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Ramesh C Gupta - One of the best experts on this subject based on the ideXlab platform.
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detection of anthocyanins Anthocyanidins in animal tissues
Journal of Agricultural and Food Chemistry, 2014Co-Authors: Farrukh Aqil, Jeyaprakash Jeyabalan, Inder Pal Singh, Manicka V Vadhanam, Jian Cai, Ramesh C GuptaAbstract:Dietary polyphenols may contribute to the prevention of several degenerative diseases, including cancer. Anthocyanins have been shown to possess potential anticancer activity. The aim of this study was to determine anthocyanin bioavailability in lung tissue of mice fed a blueberry diet (5% w/w) for 10 days or a bolus dose (10 mg/mouse; po) of a native mixture of bilberry Anthocyanidins. All five Anthocyanidins present in the blueberry were detected in the lung tissue using improved methods. The effect of various solvents on the stability of anthocyanins and their recovery from the biomatrix was analyzed. Detection of anthocyanins and their metabolites was performed by UPLC and LC-MS. Although anthocyanins were not detected, cyanidin was detected by UPLC-PDA and other Anthocyanidins were detected by LC-MS, following conversion to Anthocyanidins and selective extraction in isoamyl alcohol. The results show that anthocyanins can be detected in lung tissue of blueberry-fed mice and thus are bioavailable beyond the gastrointestinal tract.
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berry Anthocyanidins synergistically suppress growth and invasive potential of human non small cell lung cancer cells
Cancer Letters, 2012Co-Authors: Hina Kausar, Jeyaprakash Jeyabalan, Farrukh Aqil, Deepika Chabba, Jasmeen Sidana, Inder Pal Singh, Ramesh C GuptaAbstract:Berry Anthocyanidins (cyanidin, malvidin, peonidin, petunidin and delphinidin) have increasingly been explored for their anticancer effects; however, their combinatorial effects as a mixture, as present in blueberry, bilberry and Indian blackberry ('Jamun') remain untested. In this study, we demonstrate for the first time that the combination of suboptimal concentrations of equimolar Anthocyanidins synergistically inhibited growth of two aggressive non-small-cell lung cancer cell lines, with minimal effects on non-tumorigenic cell viability. The induction of cell-cycle arrest, apoptosis and suppression of NSCLC cell invasion and migration were also significantly greater with the mixture than individual Anthocyanidins. The superior effects of the combinatorial treatment presumably resulted from its effects on the oncogenic Notch and WNT pathways and their downstream targets (β-catenin, c-myc, cyclin D1, cyclin B1, pERK, MMP9 and VEGF proteins), enhanced cleavage of the apoptotic mediators Bcl2 and PARP and enhanced inhibition of TNFα-induced NF-kappa B activation. In vivo, both the native mixture of Anthocyanidins from bilberry (0.5mg/mouse) and the most potent Anthocyanidin, delphinidin (1.5mg/mouse) significantly inhibited the growth of H1299 xenografts in nude miceby ≈60%. Notably, the effective dose of delphinidin in the Anthocyanidin mixture was 8-fold lower than delphinidin alone, further emphasizing synergism. Our results thus demonstrate therapeutic potential of berries rich in this mixture of diverse Anthocyanidins for non-small-cell lung cancer treatment and to prevent its future recurrence and metastasis.
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abstract 3693 berry Anthocyanidins inhibit key events of lung cancer metastasis effects on mirna and protein targets
Cancer Research, 2011Co-Authors: Hina Kausar, Ramesh C GuptaAbstract:Lung cancer continues to represent the largest cause of mortality in the world claiming over 1.3 million lives every year. The majority of patients who succumb to lung cancer die from cancer relapse and/or metastatic disease progression making the search for new anti-cancer and anti-metastasis agents imperative. Berry phytochemicals have received increasing attention lately for their various biological effects. We previously demonstrated notable synergistic anti-tumor effects of blueberry Anthocyanidins (cyanidin, malvidin, peonidin, petunidin and delphinidin) against human lung cancer cells in culture and in vivo in nude mouse model. Herein, we show the anti-metastatic effects of all the 5 Anthocyanidins individually and in combination in the highly aggressive and invasive human NSCLC H1299 cells. Using wound-healing and Boyden chamber assays, all the five Anthocyanidins (25 µM each) were found to exhibit varied inhibitory effects on H1299 cell migration and invasion. However, an equimolar mixture containing either 3.125 or 6.25 µM of each Anthocyanidin elicited similar inhibition of H1299 cell migration and invasion indicating a synergistic effect. Given the multi-complexity of the metastasis process, the effect of Anthocyanidins on a plethora of molecular targets mediating of the metastatic process was analyzed by western blotting. We found that berry Anthocyanidins decreased the expression of several metastatic and angiogenic mediators, viz; matrix metalloproteinases (MMP-2 and MMP-9), vascular endothelial growth factor (VEGF), c-MYC, NOTCH-1, WNT1. Furthermore, the Anthocyanidins effectively inhibited TNF-α-induced NF-κB activation and suppressed of ERK-1/2 activation, which could further explain their anti-invasive capabilities. Recently, emerging evidence also suggests the involvement of miRNAs in regulating various processes of cancer cell invasion and metastasis. Effect of Anthocyanidins on four such miRNAs frequently downregulated in NSCLC and implicated in lung cancer invasion and metastasis (miR-126, miR125a-5p, miR200c) and lung cancer relapse (miR-34a) was analyzed by qPCR. We observed a significant increase in the expression of all the four miRNAs by the Anthocyanidins. Target prediction scan for gene targets revealed several angiogenic signaling molecules to be regulated by these miRNA9s. Our results thus establish that protective properties of Anthocyanidins may arise, at least, in part, from its capability to manipulate some distinct and some overlapping miRNA and protein targets that may potentiate the anti-cancer and anti-metastatic effects of the berry Anthocyanidins. Collectively, our data suggest that berry Anthocyanidins may provide a safe, effective, unconventional and user-friendly approach to prevent or delay the onset of lung cancer recurrence and metastasis (Supported from KLCRP and Agnes Brown Duggan Endowment). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3693. doi:10.1158/1538-7445.AM2011-3693
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abstract 1884 synergistic anti cancer activities of berry Anthocyanidins on human lung cancer cells
Cancer Research, 2010Co-Authors: Hina Kausar, Jeyaprakash Jeyabalan, Farrukh Aqil, Deepika Chabba, Jasmeen Sidana, Inder Pal Singh, Ramesh C GuptaAbstract:Emerging evidence suggest that cancer develops due to defects in multiple genes, therefore, a combination of naturally occurring compounds targeting multiple signal transduction pathways would be ideal for the prevention/treatment of cancer. Berries are emerging as one of the most effective fruits because of their potent antioxidant, antiproliferative and anti-inflammatory activities. The various biological activities of berries have been attributed to abundance of diverse phenolic constituents, particularly anthocyanins (Anthocyanidins glycosides) that cause intense coloration. Several studies with individual Anthocyanidins have been shown to inhibit malignant cell survival and confound many oncogenic signaling events. In this study we tested individual Anthocyanidins (cyanidin, malvidin, peonidin, petunidin and delphinidin) and their mixture isolated from bilberry or black current for their abilities to inhibit the growth of two non small cell lung cancer (NSCLC) cells in culture and in vivo. The MTT cell proliferation assay demonstrated that all the five commercial Anthocyanidins resulted in a dose- and time-dependent inhibition of H1299 and A549 cell growth, with delphinidin being the most potent. Interestingly, however, a 1:1 mixture of all these five Anthocyanidins elicited significantly higher, dose-dependent, antiproliferative activity, indicating a synergistic effect. Selected glycosides of these Anthocyanidins were found to be significantly less active. Assuming that the growth inhibition occurred due to induction of apoptosis mediated by cell-cycle arrest, we investigated the effect of individual Anthocyanidins and their mixture on cell-cycle distribution and apoptosis. Flow-cytometric analysis of apoptosis with propidium iodide staining revealed that the induction of apoptosis was significantly greater with the mixture than either agent alone. The superior apoptotic effects of the combinatorial treatment were, in part, attributed to the enhanced cleavage of PARP, decreased expression of cyclin D1, cyclin B1 and pERK proteins in H1299 cells. Anti-tumor activity of delphinidin and the Anthocyanidin mixture, isolated from black currant and bilberry, respectively was determined using nude mouse lung cancer xenograft model. We found that both delphinidin and the mixture of Anthocyanidins reduced the H1299 tumor xenograft growth by 50% compared to the vehicle treatment. The effective dose of Anthocyanidin mixture (0.5 mg/dose) was 3-times lower than delphinidin (1.5 mg/dose) when given i.p. on alternate days, indicating synergistic anti-tumor activity of Anthocyanidins, consistent with our cell culture data. Together, our results suggest that increased consumption of bilberry, blueberry, or Indian blackberry or ‘jamun’ which are rich in this mixture of Anthocyanidins would be useful for the prevention/treatment of NSCLC (Supported from KLCRP grant & Duggan Endowment). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1884.
Borhane Annabi - One of the best experts on this subject based on the ideXlab platform.
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Anthocyanidins inhibit epithelial mesenchymal transition through a tgfβ smad2 signaling pathway in glioblastoma cells
Molecular Carcinogenesis, 2017Co-Authors: Amira Ouanouki, Sylvie Lamy, Borhane AnnabiAbstract:Epidemiological studies have convincingly demonstrated that diets rich in fruits and vegetables play an important role in preventing cancer due to their polyphenol content. Among polyphenols, the Anthocyanidins are known to possess anti-inflammatory, cardioprotective, anti-angiogenic, and anti-carcinogenic properties. Despite the well-known role of transforming growth factor-β (TGF-β) in high grade gliomas, the impact of Anthocyanidins on TGF-β-induced epithelial-mesenchymal transition (EMT), a process that allows benign tumor cells to infiltrate surrounding tissues, remains poorly understood. The objective of this study is to investigate the impact of Anthocyanidins such as cyanidin (Cy), delphinidin (Dp), malvidin (Mv), pelargonidin (Pg), and petunidin (Pt) on TGF-β-induced EMT and to determine the mechanism(s) underlying such action. Human U-87 glioblastoma (U-87 MG) cells were treated with Anthocyanidins prior to, along with or following the addition of TGF-β. We found that Anthocyanidins differently affected TGF-β-induced EMT, depending on the treatment conditions. Dp was the most potent EMT inhibitor through its inhibitory effect on the TGF-β Smad and non-Smad signaling pathways. These effects altered expression of the EMT mesenchymal markers fibronectin and Snail, as well as markedly reducing U-87 MG cell migration. Our study highlights a new action of Anthocyanidins against EMT that supports their beneficial health and chemopreventive effects in dietary-based strategies against cancer. © 2016 Wiley Periodicals, Inc.
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abstract 4316 pharmacological targeting of the tgf beta induced epithelial mesenchymal transition by Anthocyanidins in glioblastoma
Cancer Research, 2016Co-Authors: Amira Ouanouki, Sylvie Lamy, Evelyne Muhire, Borhane AnnabiAbstract:Introduction: Glioblastoma multiforme (GBM) is the most common primary brain tumor, known for its invasiveness and high resistance to standard treatments. Therefore, better understanding of the mechanisms that promote mesenchymal changes in GBM are of great clinical importance. Epithelial to mesenchymal transition (EMT) is a reversible biological process in which epithelial cells adopt mesenchymal properties. During EMT, migration, adhesion and cellular morphology are altered allowing benign tumor cells to infiltrate surrounding tissues and to metastasize to distant sites. Several growth factors have been shown to trigger EMT in tumor development; the Transforming Growth Factor-beta (TGF-b) is the most prominent inducer of EMT. Epidemiological studies have shown that diets rich in fruits and vegetables play an important role in preventing cancer due to their polyphenol content. Among polyphenols, the Anthocyanidins, found in berries, red grapes, and other pigmented foods, plants and vegetables, have anti-inflammatory, cardioprotective, anti-angiogenic and anti-carcinogenic properties. Despite the well-known role of TGB-b in tumor progression, the impact of Anthocyanidins on TGF-b-induced EMT remains misunderstood. Objectives: 1) Characterize the pharmacological effects of Anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin and petunidin) on EMT, 2) identify the molecular targets leading to the inhibition of EMT modulated by Anthocyanidins, and 3) characterize their effect on cellular activities involved in this tumor process. Methodology: The human U-87 glioblastoma (U-87 MG) cells were treated with Anthocyanidins in pre-, co- and post-treatment with TGF-b. Results: Depending on the treatment, Anthocyanidins affect differently the EMT induction by inhibiting U-87 MG cell migration. This inhibition resulted in a down-regulation of mesenchymal markers (fibronectin, snail), phosphorylation of Smad2 proteins and the mitogen-activated protein kinases (ERK, JNK) in a dose-dependent manner. Overall, delphinidin was the most potent inhibitor for all treatments. Conclusion: This study highlights a new antimetastatic action of Anthocyanidins that supports the beneficial health and chemopreventive effects of dietary-based strategies against cancer. Citation Format: Amira Ouanouki, Evelyne Muhire, Sylvie Lamy, Borhane Annabi. Pharmacological targeting of the TGF-beta-induced epithelial-mesenchymal transition by Anthocyanidins in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4316.
Kazuki Saito - One of the best experts on this subject based on the ideXlab platform.
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computational study on a puzzle in the biosynthetic pathway of anthocyanin why is an enzymatic oxidation reduction process required for a simple tautomerization
PLOS ONE, 2018Co-Authors: Hajime Sato, Mami Yamazaki, Kazuki Saito, Chao Wang, Masanobu UchiyamaAbstract:In the late stage of anthocyanin biosynthesis, dihydroflavonol reductase (DFR) and Anthocyanidin synthase (ANS) mediate a formal tautomerization. However, such oxidation/reduction process requires high energy and appears to be unnecessary, as the oxidation state does not change during the transformation. Thus, a non-enzymatic pathway of tautomerization has also been proposed. To resolve the long-standing issue of whether this non-enzymatic pathway is the main contributor for the biosynthesis, we carried out density functional theory (DFT) calculations to examine this non-enzymatic pathway from dihydroflavonol to Anthocyanidin. We show here that the activation barriers for the proposed non-enzymatic tautomerization are too high to enable the reaction to proceed under normal aqueous conditions in plants. The calculations also explain the experimentally observed requirement for acidic conditions during the final step of conversion of 2-flaven-3,4-diol to Anthocyanidin; a thermodynamically and kinetically favorable concerted pathway can operate under these conditions.
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two flavonoid glucosyltransferases from petunia hybrida molecular cloning biochemical properties and developmentally regulated expression
Plant Molecular Biology, 2002Co-Authors: Mami Yamazaki, Zhizhong Gong, Yoshikazu Tanaka, Yuko Fukui, Masako Fukuchimizutani, Takaaki Kusumi, Emiko Yamagishi, Masaatsu Yamaguchi, Kazuki SaitoAbstract:Two flavonoid glucosyltransferases, UDP-glucose:flavonoid 3-0-glucosyltransferase (3-GT) and UDP-glucose: anthocyanin 5-O-glucosyltransferase (5-GT), are responsible for the glucosylation of anthocyani(di)ns to produce stable molecules in the anthocyanin biosynthetic pathway. The cDNAs encoding 3-GT and 5-GT were isolated from Petunia hybrida by hybridization screening with heterologous probes. The cDNA clones of 3-GT, PGT8, and 5-GT, PH1, encode putative polypeptides of 448 and 468 amino acids, respectively. A phylogenetic tree based on amino acid sequences of the family of glycosyltransferases from various plants shows that PGT8 belongs to the 3-GT subfamily and PH1 belongs to the 5-GT subfamily. The function of isolated cDNAs was identified by the catalytic activities for 3-GT and 5-GT exhibited by the recombinant proteins produced in yeast. The recombinant PGT8 protein could convert not only Anthocyanidins but also flavonols into the corresponding 3-O-glucosides. In contrast, the recombinant PH1 protein exhibited a strict substrate specificity towards Anthocyanidin 3-acylrutinoside, comparing with other 5-GTs from Perilla frutescens and Verbena hybrida, which showed broad substrate specificities towards several Anthocyanidin 3-glucosides. The mRNA expression of both 3-GT and 5-GT increased in the early developmental stages of P. hybrida flower, reaching the maximum at the stage before flower opening. Southern blotting analysis of genomic DNA indicates that both 3-GT and 5-GT genes exist in two copies in P. hybrida, respectively. The results are discussed in relation to the molecular evolution of flavonoid glycosyltransferases.
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reaction mechanism from leucoAnthocyanidin to Anthocyanidin 3 glucoside a key reaction for coloring in anthocyanin biosynthesis
Journal of Biological Chemistry, 2001Co-Authors: Junichiro Nakajima, Mami Yamazaki, Yoshikazu Tanaka, Kazuki SaitoAbstract:Abstract In the conversion from colorless leucoAnthocyanidin to colored Anthocyanidin 3-glucoside, at least two enzymes, Anthocyanidin synthase (ANS) and UDP-glucose:flavonoid 3-O-glucosyltransferase (3-GT), are postulated to be involved. Despite the importance of this reaction sequence for coloring in anthocyanin biosynthesis, the biochemical reaction mechanism has not been clarified, and the possible involvement of a dehydratase has not been excluded. Here we show that recombinant ANSs from several model plant species, snapdragon, petunia, torenia, and maize, catalyze the formation of Anthocyanidin in vitro through a 2-oxoglutarate-dependent oxidation of leucoAnthocyanidin. Crude extracts of Escherichia coli, expressing recombinant ANSs from these plant species, and purified recombinant enzymes of petunia and maize catalyzed the formation of Anthocyanidin in the presence of ferrous ion, 2-oxoglutarate, and ascorbate. The in vitro formation of colored cyanidin 3-glucoside from leucocyanidin, via a cyanidin intermediate, was demonstrated using petunia ANS and 3-GT. The entire reaction sequence did not require any additional dehydratase but was dependent on moderate acidic pH conditions following the enzymatic steps. The present study indicated that the in vivo cytosolic reaction sequence involves an ANS-catalyzed 2-oxoglutarate-dependent conversion of leucoAnthocyanidin (flavan-3,4-cis-diol) to 3-flaven-2,3-diol (pseudobase), most probably through 2,3-desaturation and isomerization, followed by glucosylation at the C-3 position by 3-GT.
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Direct evidence for Anthocyanidin synthase as a 2-oxoglutarate-dependent oxygenase: molecular cloning and functional expression of cDNA from a red forma of Perilla frutescens.
Plant Journal, 1999Co-Authors: Kazuki Saito, Mii Kobayashi, Zhizhong Gong, Yoshikazu Tanaka, Mami YamazakiAbstract:Summary Anthocyanidin synthase (ANS), an enzyme of the biosynthetic pathway to anthocyanin, has been postulated to catalyze the reaction(s) from the colorless leucoAnthocyanidins to the colored Anthocyanidins. Although cDNAs have been isolated that encode putative ANS, which exhibits significant similarities in amino acid sequence with members of a family of 2-oxoglutarate-dependent oxygenases, no biochemical evidence has been presented which identifies the actual reaction that is catalyzed by ANS. Here we show that Anthocyanidins are formedin vitrothrough 2-oxoglutarate-dependent oxidation of leucoAnthocyanidins catalyzed by the recombinant ANS and subsequent acid treatment. A cDNA encoding ANS was isolated from red and green formas ofPerilla frutescensby differential display of mRNA. Recombinant ANS tagged with maltose-binding-protein (MBP) was purified, and the formation of Anthocyanidins from leucoAnthocyanidins was detected by the ANS-catalyzed reaction in the presence of ferrous ion, 2-oxoglutarate and ascorbate, being followed by acidification with HCl. Equimolar stoichiometry was confirmed for Anthocyanidin formation and liberation of CO2 from 2-oxoglutarate. The presumptive two-copy gene of ANS was expressed in leaves and stems of the red forma ofP. frutescensbut not in the green forma plant. This corresponds to the accumulation pattern of anthocyanin. The mechanism of the reaction catalyzed by ANS is discussed in relation to the molecular evolution of a family of 2-oxoglutarate-dependent oxygenases.
Amira Ouanouki - One of the best experts on this subject based on the ideXlab platform.
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Anthocyanidins inhibit epithelial mesenchymal transition through a tgfβ smad2 signaling pathway in glioblastoma cells
Molecular Carcinogenesis, 2017Co-Authors: Amira Ouanouki, Sylvie Lamy, Borhane AnnabiAbstract:Epidemiological studies have convincingly demonstrated that diets rich in fruits and vegetables play an important role in preventing cancer due to their polyphenol content. Among polyphenols, the Anthocyanidins are known to possess anti-inflammatory, cardioprotective, anti-angiogenic, and anti-carcinogenic properties. Despite the well-known role of transforming growth factor-β (TGF-β) in high grade gliomas, the impact of Anthocyanidins on TGF-β-induced epithelial-mesenchymal transition (EMT), a process that allows benign tumor cells to infiltrate surrounding tissues, remains poorly understood. The objective of this study is to investigate the impact of Anthocyanidins such as cyanidin (Cy), delphinidin (Dp), malvidin (Mv), pelargonidin (Pg), and petunidin (Pt) on TGF-β-induced EMT and to determine the mechanism(s) underlying such action. Human U-87 glioblastoma (U-87 MG) cells were treated with Anthocyanidins prior to, along with or following the addition of TGF-β. We found that Anthocyanidins differently affected TGF-β-induced EMT, depending on the treatment conditions. Dp was the most potent EMT inhibitor through its inhibitory effect on the TGF-β Smad and non-Smad signaling pathways. These effects altered expression of the EMT mesenchymal markers fibronectin and Snail, as well as markedly reducing U-87 MG cell migration. Our study highlights a new action of Anthocyanidins against EMT that supports their beneficial health and chemopreventive effects in dietary-based strategies against cancer. © 2016 Wiley Periodicals, Inc.
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abstract 4316 pharmacological targeting of the tgf beta induced epithelial mesenchymal transition by Anthocyanidins in glioblastoma
Cancer Research, 2016Co-Authors: Amira Ouanouki, Sylvie Lamy, Evelyne Muhire, Borhane AnnabiAbstract:Introduction: Glioblastoma multiforme (GBM) is the most common primary brain tumor, known for its invasiveness and high resistance to standard treatments. Therefore, better understanding of the mechanisms that promote mesenchymal changes in GBM are of great clinical importance. Epithelial to mesenchymal transition (EMT) is a reversible biological process in which epithelial cells adopt mesenchymal properties. During EMT, migration, adhesion and cellular morphology are altered allowing benign tumor cells to infiltrate surrounding tissues and to metastasize to distant sites. Several growth factors have been shown to trigger EMT in tumor development; the Transforming Growth Factor-beta (TGF-b) is the most prominent inducer of EMT. Epidemiological studies have shown that diets rich in fruits and vegetables play an important role in preventing cancer due to their polyphenol content. Among polyphenols, the Anthocyanidins, found in berries, red grapes, and other pigmented foods, plants and vegetables, have anti-inflammatory, cardioprotective, anti-angiogenic and anti-carcinogenic properties. Despite the well-known role of TGB-b in tumor progression, the impact of Anthocyanidins on TGF-b-induced EMT remains misunderstood. Objectives: 1) Characterize the pharmacological effects of Anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin and petunidin) on EMT, 2) identify the molecular targets leading to the inhibition of EMT modulated by Anthocyanidins, and 3) characterize their effect on cellular activities involved in this tumor process. Methodology: The human U-87 glioblastoma (U-87 MG) cells were treated with Anthocyanidins in pre-, co- and post-treatment with TGF-b. Results: Depending on the treatment, Anthocyanidins affect differently the EMT induction by inhibiting U-87 MG cell migration. This inhibition resulted in a down-regulation of mesenchymal markers (fibronectin, snail), phosphorylation of Smad2 proteins and the mitogen-activated protein kinases (ERK, JNK) in a dose-dependent manner. Overall, delphinidin was the most potent inhibitor for all treatments. Conclusion: This study highlights a new antimetastatic action of Anthocyanidins that supports the beneficial health and chemopreventive effects of dietary-based strategies against cancer. Citation Format: Amira Ouanouki, Evelyne Muhire, Sylvie Lamy, Borhane Annabi. Pharmacological targeting of the TGF-beta-induced epithelial-mesenchymal transition by Anthocyanidins in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4316.
Wilfried Schwab - One of the best experts on this subject based on the ideXlab platform.
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redirection of flavonoid biosynthesis through the down regulation of an Anthocyanidin glucosyltransferase in ripening strawberry fruit
Plant Physiology, 2008Co-Authors: Markus Griesser, Thomas Hoffmann, Mari Luz Bellido, Carlo Rosati, Barbara Fink, Robert Kurtzer, Asaph Aharoni, Juan Munozblanco, Wilfried SchwabAbstract:Strawberry (Fragaria × ananassa) fruit contains several anthocyanins that give the ripe fruits their attractive red color. The enzyme that catalyzes the formation of the first stable intermediate in the anthocyanin pathway is Anthocyanidin-3-O-glucosyltransferase. A putative glycosyltransferase sequence (FaGT1) was cloned from a strawberry fruit cDNA library and the recombinant FaGT1 transferred UDP-glucose to Anthocyanidins and, to a lesser extent, flavonols, generating the respective 3-O-glucosides. Quantitative polymerase chain reaction revealed that transcripts of FaGT1 were almost undetectable in green fruits, but gene expression increased dramatically in both turning and ripe red fruit, corresponding closely to the accumulation of anthocyanins during fruit ripening. The expression of FaGT1 is fruit associated and negatively regulated by auxin. To elucidate the in planta function of FaGT1, Agrobacterium tumefaciens cells harboring an intron-hairpin construct of a partial FaGT1 sequence were injected into midsized ripening fruits. In about one-third of the injected fruits, this led to significant down-regulation of FaGT1 transcript levels that corresponded to reduced concentrations of anthocyanin pigments in ripe strawberry fruits. In contrast, significant levels of epiafzelechin—formed by Anthocyanidin reductase (ANR) from pelargonidin—were identified in FaGT1-silenced fruits, indicating competition of FaGT1 and FaANR for the common Anthocyanidin substrate. Thus, FaGT1 represents an important branching-point enzyme because it is channeling the flavonoid pathway to anthocyanins. These results demonstrate a method to redirect the anthocyanin biosynthesis into flavan-3-ol production to increase the levels of bioactive natural products or modify pigments in plant tissues.
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Anthocyanidin synthase from gerbera hybrida catalyzes the conversion of catechin to cyanidin and a novel procyanidin
FEBS Letters, 2006Co-Authors: Frank Wellmann, Markus Griesser, Wilfried Schwab, Stefan Martens, Wolfgang Eisenreich, Ulrich Matern, Richard LukacinAbstract:Abstract Anthocyanidins were proposed to derive from (+)-naringenin via (2R,3R)-dihydroflavonol(s) and (2R,3S,4S)-leucocyanidin(s) which are eventually oxidized by Anthocyanidin synthase (ANS). Recently, the role of ANS has been put into question, because the recombinant enzyme from Arabidopsis exhibited primarily flavonol synthase (FLS) activity with negligible ANS activity. This and other studies led to the proposal that ANS as well as FLS may select for dihydroflavonoid substrates carrying a “β-face” C-3 hydroxyl group and initially form the 3-geminal diol by “α-face” hydroxylation. Assays with recombinant ANS from Gerbera hybrida fully supported the proposal and were extended to catechin and epicatechin isomers as potential substrates to delineate the enzyme specificity. Gerbera ANS converted (+)-catechin to two major and one minor product, whereas ent(−)-catechin (2S,3R-trans-catechin), (−)-epicatechin, ent(+)-epicatechin (2S,3S-cis-epicatechin) and (−)-gallocatechin were not accepted. The Km value for (+)-catechin was determined at 175 μM, and the products were identified by LC–MSn and NMR as the 4,4-dimer of oxidized (+)-catechin (93%), cyanidin (7%) and quercetin (trace). When these incubations were repeated in the presence of UDP-glucose:flavonoid 3-O-glucosyltransferase from Fragaria × ananassa (FaGT1), the product ratio shifted to cyanidin 3-O-glucoside (60%), cyanidin (14%) and dimeric oxidized (+)-catechin (26%) at an overall equivalent rate of conversion. The data appear to identify (+)-catechin as another substrate of ANS in vivo and shed new light on the mechanism of its catalysis. Moreover, the enzymatic dimerization of catechin monomers is reported for the first time suggesting a role for ANS beyond the oxidation of leucocyanidins.
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Anthocyanidin synthase from gerbera hybrida catalyzes the conversion of catechin to cyanidin and a novel procyanidin
FEBS Letters, 2006Co-Authors: Frank Wellmann, Markus Griesser, Wilfried Schwab, Stefan Martens, Wolfgang Eisenreich, Ulrich Matern, Richard LukacinAbstract:Anthocyanidins were proposed to derive from (+)-naringenin via (2R,3R)-dihydroflavonol(s) and (2R,3S,4S)-leucocyanidin(s) which are eventually oxidized by Anthocyanidin synthase (ANS). Recently, the role of ANS has been put into question, because the recombinant enzyme from Arabidopsis exhibited primarily flavonol synthase (FLS) activity with negligible ANS activity. This and other studies led to the proposal that ANS as well as FLS may select for dihydroflavonoid substrates carrying a "beta-face" C-3 hydroxyl group and initially form the 3-geminal diol by "alpha-face" hydroxylation. Assays with recombinant ANS from Gerbera hybrida fully supported the proposal and were extended to catechin and epicatechin isomers as potential substrates to delineate the enzyme specificity. Gerbera ANS converted (+)-catechin to two major and one minor product, whereas ent(-)-catechin (2S,3R-trans-catechin), (-)-epicatechin, ent(+)-epicatechin (2S,3S-cis-epicatechin) and (-)-gallocatechin were not accepted. The K(m) value for (+)-catechin was determined at 175 microM, and the products were identified by LC-MS(n) and NMR as the 4,4-dimer of oxidized (+)-catechin (93%), cyanidin (7%) and quercetin (trace). When these incubations were repeated in the presence of UDP-glucose:flavonoid 3-O-glucosyltransferase from Fragariaxananassa (FaGT1), the product ratio shifted to cyanidin 3-O-glucoside (60%), cyanidin (14%) and dimeric oxidized (+)-catechin (26%) at an overall equivalent rate of conversion. The data appear to identify (+)-catechin as another substrate of ANS in vivo and shed new light on the mechanism of its catalysis. Moreover, the enzymatic dimerization of catechin monomers is reported for the first time suggesting a role for ANS beyond the oxidation of leucocyanidins.