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1.
J Microbiol Biotechnol ; 33(12): 1606-1614, 2023 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-37789701

RESUMO

Biochemical gut metabolism of dietary bioactive compounds is of great significance in elucidating health-related issues at the molecular level. In this study, a human gut bacterium cleaving C-C glycosidic bond was screened from puerarin conversion to daidzein, and a new, gram-positive C-glycoside-deglycosylating strain, Dorea sp. MRG-IFC3, was isolated from human fecal sample under anaerobic conditions. Though MRG-IFC3 biotransformed isoflavone C-glycoside, it could not metabolize other C-glycosides, such as vitexin, bergenin, and aloin. As evident from the production of the corresponding aglycons from various 7-O-glucosides, MRG-IFC3 strain also showed 7-O-glycoside cleavage activity; however, flavone 3-O-glucoside icariside II was not metabolized. In addition, for mechanism study, C-glycosyl bond cleavage of puerarin by MRG-IFC3 strain was performed in D2O GAM medium. The complete deuterium enrichment on C-8 position of daidzein was confirmed by 1H NMR spectroscopy, and the result clearly proved for the first time that daidzein is produced from puerarin. Two possible reaction intermediates, the quinoids and 8-dehydrodaidzein anion, were proposed for the production of daidzein-8d. These results will provide the basis for the mechanism study of stable C-glycosidic bond cleavage at the molecular level.


Assuntos
Bactérias , Isoflavonas , Humanos , Bactérias/metabolismo , Glicosídeos/metabolismo , Isoflavonas/metabolismo , Glucosídeos/metabolismo , Fezes/microbiologia
2.
Sci Rep ; 13(1): 16282, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37770535

RESUMO

Puerarin, daidzein C-glucoside, was known to be biotransformed to daidzein by human intestinal bacteria, which is eventually converted to (S)-equol. The metabolic pathway of puerarin to daidzein by DgpABC of Dorea sp. PUE strain was reported as puerarin (1) → 3''-oxo-puerarin (2) → daidzein (3) + hexose enediolone (C). The second reaction is the cleavage of the glycosidic C-C bond, supposedly through the quinoid intermediate (4). In this work, the glycosidic C-C bond cleavage reaction of 3''-oxo-puerarin (2) was theoretically studied by means of DFT calculation to elucidate chemical reaction mechanism, along with biochemical energetics of puerarin metabolism. It was found that bioenergetics of puerarin metabolism is slightly endergonic by 4.99 kcal/mol, mainly due to the reaction step of hexose enediolone (C) to 3''-oxo-glucose (A). The result implied that there could be additional biochemical reactions for the metabolism of hexose enediolone (C) to overcome the thermodynamic energy barrier of 4.59 kcal/mol. The computational study focused on the C-C bond cleavage of 3''-oxo-puerarin (2) found that formation of the quinoid intermediate (4) was not accessible thermodynamically, rather the reaction was initiated by the deprotonation of 2''C-H proton of 3''-oxo-puerarin (2). The 2''C-dehydro-3''-oxo-puerarin (2a2C) anionic species produced hexose enediolone (C) and 8-dehydro-daidzein anion (3a8), and the latter quickly converted to daidzein through the daidzein anion (3a7). Our study also explains why the reverse reaction of C-glycoside formation from daidzein (3) and hexose enediolone (C) is not feasible.


Assuntos
Glicosídeos Cardíacos , Isoflavonas , Humanos , Isoflavonas/química , Glucosídeos/metabolismo , Equol , Glucose/metabolismo , Modelos Teóricos
3.
Antioxidants (Basel) ; 12(7)2023 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-37507966

RESUMO

Tri-Yannarose is a Thai traditional herbal medicine formula composed of Areca catechu, Azadirachta indica, and Tinospora crispa. It possesses antipyretic, diuretic, expectorant, and appetite-stimulating effects. This study aimed to evaluate the antioxidant activities, cytotoxicity, and chemical constituents of an aqueous extract following a Tri-Yannarose recipe and its plant ingredients. The phytochemical analysis was performed using LC-QTOF-MS. Antioxidant activities were determined using DPPH, ABTS, TPC, TFC, FRAP, NBT, MCA, and ORAC assays. Cytotoxicity was investigated using a methyl thiazol tetrazolium (MTT) assay. In addition, the relationship between the chemical composition of Tri-Yannarose and antioxidant activities was investigated by examining the structure-activity relationship (SAR). The results of the LC-QTOF-MS analysis revealed trigonelline, succinic acid, citric acid, and other chemical constituents. The aqueous extract of the recipe showed significant scavenging effects against ABTS and DPPH radicals, with IC50 values of 1054.843 ± 151.330 and 747.210 ± 44.173 µg/mL, respectively. The TPC of the recipe was 92.685 mg of gallic acid equivalent/g of extract and the TFC was 14.160 mg of catechin equivalent/g of extract. All extracts demonstrated lower toxicity in the Vero cell line according to the MTT assay. In addition, the SAR analysis indicated that prenyl arabinosyl-(1-6)-glucoside and quinic acid were the primary antioxidant compounds in the Tri-Yannarose extract. In conclusion, this study demonstrates that Tri-Yannarose and its plant ingredients have potent antioxidant activities with low toxicity. These results support the application of the Tri-Yannarose recipe for the management of a range of disorders related to oxidative stress.

5.
Microbiol Spectr ; 10(5): e0330522, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36197289

RESUMO

Coabalamin-dependent O-demethylase in Blautia sp. strain MRG-PMF1 was found to catalyze the unprecedented allyl aryl ether cleavage reaction. To expand the potential biotechnological applications, the reaction mechanism of the allyl aryl ether C-O bond cleavage, proposed to utilize the reactive Co(I) supernucleophile species, was studied further from the anaerobic whole-cell biotransformation. Various allyl naphthyl ether derivatives were reacted with Blautia sp. MRG-PMF1 O-demethylase, and stereoisomers of allyl naphthyl ethers, including prenyl and but-2-enyl naphthyl ethers, were converted to the corresponding naphthol in a stereoselective manner. The allyl aryl ether cleavage reaction was regioselective, and 2-naphthyl ethers were converted faster than the corresponding 1-naphthyl ethers. However, MRG-PMF1 cocorrinoid O-demethylase was not able to convert (2-methylallyl) naphthyl ether substrates, and the conversion of propargyl naphthyl ether was extremely slow. From the results, it was proposed that the allyl ether cleavage reaction follows the nucleophilic conjugate substitution (SN2') mechanism. The reactivity and mechanism of the new allyl ether cleavage reaction by cobalamin-dependent O-demethylase would facilitate the application of Blautia sp. MRG-PMF1 O-demethylase in the area of green biotechnology. IMPORTANCE Biodegradation of environmental pollutants and valorization of biomaterials in a greener way is of great interest. Cobalamin-dependent O-demethylase in Blautia sp. MRG-PMF1 exclusively involves anaerobic C1 metabolism by cleaving the C-O bond of aromatic methoxy group and also produces various aryl alcohols by metabolizing allyl aryl ether compounds. Whereas methyl ether cleavage reaction is known to follow the SN2' mechanism, the reaction pattern and mechanism of the new allyl ether cleavage reaction by cobalamin-dependent O-demethylase have never been studied. For the first time, stereoselectivity and the SN2' mechanism of allyl aryl ether cleavage reaction by Blautia sp. MRG-PMF1 O-demethylase is reported, and the results would facilitate the application of Blautia sp. MRG-PMF1 O-demethylase in the area of green biotechnology.


Assuntos
Poluentes Ambientais , Éteres Metílicos , Éter , Oxirredutases O-Desmetilantes , Naftóis , Éteres/química , Éteres/metabolismo , Etil-Éteres , Vitamina B 12 , Materiais Biocompatíveis
6.
Front Pharmacol ; 13: 815603, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35418870

RESUMO

Multidrug resistance (MDR) is one of the main impediments in successful chemotherapy in cancer treatment. Overexpression of ATP-binding cassette (ABC) transporter proteins is one of the most important mechanisms of MDR. Natural products have their unique advantages in reversing MDR, among which diterpenoids have attracted great attention of the researchers around the world. This review article summarizes and discusses the research progress on diterpenoids in reversing MDR.

7.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361729

RESUMO

Tyrosinase (TYR) is a type III copper oxidase present in fungi, plants and animals. The inhibitor of human TYR plays a vital role in pharmaceutical and cosmetic fields by preventing synthesis of melanin in the skin. To search for an effective TYR inhibitor from various plant extracts, a kinetic study of TYR inhibition was performed with mushroom TYR. Among Panax ginseng, Alpinia galanga, Vitis vinifera and Moringa oleifera, the extracts of V. vinifera seed, A. galanga rhizome and M. oleifera leaf reversibly inhibited TYR diphenolase activity with IC50 values of 94.8 ± 0.2 µg/mL, 105.4 ± 0.2 µg/mL and 121.3 ± 0.4 µg/mL, respectively. Under the same conditions, the IC50 values of the representative TYR inhibitors of ascorbic acid and kojic acid were found at 235.7 ± 1.0 and 192.3 ± 0.4 µg/mL, respectively. An inhibition kinetics study demonstrated mixed-type inhibition of TYR diphenolase by A. galanga and V. vinifera, whereas a rare uncompetitive inhibition pattern was found from M. oleifera with an inhibition constant of Kii 73 µg/mL. Phytochemical investigation by HPLC-MS proposed luteolin as a specific TYR diphenolase ES complex inhibitor, which was confirmed by the inhibition kinetics of luteolin. The results clearly showed that studying TYR inhibition kinetics with plant extract mixtures can be utilized for the screening of specific TYR inhibitors.


Assuntos
Inibidores Enzimáticos/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Luteolina/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Moringa oleifera/química , Agaricales/química , Agaricales/enzimologia , Alpinia/química , Ácido Ascórbico/química , Ácido Ascórbico/isolamento & purificação , Ácido Ascórbico/farmacologia , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Proteínas Fúngicas/isolamento & purificação , Ensaios de Triagem em Larga Escala , Concentração Inibidora 50 , Cinética , Luteolina/química , Luteolina/isolamento & purificação , Monofenol Mono-Oxigenase/isolamento & purificação , Panax/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Pironas/química , Pironas/isolamento & purificação , Pironas/farmacologia , Rizoma/química , Sementes/química , Vitis/química
8.
ACS Omega ; 5(47): 30696-30703, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33283118

RESUMO

Gut metabolism of natural products is of great interest due to the altered biological activity of the metabolites. To study the gut metabolism of the dietary furanocoumarins, the biotransformation of Angelica dahurica was studied with human gut microbiota. The major components of Avenula dahurica, including xanthotoxin (1), bergapten (2), imperatorin (3), isoimperatorin (4), oxypeucedanin (5), and byakangelicol (6), were all metabolized by the human fecal sample, and each furanocoumarin was also biotransformed by Blautia sp. MRG-PMF1 responsible for intestinal O-demethylation. Oxypeucedanin (5) and byakangelicol (6) were converted to oxypeucedanin hydrate (9) and desmethylbyakangelicin (12), respectively. The gut microbial conversion of xanthotoxin (1) and bergapten (2) with the MRG-PMF1 strain resulted in the production of xanthotoxol (7) and bergaptol (8), respectively, due to the methyl aryl ether cleavage by O-methyltransferase. Unexpectedly, the biotransformation of prenylated furanocoumarins, imperatorin (3), and isoimperatorin (4) resulted in the corresponding deprenylated furanocoumarins of xanthotoxol (7) and bergaptol (8), respectively. The cleavage of the prenyl aryl ether group by gut microbiota was unprecedented metabolism. Our data presented the first deprenylation of prenylated natural products, presumably by the anaerobic prenyl aryl ether cleavage reaction catalyzed by Co-corrinoid enzyme.

9.
Foods ; 9(9)2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32887356

RESUMO

For the functional food applications, antioxidant properties and the bioactive compounds of the 23 Curcuma species commercially cultivated in Thailand were studied. Total phenolic content and DPPH radical scavenging activity were determined. The concentrations of eight bioactive compounds, including curcumin (1), demethoxycurcumin (2), bisdemethoxycurcumin (3), 1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (4), germacrone (5), furanodienone (6), zederone (7), and ar-turmerone (8), were determined from the Curcuma by HPLC. While the total phenolic content of C. longa was highest (22.3 ± 2.4 mg GAE/g, mg of gallic acid equivalents), C. Wan Na-Natong exhibited the highest DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) radical scavenging activity. Twenty-three Curcuma species showed characteristic distributions of the bioactive compounds, which can be utilized for the identification and authentication of the cultivated Curcuma species. C. longa contained the highest content of curcumin (1) (304.9 ± 0.1 mg/g) and C. angustifolia contained the highest content of germacrone (5) (373.9 ± 1.1 mg/g). It was noteworthy that 1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (4) was found only from C. comosa at a very high concentration (300.7 ± 1.4 mg/g). It was concluded that Thai Curcuma species have a great potential for the application of functional foods and ingredients.

10.
Metabolites ; 9(7)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295867

RESUMO

The intestine is a small world where all the chemical reactions are operated by gut microbiota. Study on the gut metabolism of natural products is a new and expanding research area that leads to new bioactive metabolites, as well as novel chemical reactions. To provide exemplary cases, flavonoid biotransformation by intestinal bacteria with focus on S-equol biosynthesis and aryl methyl ether cleavage reaction, is described in this review.

11.
Nutr Cancer ; 70(6): 984-996, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30273054

RESUMO

Kaempferia parviflora (KP) is a famous medicinal plant from Thailand, and is a rich source of various kinds of methoxyflavones (MFs). Many kinds of food products such as tea, capsule, and liquor are manufactured from the rhizomes of KP. In this study, KP infusions were prepared with different brewing conditions, and the amounts of three major methoxylflavones, 5,7-dimethoxyflavone (DMF), 5,7,4'-trimethoxyflavone (TMF), and 3,5,7,3',4'-pentamethoxyflavone (PMF), were analyzed. The antiproliferative activities of DMF, TMF, and PMF isolated from the brewed tea samples were evaluated. TMF was discovered to be significantly effective at inhibiting proliferation of SNU-16 human gastric cancer cells in a concentration dependent manner. TMF induced apoptosis, as evidenced by increments of sub-G1 phase, DNA fragmentation, annexin-V/PI staining, the Bax/Bcl-xL ratio, proteolytic activation of caspase-3,-7,-8, and degradation of poly (ADP-ribose) polymerase (PARP) protein. Furthermore, it was found that TMF induced apoptosis via ER stress, verified by an increase in the level of C/EBP homologous protein (CHOP), glucose regulated protein 78 (GRP78), inositol-requiring enzyme 1 α (IRE1α), activating transcription factor-4 (ATF-4), and the splice isoform of X-box-binding protein-1 (XBP-1) mRNA.


Assuntos
Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Flavonas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Zingiberaceae/química , Fator 4 Ativador da Transcrição/análise , Linhagem Celular Tumoral , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/fisiologia , Flavonas/análise , Flavonas/isolamento & purificação , Glicogênio Sintase Quinase 3 beta/análise , Humanos , Proteínas Proto-Oncogênicas c-akt/fisiologia , Neoplasias Gástricas/patologia , Serina-Treonina Quinases TOR/análise , Fator de Transcrição CHOP/análise , Proteína 1 de Ligação a X-Box/genética , Proteína bcl-X/análise
12.
Molecules ; 23(7)2018 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-30041413

RESUMO

Whereas Korean ginseng, Panax ginseng Meyer, is harvested in the fall, the variation of ginsenoside content in field-grown ginseng across seasonal development has never been investigated in Korea. Thus, ultra-high performance liquid chromatography (UHPLC) analysis of nine major ginsenosides, including ginsenoside Rg1, Re, Rf, Rg2, Rb1, Rc, Rb2, Rd, and Ro, in the roots of five-year-old P. ginseng cultivated in Bongwha, Korea in 2017 was performed. The total ginsenoside content changed as many as three times throughout the year, ranging from 1.37 ± 0.02 (dry wt %) in January to 4.26 ± 0.03% in May. Total ginsenoside content in the harvest season was 2.49 ± 0.03%. Seasonal variations of panaxadiol-type ginsenosides (PPD) and panaxatriol-type ginsenosides (PPT) were found to be similar, but more PPD was always measured. However, the seasonal variation of oleanolic acid-type ginsenoside, Ro, was different from that of PPD and PPT, and the highest Ro content was observed in May. The ratio of PPD/PPT, as well as other representative ginsenosides, was compared throughout the year. Moreover, the percent composition of certain ginsenosides in both PPD and PPT types was found to be in a complementary relationship each other, which possibly reflected the biosynthetic pathway of the related ginsenosides. This finding would not only provide scientific support for the production and quality control of the value-added ginseng products, but also facilitate the elucidation of the ginsenoside biosynthetic pathway.


Assuntos
Vias Biossintéticas , Ginsenosídeos/biossíntese , Ginsenosídeos/química , Panax/química , Panax/metabolismo , Estações do Ano , Cromatografia Líquida de Alta Pressão , Estrutura Molecular , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Fatores de Tempo
13.
J Microbiol Biotechnol ; 28(4): 579-587, 2018 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-29385667

RESUMO

For biotechnological production of high-valued ß-D-hexyl glucoside, the catalytic properties of Hanseniaspora thailandica BC9 ß-glucosidase purified from the periplasmic fraction were studied, and the transglycosylation activity for the production of ß-D-hexyl glucoside was optimized. The constitutive BC9 ß-glucosidase exhibited maximum specific activity at pH 6.0 and 40ºC, and the activity of BC9 ß-glucosidase was not significantly inhibited by various metal ions. BC9 ß-glucosidase did not show a significant activity of cellobiose hydrolysis, but the activity was rather enhanced in the presence of sucrose and medium-chain alcohols. BC9 ß-glucosidase exhibited enhanced production of ß-D-hexyl glucoside in the presence of DMSO, and 62% of ß-D-hexyl glucoside conversion was recorded in 4 h in the presence of 5% 1-hexanol and 15% DMSO.


Assuntos
Glucosídeos/biossíntese , Hanseniaspora/enzimologia , beta-Glucosidase/química , beta-Glucosidase/metabolismo , Álcoois/metabolismo , Catálise , Celobiose/metabolismo , Estabilidade Enzimática , Proteínas Fúngicas/química , Proteínas Fúngicas/isolamento & purificação , Proteínas Fúngicas/metabolismo , Glicosilação , Concentração de Íons de Hidrogênio , Hidrólise , Cinética , Metais/metabolismo , Solventes , Especificidade por Substrato , Sacarose/metabolismo , Açúcares/metabolismo , Temperatura , Fatores de Tempo , beta-Glucosidase/isolamento & purificação
14.
J Agric Food Chem ; 65(16): 3305-3310, 2017 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-28401758

RESUMO

Curcumin and other curcuminoids from Curcuma longa are important bioactive compounds exhibiting various pharmacological activities. In addition to the known reductive metabolism of curcuminoids, an alternative biotransformation of curcuminoids by human gut microbiota is reported herein. A curcuminoid mixture, composed of curcumin (1), demethoxycurcumin (2), and bisdemethoxycurcumin (3), was metabolized by the human intestinal bacterium Blautia sp. MRG-PMF1. 1 and 2 were converted to new metabolites by the methyl aryl ether cleavage reaction. Two metabolites, demethylcurcumin (4) and bisdemethylcurcumin (5), were sequentially produced from 1, and demethyldemethoxycurcumin (6) was produced from 2. Until now, sequential reduction of the heptadienone backbone of curcuminoids was the only known metabolism to occur in the human intestine. In this study, a new intestinal metabolism of curcuminoids was discovered. Demethylation of curcuminoids produced three new colonic metabolites that were already known as promising synthetic curcumin analogues. The results could explain the observed beneficial effects of turmeric.


Assuntos
Bactérias/metabolismo , Curcuma/metabolismo , Curcumina/metabolismo , Microbioma Gastrointestinal , Mucosa Intestinal/metabolismo , Intestinos/microbiologia , Extratos Vegetais/metabolismo , Bactérias/classificação , Bactérias/isolamento & purificação , Curcumina/análogos & derivados , Curcumina/química , Diarileptanoides , Humanos , Metilação , Estrutura Molecular , Extratos Vegetais/química
15.
Phytochemistry ; 136: 9-14, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28139297

RESUMO

(E)-4-Hydroxy-3-methylbut-2-enyl diphosphate (HMBPP) reductase (IspH, HDR or LytB) is an Fe/S enzyme catalyzing the reductive dehydroxylation of HMBPP to isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) in the last step of methylerythritol phosphate (MEP) pathway. The MEP pathway is known to produce 4-6:1 ratio of IPP and DMAPP mixture by the last enzyme, IspH. Plant IspH in plastids follows same catalytic mechanism as others, but GbIspH (Ginkgo biloba IspH) was reported to produce a mixture of IPP and DMAPP in a ratio of 16:1. Present catalytic mechanisms of IspH involve a common allyl anion intermediate, and the intramolecular proton transfer to the allyl moiety is considered as the key reaction step determining the product between IPP and DMAPP. The F212 residue in plant IspH was found as a potential amino acid residue that could mediate the proton transfer to the allyl anion intermediate before the product release. In this report, catalytic function of GbIspH F212 residue (H74 in E. coli), especially during the product formation in the active site, was studied by means of site-directed mutation. The product ratio of IPP/DMAPP was measured as 6.5 ± 0.1 for F212H GbIspH, and the value was close to the reported bacterial IspH having His residue on that specific position. Along with the other F212Y mutant, of which ratio was determined as 10.9 ± 0.1, the results strongly support that the Phe residue in plant IspH is the key amino acid residue that allows exclusive production of IPP in plant chloroplast.


Assuntos
Ginkgo biloba/química , Hemiterpenos/metabolismo , Compostos Organofosforados/metabolismo , Domínio Catalítico , Cloroplastos/metabolismo , Ginkgo biloba/metabolismo , Ferro/metabolismo , Dados de Sequência Molecular , Estrutura Molecular , Organofosfatos/metabolismo , Conformação Proteica , Estereoisomerismo , Sulfetos/metabolismo
16.
J Agric Food Chem ; 65(8): 1620-1629, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28211698

RESUMO

Polymethoxyflavones (PMFs) were biotransformed to various demethylated metabolites in the human intestine by the PMF-metabolizing bacterium, Blautia sp. MRG-PMF1. Because the newly formed metabolites can have different biological activities, the pathways and regioselectivity of PMF bioconversion were investigated. Using an anaerobic in vitro study, 12 PMFs, 5,7-dimethoxyflavone (5,7-DMF), 5-hydroxy-7-methoxyflavone (5-OH-7-MF), 3,5,7-trimethoxyflavone (3,5,7-TMF), 5-hydroxy-3,7-dimethoxyflavone (5-OH-3,7-DMF), 5,7,4'-trimethoxyflavone (5,7,4'-TMF), 5-hydroxy-7,4'-dimethoxyflavone (5-OH-7,4'-DMF), 3,5,7,4'-tetramethoxyflavone (3,5,7,4'-TMF), 5-hydroxy-3,7,4'-trimethoxyflavone (5-OH-3,7,4'-TMF), 5,7,3',4'-tetramethoxyflavone (5,7,3',4'-TMF), 3,5,7,3',4'-pentamethoxyflavone (3,5,7,3',4'-PMF), 5-hydroxy-3,7,3',4'-tetramethoxyflavone (5-OH-3,7,3',4'-TMF), and 5,3'-dihydroxy-3,7,4'-trimethoxyflavone (5,3'-diOH-3,7,4'-TMF), were converted to chrysin, apigenin, galangin, kaempferol, luteolin, and quercetin after complete demethylation. The time-course monitoring of PMF biotransformations elucidated bioconversion pathways, including the identification of metabolic intermediates. As a robust flavonoid demethylase, regioselectivity of PMF demethylation generally followed the order C-7 > C-4' ≈ C-3' > C-5 > C-3. PMF demethylase in the MRG-PMF1 strain was suggested as a Co-corrinoid methyltransferase system, and this was supported by the experiments utilizing other methyl aryl ether substrates and inhibitors.


Assuntos
Firmicutes/metabolismo , Flavonoides/metabolismo , Microbioma Gastrointestinal , Intestinos/microbiologia , Biotransformação , Firmicutes/isolamento & purificação , Flavonoides/química , Humanos , Metilação
17.
Biomed Pharmacother ; 88: 151-161, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28103509

RESUMO

Quercetin, a well cognized bioactive flavone possessing great medicinal value, has limited usage. The rapid gastrointestinal digestion of quercetin is also a major obstacle for its clinical implementation due to low bioavailability and poor aqueous solubility. 3',5-dihydroxy-3,4',7-trimethoxyflavone (DTMF), a novel semi-synthetic derivative of quercetin, is known to modulate several biological activities. Therefore, in the present study we examined the cytotoxic mechanism of DTMF in concentration-dependent manner (25, 50, and 100µM; 24h) against HCT-116 human colon carcinoma cells. The cytotoxic potential of DTMF was characterized based on deformed cell morphology, increased ROS accumulation, loss of mitochondrial membrane potential (ΔÑ°m), increased mitochondrial mass, chromatin condensation, and typical DNA-fragmentation in HCT-116 cells. The results showed that DTMF-induced enhanced ROS production at higher concentration (100µM) as evidenced by upregulated expression of ER stress and apoptotic proteins with concomitant increase in PERK, CHOP, and JNK levels, when compared to N-acetyl cysteine (NAC, ROS inhibitor) treated HCT-116 cells, which depicts that DTMF might act as a crucial mediator of apoptosis signaling. Collectively, our results suggest that DTMF stimulates ROS-mediated oxidative stress, which in turn induces PERK-CHOP and JNK pathway of apoptosis to promote HCT-116 cell death.


Assuntos
Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Flavonas/farmacologia , Quercetina/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Acetilcisteína/farmacologia , Antioxidantes/metabolismo , Cálcio/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Flavonas/química , Células HCT116 , Humanos , Espaço Intracelular/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Quercetina/química , Quercetina/farmacologia , Espécies Reativas de Oxigênio/metabolismo
18.
Nat Prod Commun ; 12(3): 461-472, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30549910

RESUMO

Indonesia is one of the richest countries with respect to plants resources. People from various ethnic, language, and religious groups have used the plants. as alternative medicines, health foods and beverages for hundreds of years. To establish modem application for these understudied plant resources, ethnopharmacological data from more than 40 leguminous plants in Indonesia, spanning the western to the eastern parts of the Indonesian archipelago, were reviewed. In particular, bioactive secondary metabolites, including flavonoids, were described in detail to promote research into these plants as functional foods, nutraceuticals, and medicines.


Assuntos
Fabaceae/química , Medicina Tradicional , Compostos Fitoquímicos/química , Fabaceae/metabolismo , Humanos , Indonésia , Estrutura Molecular , Compostos Fitoquímicos/metabolismo
19.
Biomed Pharmacother ; 84: 789-799, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27721177

RESUMO

Although quercetin is very well known for its anticancer activity, however it shows some drawbacks. Herein, we have evaluated the apoptotic effect TEF (5, 3'-dihydroxy-3, 7, 4'-triethoxyflavone), a newly synthesized quercetin derivative on HCT-116 colon cancer cells. After 24h of treatment, the proliferation of colon cancer cells was inhibited by TEF. TEF induced apoptosis, as confirmed by the presence of fragmented nuclei, reduced mitochondrial membrane potential, and elevated cytoplasmic and mitochondrial reactive oxygen species (ROS) levels. TEF treatment causes elevation of IRE1-α and activates calcium ions (Ca2+) with concomitant increase in JNK levels. Elevated Ca2+ ion translocates from ER to mitochondria which leads to ROS release and oxidative stress. TEF treatment further elevated levels of pro-apoptotic factors and down-regulated the level of Bcl2. TEF led to activation of mito-JNK (mitochondrial JNK), which plays a crucial role in activation of oxidative stress and caspase mediated apoptotic cell death. Moreover, JNK inhibition shown to suppress TEF induced apoptosis in HCT-116 colon cancer cells. Therefore, this study reveals the apoptotic role of TEF against HCT-116 cell line via IRE1-α and mito-JNK pathway.


Assuntos
Apoptose/fisiologia , Neoplasias do Colo/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Mitocôndrias/metabolismo , Quercetina/análogos & derivados , Quercetina/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Relação Dose-Resposta a Droga , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células HCT116 , Humanos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Silanos/química , Silanos/farmacologia
20.
Molecules ; 21(9)2016 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-27589718

RESUMO

Icariin is a major bioactive compound of Epimedii Herba, a traditional oriental medicine exhibiting anti-cancer, anti-inflammatory and anti-osteoporosis activities. Recently, the estrogenic activities of icariin drew significant attention, but the published scientific data seemed not to be so consistent. To provide fundamental information for the study of the icaritin metabolism, the biotransformation of icariin by the human intestinal bacteria is reported for the first time. Together with human intestinal microflora, the three bacteria Streptococcus sp. MRG-ICA-B, Enterococcus sp. MRG-ICA-E, and Blautia sp. MRG-PMF-1 isolated from human intestine were reacted with icariin under anaerobic conditions. The metabolites including icariside II, icaritin, and desmethylicaritin, but not icariside I, were produced. The MRG-ICA-B and E strains hydrolyzed only the glucose moiety of icariin, and icariside II was the only metabolite. However, the MRG-PMF-1 strain metabolized icariin further to desmethylicaritin via icariside II and icaritin. From the results, along with the icariin metabolism by human microflora, it was evident that most icariin is quickly transformed to icariside II before absorption in the human intestine. We propose the pharmacokinetics of icariin should focus on metabolites such as icariside II, icaritin and desmethylicaritin to explain the discrepancy between the in vitro bioassay and pharmacological effects.


Assuntos
Enterococcus/metabolismo , Flavonoides/metabolismo , Microbioma Gastrointestinal , Streptococcus/metabolismo , Anaerobiose/efeitos dos fármacos , Feminino , Flavonoides/farmacologia , Humanos , Masculino
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