerobic Bacteroides species named MANG, transformed mangiferin to the aglycone, norathyriol, suggesting cleavage of a C-glucosyl bond. However, B. sp. MANG cleaved C-glucosyl in a dose-and time-dependent manner only when cultivated in the presence of mangiferin. Cleavage was abolished by inhibitors of RNA and protein syntheses, such as rifampicin and chloramphenicol, respectively, indicating that the enzyme that cleaves C-glucosyl is induced by mangiferin....

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Section: -8)mentioning

confidence: 99%

Isolation of a Human Intestinal Bacterium That Transforms Mangiferin to Norathyriol and Inducibility of the Enzyme That Cleaves a C-Glucosyl Bond

Sanugul

Akao

et al. 2005

Biological & Pharmaceutical Bulletin

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“…Cellular proteins were fractionated into cytosolic and particulate fractions as previously described (Lee et al, 1998). Briefly, rat heart endothelial cells were seeded onto 100-mm dishes.…”

Section: Preparation Of Subcellular Fractionsmentioning

confidence: 99%

The effect of elevated extracellular glucose on adherens junction proteins in cultured rat heart endothelial cells

Lee

Yeh

2004

Life Sciences

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“…Norathyriol is known to possess antioxidant, anti-inflammatory and antitumor properties (11–13). This compound has multiple targets and inhibits the transactivation of peroxisome proliferator-activated receptor isoforms (14), ABCB1/P-glycoprotein activity (11), protein kinase C activity (13), and cyclooxygenase and lipoxygenase activity (12). Norathyriol was reported to inhibit platelet aggregation (15), relax the rat thoracic aorta (16), and inhibit cutaneous plasma extravasation (17).…”

Section: Introductionmentioning

confidence: 99%

Norathyriol Suppresses Skin Cancers Induced by Solar Ultraviolet Radiation by Targeting ERK Kinases

Malakhova

Mottamal

et al. 2012

Cancer Research

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Ultraviolet (UV) irradiation is the most important factor contributing to the development of skin cancer. The use of chemopreventive agents, especially naturally occurring plant products, to prevent skin cancer caused by UV might an effective therapeutic or preventive intervention. Using in silico virtual screening of the Chinese Medicine Library, we identified norathyriol as a potential ERK2 inhibitor. Norathyriol is a metabolite of mangiferin, which is found in mango, Hypericum elegans, and Tripterospermum lanceolatum, and has potent anticancer-promoting activity. Here, we show that norathyriol inhibits ERK1/2 kinase activities and attenuates UVB-induced phosphorylation of the mitogen-activated protein kinase (MAPK) cascades. Direct binding of norathyriol with ERK2 was confirmed by a co-crystal structure. The norathyriol xanthone moiety acts as an adenine mimeric and anchors the compound by hydrogen bonds to the hinge region of the protein ATP-binding site. Norathyriol inhibited cell growth in mouse skin epidermal JB6 P+ cells by inducing G2-M phase arrest. Mouse skin tumorigenesis data clearly showed that treatment with norathyriol significantly suppressed solar UV-induced skin carcinogenesis in vivo. Results also indicated that norathyriol exhibits a potent chemopreventive activity through the inhibition of transcription factor AP-1 and NF-κB by targeting ERKs in UV-induced skin carcinogenesis.

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Decreased protein kinase C activation mediates inhibitory effect of norathyriol on serotonin-mediated endothelial permeability

Cited by 19 publications

References 38 publications

Isolation of a Human Intestinal Bacterium That Transforms Mangiferin to Norathyriol and Inducibility of the Enzyme That Cleaves a C-Glucosyl Bond

Isolation of a Human Intestinal Bacterium That Transforms Mangiferin to Norathyriol and Inducibility of the Enzyme That Cleaves a C-Glucosyl Bond

The effect of elevated extracellular glucose on adherens junction proteins in cultured rat heart endothelial cells

Norathyriol Suppresses Skin Cancers Induced by Solar Ultraviolet Radiation by Targeting ERK Kinases

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