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1.
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
2.
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.

3.
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.

4.
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.

5.
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 , 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
6.
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
7.
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
8.
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
9.
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
10.
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
11.
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
12.
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
13.
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
14.
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
15.
PLoS One ; 11(4): e0154525, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27116119

RESUMO

Plant-derived compounds are an important source of clinically useful anti-cancer agents. Chrysin, a biologically active flavone found in many plants, has limited usage for cancer chemotherapeutics due to its poor oral bioavailability. 5-Hydroxy-7-methoxyflavone (HMF), an active natural chrysin derivative found in various plant sources, is known to modulate several biological activities. However, the mechanism underlying HMF-induced apoptotic cell death in human colorectal carcinoma cells in vitro is still unknown. Herein, HMF was shown to be capable of inducing cytotoxicity in HCT-116 cells and induced cell death in a dose-dependent manner. Treatment of HCT-116 cells with HMF caused DNA damage and triggered mitochondrial membrane perturbation accompanied by Cyt c release, down-regulation of Bcl-2, activation of BID and Bax, and caspase-3-mediated apoptosis. These results show that ROS generation by HMF was the crucial mediator behind ER stress induction, resulting in intracellular Ca2+ release, JNK phosphorylation, and activation of the mitochondrial apoptosis pathway. Furthermore, time course study also reveals that HMF treatment leads to increase in mitochondrial and cytosolic ROS generation and decrease in antioxidant enzymes expression. Temporal upregulation of IRE1-α expression and JNK phosphorylation was noticed after HMF treatment. These results were further confirmed by pre-treatment with the ROS scavenger N-acetyl-l-cysteine (NAC), which completely reversed the effects of HMF treatment by preventing lipid peroxidation, followed by abolishment of JNK phosphorylation and attenuation of apoptogenic marker proteins. These results emphasize that ROS generation by HMF treatment regulates the mitochondrial-mediated apoptotic signaling pathway in HCT-116 cells, demonstrating HMF as a promising pro-oxidant therapeutic candidate for targeting colorectal cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias do Colo/metabolismo , Flavonoides/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Relação Dose-Resposta a Droga , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos
16.
Anticancer Res ; 36(2): 785-92, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26851040

RESUMO

AIM: The purpose of the present study was to identify variables associated with high risk of failure in patients with locally advanced squamous cell carcinoma of the oral cavity (SCC-OC). PATIENTS AND METHODS: This retrospective study included 191 patients with stage III-IVb SCC-OC treated with post-operative radiotherapy (RT) or chemoradiotherapy (CRT) between 1995 and 2013. Disease-free (DFS) and overall survival (OS) were analyzed; variables associated with inferior DFS were identified. RESULTS: Seventy-five patients (39%) recurred. DFS and five-year OS were 52% and 54%, respectively. Poorly differentiated tumors (p=0.03), recurrent tumors (p=0.02) and high nodal ratio (p=0.02) were associated with an increased risk of recurrence. CRT was associated with improved DFS in patients with positive margins and/or extracapsular extension (p=0.021). CONCLUSION: Tumors that are recurrent, high grade, or have high nodal ratio are at risk of recurrence. Presence of these disease features should be taken into consideration for better risk stratification.


Assuntos
Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias Bucais/terapia , Boca/efeitos da radiação , Boca/cirurgia , Recidiva Local de Neoplasia , Procedimentos Cirúrgicos Bucais/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia Adjuvante , Progressão da Doença , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Estimativa de Kaplan-Meier , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Boca/patologia , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Estadiamento de Neoplasias , Neoplasia Residual , Procedimentos Cirúrgicos Bucais/mortalidade , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
17.
Invest Ophthalmol Vis Sci ; 56(12): 7324-30, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26559478

RESUMO

PURPOSE: To assess retinal architectural alterations that occur following membrane peeling procedures and the impact of peel technique on these alterations utilizing intraoperative optical coherence tomography (iOCT). METHODS: This is a subanalysis of the prospective PIONEER iOCT study of eyes undergoing a membrane peeling for a vitreomacular interface (VMI) disorder. Intraoperative scanning was performed with a microscope-mounted OCT system. Macroarchitectural alterations (e.g., full-thickness retinal elevations) and microarchitectural alterations (e.g., relative layer thickness alterations) were analyzed. Video/iOCT correlation was performed to identify instrument-tissue manipulations resulting in macroarchitectural alterations. RESULTS: One hundred sixty-three eyes were included in the macroarchitectural analysis. Instrumentation utilized for membrane peeling included forceps alone for 73 eyes (45%), combined diamond-dusted membrane scraper (DDMS) and forceps for 87 eyes (53%), and other techniques in three eyes (2%). Focal retinal elevations were identified in 45 of 163 eyes (28%). Video/iOCT correlation identified 69% of alterations involved forceps compared to 26% due to DDMS. Sixteen percent of retinal alterations persisted 1 month following surgery. The microarchitectural analysis included 134 eyes. Immediately following membrane peeling, there was a significant increase in the ellipsoid zone to retinal pigment epithelium height (+20%, P < 0.00001) and the cone outer segment tips to retinal pigment epithelium height (+18%, P < 0.00001). CONCLUSIONS: Significant subclinical retinal architectural changes occur during membrane peeling for VMI conditions. Differences in surgical instruments may impact these architectural alterations.


Assuntos
Monitorização Intraoperatória/métodos , Perfurações Retinianas/cirurgia , Epitélio Pigmentado da Retina/patologia , Tomografia de Coerência Óptica/métodos , Vitrectomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Perfurações Retinianas/diagnóstico , Gravação em Vídeo
18.
Bioinorg Chem Appl ; 2015: 241479, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25892986

RESUMO

GbIspH1, IspH type 1 in Ginkgo biloba chloroplast, is the Fe/S enzyme catalyzing the reductive dehydroxylation of HMBPP to isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) at the final step of methylerythritol phosphate pathway in chloroplast. Compared to the bacterial IspH, plant IspH, including GbIspH1, has an additional polypeptide chain at the N-terminus. Here, biochemical function of the N-terminal region of GbIspH1 was investigated with the N-terminal truncated GbIspH1 (GbIspH1-truncated). Both wild type GbIspH1 (GbIspH1-full) and GbIspH1-truncated were catalytically active and produced IPP and DMAPP in a ratio of 15 : 1. Kinetic parameters of K M (17.3 ± 1.9 and 14.9 ± 2.3 µM) and k cat (369 ± 10 and 347 ± 12 min(-1)) at pH 8.0 were obtained for GbIspH1-full and GbIspH1-truncated, respectively. Interestingly, GbIspH1-full and GbIspH1-truncated showed significantly different pH-dependent activities, and the maximum enzyme activities were obtained at pH 8.0 and 7.5, respectively. However, catalytic activation energies (E a ) of GbIspH1-full and GbIspH1-truncated were almost the same with 36.5 ± 1.6 and 35.0 ± 1.9 kJ/mol, respectively. It was suggested that the N-terminal region of GbIspH1 is involved in the pH-dependent regulation of enzyme activity during photosynthesis.

19.
J Sci Food Agric ; 95(9): 1925-31, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25199800

RESUMO

BACKGROUND: Plant isoflavones are mostly present in the glycoside form. Isoflavone aglycones produced by intestinal microflora are reported to be more bioactive than the glycoside form. However, the deglycosylation of isoflavone C-glycosides is known to be rare, and is less studied. RESULTS: Three new bacteria were isolated from human faecal samples, two of which hydrolysed the C-glycosidic bond of puerarin, daidzein-8-C-glucoside. They were identified as two Lactococcus species, herein designated as MRG-IFC-1 and MRG-IFC-3, and an Enterococcus species, herein designated MRG-IFC-2, based on their 16S rDNA sequences. From a reactivity study, it was found that Lactococcus sp. MRG-IFC-1 and Enterococcus sp. MRG-IFC-2 hydrolysed isoflavone C- and O-glycosides, as well as the flavone O-glycoside apigetrin, but could not hydrolyse the flavone C-glycosidic bond of vitexin. The other Lactococcus sp., MRG-IF-3, could not hydrolyse the C-glycosidic linkage of puerarin, while it showed a broad substrate spectrum of O-glycosidase activity similar to the other two bacteria. Puerarin was completely converted to daidzein within 100 min by Lactococcus sp. MRG-IFC-1 and Enterococcus sp. MRG-IFC-2, which is the fastest conversion among the reported human intestinal bacteria. CONCLUSION: Two new puerarin-metabolising human intestinal bacteria were isolated and identified, and the deglycosylation activity for various flavonoid glycosides was investigated. The results could facilitate the study of C-glycosidase reaction mechanisms, as well as the pharmacokinetics of bioactive C-glycoside natural products.


Assuntos
Proteínas de Bactérias/metabolismo , Enterococcus/metabolismo , Glicosídeo Hidrolases/metabolismo , Glicosídeos/metabolismo , Intestinos/microbiologia , Isoflavonas/metabolismo , Lactococcus/metabolismo , Adulto , Apigenina/metabolismo , Enterococcus/classificação , Enterococcus/isolamento & purificação , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal , Glicosilação , Humanos , Hidrólise , Cinética , Lactococcus/classificação , Lactococcus/isolamento & purificação , Tipagem Molecular , República da Coreia , Especificidade por Substrato
20.
J Agric Food Chem ; 62(51): 12377-83, 2014 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-25437273

RESUMO

Poylmethoxyflavones (PMFs) are major bioactive flavonoids, which exhibit various biological activities, such as anticancer effects. The biotransformation of PMFs and characterization of a PMF-metabolizing human intestinal bacterium were studied herein for the first time. Hydrolysis of aryl methyl ether functional groups by human fecal samples was observed from the bioconversion of various PMFs. Activity-guided screening for PMF-metabolizing intestinal bacteria under anaerobic conditions resulted in the isolation of a strict anaerobic bacterium, which was identified as Blautia sp. MRG-PMF1. The isolated MRG-PMF1 was able to metabolize various PMFs to the corresponding demethylated flavones. The microbial conversion of bioactive 5,7-dimethoxyflavone (5,7-DMF) and 5,7,4'-trimethoxyflavone (5,7,4'-TMF) was studied in detail. 5,7-DMF and 5,7,4'-TMF were completely metabolized to 5,7-dihydroxyflavone (chrysin) and 5,7,4'-trihydroxyflavone (apigenin), respectively. From a kinetics study, the methoxy group on the flavone C-7 position was found to be preferentially hydrolyzed. 5-Methoxychrysin, the intermediate of 5,7-DMF metabolism by Blautia sp. MRG-PMF1, was isolated and characterized by nuclear magnetic resonance spectroscopy. Apigenin was produced from the sequential demethylation of 5,7,4'-TMF, via 5,4'-dimethoxy-7-hydroxyflavone and 7,4'-dihydroxy-5-methoxyflavone (thevetiaflavone). Not only demethylation activity but also deglycosylation activity was exhibited by Blautia sp. MRG-PMF1, and various flavonoids, including isoflavones, flavones, and flavanones, were found to be metabolized to the corresponding aglycones. The unprecedented PMF demethylation activity of Blautia sp. MRG-PMF1 will expand our understanding of flavonoid metabolism in the human intestine and lead to novel bioactive compounds.


Assuntos
Bactérias/metabolismo , Flavonas/metabolismo , Intestinos/microbiologia , Zingiberaceae/metabolismo , Bactérias/genética , Bactérias/isolamento & purificação , Flavonas/química , Humanos , Mucosa Intestinal/metabolismo , Cinética , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/metabolismo
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