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1.
J Biomol Struct Dyn ; 40(20): 9636-9647, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34074230

RESUMO

The chemical constituents of the nonpolar fractions of the bamboo shoot skin Phyllostachys heterocycla were extensively studied. The phytochemical study was divided into two parts: the first deals with isolation of the chemical constituents using different chromatographic techniques that resulted in isolation of four compounds. The chemical structures of the pure isolated compounds were elucidated using different spectroscopic data. The second part deals with identification of the rest of the constituents using the GC technique. Additionally, both crude extract and the pure isolated compounds were investigated for cytotoxic activity. One of the isolated compounds; namely glyceryl 1-monopalmitate showed highly promising effect against the MCF-7 cells with (IC50 = 19.78 µM) compared to 5-FU (26.98 µM), and it remarkably stimulated apoptotic breast cancer cell death with 31.6-fold (16.13% compared to 0.51 for the control) at pre-G1 and G2/M-phase cell cycle arrest and blocked the progression of MCF-7 cells. Moreover, the identified compounds especially 1 were found to have high binding affinity towards both TPK and VEGFR-2 through the molecular docking studies which highlight its mode of action. HighlightsChemical profiling of Phyllostachys heterocycla bark nonpolar extract was fully identified.Glyceryl 1-monopalmitate showed highly promising effect against the MCF-7 cells with (IC50 = 19.78 µM) compared to 5-FU (26.98 µM).Glyceryl 1-monopalmitate significantly stimulated apoptotic breast cancer cell death with 31.6-fold by arresting cell cycle at G2/M and preG1 phases.Molecular docking simulation showed good binding affinities towards TPK and VEGFR-2 proteins.Communicated by Ramaswamy H. Sarma.


Assuntos
Antineoplásicos , Neoplasias da Mama , Extratos Vegetais , Feminino , Humanos , Antineoplásicos/química , Apoptose , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Casca de Planta/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Extratos Vegetais/farmacologia , Poaceae/química
2.
Molecules ; 26(4)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578916

RESUMO

Different extracts of the Bamboo shoot skin Phyllostachys heterocycla var. pubescens were screened against panel of cancer cell lines and normal one. The cell viability results exhibited that the ethyl acetate extract showed the least vitality percentage of 2.14% of HepG2 cells. Accordingly, it was subjected to chromatographic separation, which resulted in the isolation of a new natural product; 7-hydroxy, 5-methoxy, methyl cinnamate (1), together with four known compounds. The structures of the pure isolated compounds were deduced based on different spectroscopic data. The new compound (1) was screened against the HepG2 and MCF-7 cells and showed IC50 values of 7.43 and 10.65 µM, respectively. It induced apoptotic cell death in HepG2 with total apoptotic cell death of 58.6% (12.44-fold) compared to 4.71% in control by arresting cell cycle progression at the G1 phase. Finally, compound 1 was validated as EGFR tyrosine kinase inhibitor in both enzymatic levels (IC50 = 98.65 nM compared to Erlotinib (IC50 = 78.65 nM). Finally, in silico studies of compound 1 through the molecular docking indicated its high binding affinity towards EGFR protein and the ADME pharmacokinetics indicated it as a drug-like.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Extratos Vegetais/farmacologia , Poaceae/química , Inibidores de Proteínas Quinases/farmacologia , Apoptose , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Células Hep G2 , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Neoplasias/patologia , Extratos Vegetais/análise , Poaceae/classificação , Relação Estrutura-Atividade
3.
Pediatr Surg Int ; 37(3): 353-361, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33388954

RESUMO

PURPOSE: Total parenteral nutrition (TPN) sometimes induces parenteral nutrition-associated liver disease (PNALD). Hepatocyte growth factor (HGF) acts as a potent hepatocyte mitogen anti-inflammatory and antioxidant actions. We aimed to evaluate the effect of HGF on PNALD in a rat model of TPN. METHODS: A catheter was placed in the right jugular vein for 7-day continuous TPN. All rats were divided into three groups: TPN alone (TPN group), TPN plus intravenous HGF at 0.3 mg/kg/day [TPN + HGF (low) group], and TPN plus HGF at 1.0 mg/kg/day [TPN + HGF (high) group]. On day 7, livers were harvested and the histology, inflammatory cytokines and apoptosis were evaluated. RESULTS: Histologically, lipid droplets were apparent in the TPN group, but decreased in the TPN + HGF (low) and TPN + HGF (high) groups. The histological nonalcoholic fatty liver disease activity scores in the TPN + HGF (low) and TPN + HGF (high) groups were significantly lower than that in the TPN group (p < 0.01). There were no significant differences in the inflammatory cytokine levels of the three groups. The caspase-9 expression levels in the TPN + HGF (low) and TPN + HGF (high) groups were significantly decreased in comparison to that in the control group (p < 0.05). CONCLUSION: The intravenous administration of HGF attenuated hepatic steatosis induced by 7-day TPN dose dependently.


Assuntos
Fator de Crescimento de Hepatócito/uso terapêutico , Nutrição Parenteral Total , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Modelos Animais de Doenças , Fígado/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Ratos
4.
Molecules ; 25(23)2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33266171

RESUMO

Phytochemical screening of nonpolar fractions from the methanol extract of the Bamboo shoot skin Phyllostachys heterocycla var. pubescens resulted in the isolation of a new sterol-glucoside-fatty acid derivative (6'-O-octadeca-8'',11''-dienoyl)-sitosterol-3-O-ß-d-glucoside (1), together with six known compounds. The chemical structures of the pure isolated compounds were deduced based on different spectral data. The isolated compounds were assessed to determine their cytotoxic activity, and the results were confirmed by determining their apoptotic activity. Compound 1 was more cytotoxic against the MCF-7 cells (IC50 = 25.8 µM) compared to Fluorouracil (5-FU) (26.98 µM), and it significantly stimulated apoptotic breast cancer cell death with 32.6-fold (16.63% compared to 0.51 for the control) at pre-G1 and G2/M-phase cell cycle arrest and blocked the progression of MCF-7 cells. Additionally, RT-PCR results further confirmed the apoptotic activity of compound 1 by the upregulation of proapoptotic genes (P53; Bax; and caspases 3, 8, and 9) and downregulation of the antiapoptotic genes (BCL2). Finally, the identified compounds, especially 1, were found to have high binding affinity towards both tyrosine-specific protein kinase (TPK) and vascular endothelial growth factor receptor (VEGFR-2) through the molecular docking studies that highlight its mode of action.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose , Bambusa/química , Neoplasias da Mama/tratamento farmacológico , Brotos de Planta/química , Esteróis/farmacologia , Antineoplásicos Fitogênicos/química , Neoplasias da Mama/patologia , Ciclo Celular , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Extratos Vegetais/farmacologia , Esteróis/química , Relação Estrutura-Atividade
5.
Opt Lett ; 45(7): 2095-2098, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32236077

RESUMO

A simple low-loss fiber coupling structure consisting of a Si inverted-taper waveguide and a 435 nm wide and 290 nm thick SiN waveguide was fabricated with fully complementary metal-oxide semiconductor (CMOS)-compatible processes. The small SiN waveguide can expand to the optical field corresponding to a fiber with a mode-field diameter of 4.1 µm. The fiber-to-chip coupling losses were 0.25 and 0.51 dB/facet for quasi-TE and quasi-TM modes, respectively, at a 1550 nm wavelength. Polarization-dependent losses of the conversion in the Si-to-SiN waveguide transition and the fiber-to-chip coupling were less than 0.3 and 0.5 dB, respectively, in the wavelength range of 1520-1580 nm.

6.
Mar Drugs ; 18(1)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963531

RESUMO

Very recently, the immunotherapies against cancer, autoimmune diseases, and infection have been feasible and promising. Thus, we have examined the possibility whether or not human gamma delta T cells can be applied for the novel immunotherapies. We previously established the cells stably maintaining NFkB-driven human secreted embryonic alkaline phosphatase (SEAP) expression. The cells can be used to determine the transcription activity of NFkB with high-standard dynamic range and accuracy. Because IL-18 is a kind of cytokines that enhances cytotoxicity and activity of human gamma delta T cells through NFkB activation, we have focused on the activity and signaling of IL-18. In this study, we modified the previous reporter cell that can determine the transcription activity of NFkB to express two subunits consisted of human IL-18 receptor. The modified cells secreted SEAP in response to treatment with human recombinant IL-18 in a concentration-dependent manner. We also observed the concentration-dependently enhancement of NFkB activity in the cells treated with mouse recombinant IL-18 although the affinity was lower compared to human recombinant IL-18. We also previously established the cells stably expressing and secreting human recombinant IL-18 and then validated whether or not the conditioned medium from the cells activate NFkB transcription activity using this assay. Our university has kept collecting many extracts from over 18,000 marine bacteria in our local sea around Omura bay-fungi, plants for Chinese herbal medicine, and so on-and also have kept gathering synthetic compounds from many Japanese chemists as drug libraries. Finally, in order to identify drugs mimicking IL-18 biological activity or possessing inhibitory effects on IL-18-induced NFkB, we demonstrated drug screening using number of extracts derived from marine bacteria and synthetic compounds.


Assuntos
Interleucina-18/metabolismo , Transdução de Sinais/fisiologia , Organismos Aquáticos/metabolismo , Bactérias/metabolismo , Bioensaio/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Humanos , NF-kappa B/metabolismo
7.
RSC Adv ; 8(37): 21002-21011, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-35542344

RESUMO

Thonningia sanguinea Vahl plays an important role in traditional medicine in many African cultures. A study of the n-hexane fraction of the whole plant of T. sanguinea led to the isolation of two glucocerebroside molecular species TSC-1 and TSC-2, one ß-sitosteryl-3ß-d-glucopyranoside-6'-O-fatty acid ester molecular species, TSS-1, and seven known triterpenes (1-7). The ethyl acetate fraction also afforded five known lignans (8-12) and one known flavanone (13). Their structures were elucidated by means of chemical and spectroscopic methods (methanolysis, NMR and mass spectrometry). Spectral analyses of the glucocerebrosides revealed mainly sphingosine-type (TSC-1) and phytosphingosine-type (TSC-2) cerebrosides, with both possessing mainly 2-hydroxy fatty acid and ß-d-glucopyranose moieties. TSS-1 was found to be a ß-sitosterol-type with fatty acid methyl esters and ß-d-glucopyranoside moieties. The classes of compounds isolated from this plant are well known for their interesting biological activities including antimicrobial, antioxidant, anticancer, antiinflammatory and analgesic. They may therefore be responsible in part or in whole for these activities, hence validating the traditional uses of the plant. To the best of our knowledge, this is the first report on the isolation of all these compounds from T. sanguinea.

8.
Opt Express ; 25(25): 31407-31416, 2017 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-29245815

RESUMO

We demonstrate a silicon Mach-Zehnder modulator (MZM) based on hydrogenated amorphous silicon (a-Si:H) strip-loaded waveguides on a silicon on insulator (SOI) platform, which can be fabricated by using a complementary metal-oxide semiconductor (CMOS) compatible process without half etching of the SOI layer. Constructing a vertical p-n junction in a flat etchless SOI layer provides superior controllability and uniformity of carrier profiles. Moreover, the waveguide structure based on a thin a-Si:H strip line can be fabricated easily and precisely. Thanks to a large overlap between the depletion region and optical field in the SOI layer with a vertical p-n junction, the MZM provides 0.80- to 1.86-Vcm modulation efficiency and a 12.1- to 16.9-dBV loss-efficiency product, besides guaranteeing a 3-dB bandwidth of about 17 GHz and 28-Gbps high-speed operation. The αVπL is considerably lower than that of conventional high-speed modulators.

9.
Biosci Biotechnol Biochem ; 81(8): 1569-1575, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28463548

RESUMO

Oxidation of low-density lipoprotein (LDL) by reactive oxygen species (ROS) and reactive nitrogen species (RNS) has been suggested to be involved in the onset of atherosclerosis. Oolong tea contains unique polyphenols including oolonghomobisflavan A (OFA). In this study, the effects of OFA on LDL oxidation by ROS and RNS were investigated in vitro. OFA suppressed formation of cholesterol ester hydroperoxides in LDL oxidized by peroxyl radical and peroxynitrite, and formation of thiobarbituric acid reactive substances in LDL oxidized by Cu2+. In addition, OFA inhibited fragmentation, carbonylation, and nitration of apolipoprotein B-100 (apo B-100) in the oxidized LDL, in which heparin-binding activity of apo B-100 was protected by OFA. Our results suggest that OFA exhibits antioxidant activity against both lipid peroxidation and oxidative modification of apo B-100 in LDL oxidized by ROS and RNS. Polyphenols in oolong tea may prevent atherosclerosis by reducing oxidative stress.


Assuntos
Camellia sinensis/química , Flavonoides/química , Lipoproteínas LDL/antagonistas & inibidores , Polifenóis/química , Apolipoproteína B-100/antagonistas & inibidores , Cátions Bivalentes , Ésteres do Colesterol/antagonistas & inibidores , Cobre/química , Flavonoides/isolamento & purificação , Heparina/química , Humanos , Cinética , Peroxidação de Lipídeos , Oxirredução , Peróxidos/antagonistas & inibidores , Ácido Peroxinitroso/antagonistas & inibidores , Extratos Vegetais/química , Polifenóis/isolamento & purificação , Ligação Proteica , Espécies Reativas de Nitrogênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/antagonistas & inibidores , Tiobarbitúricos/antagonistas & inibidores
10.
Pediatr Surg Int ; 32(9): 863-7, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27461433

RESUMO

PURPOSE: Children with intestinal failure (IF) requiring central venous catheters (CVCs) often experience frequent catheter-related bloodstream infections (CRBSIs), which is a serious and life-threatening complication. To reduce the incidence of CRBSI, prophylactic ethanol lock therapy (ELT) was initiated. METHODS: Patients with IF received home parenteral nutrition via a silicone tunneled CVC. All of them had received therapeutic ELT from January 2009 (first period) and prophylactic ELT from December 2012 (second period). Prophylactic ELT refers to ethanol lock for 2 h during the monthly hospital visit. We compared the CRBSI rate and number of CVC replacements between both periods. RESULTS: Four patients received 19 CVCs for a total of 5623 catheter days. In the first period, there were 12 CRBSIs in 1823 catheter days (rate 6.77 per 1000 catheter days). In the second period, there were 9 CRBSIs in 3800 catheter days (rate 3.13 per 1000 catheter days). Overall, the rate of CVC replacement decreased from 4.92 to 1.72 per 1000 catheter days (p = 0.04). No adverse reactions were experienced during ethanol instillation. CONCLUSION: Monthly prophylactic ELT for IF patients is considered to be a safe and effective modality for reducing the replacement of CVCs due to CRBSIs.


Assuntos
Anti-Infecciosos Locais/administração & dosagem , Bacteriemia/prevenção & controle , Infecções Relacionadas a Cateter/prevenção & controle , Etanol/administração & dosagem , Nutrição Parenteral no Domicílio , Cateterismo/estatística & dados numéricos , Cateteres de Demora , Cateteres Venosos Centrais , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
11.
Arch Pharm Res ; 39(7): 897-911, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27350550

RESUMO

Phytochemical investigation of Ficus pandurata Hance (Moraceae) fruits has led to the isolation of two new triterpenoids, ficupanduratin A [1ß-hydroxy-3ß-acetoxy-11α-methoxy-urs-12-ene] (11) and ficupanduratin B [21α-hydroxy-3ß-acetoxy-11α-methoxy-urs-12-ene] (17), along with 20 known compounds: α-amyrin acetate (1), α-amyrin (2), 3ß-acetoxy-20-taraxasten-22-one (3), 3ß-acetoxy-11α-methoxy-olean-12-ene (4), 3ß-acetoxy-11α-methoxy-12-ursene (5), 11-oxo-α-amyrin acetate (6), 11-oxo-ß-amyrin acetate (7), palmitic acid (8), stigmast-4,22-diene-3,6-dione (9), stigmast-4-ene-3,6-dione (10), stigmasterol (12), ß-sitosterol (13), stigmast-22-ene-3,6-dione (14), stigmastane-3,6-dione (15), 3ß,21ß-dihydroxy-11α-methoxy-olean-12-ene (16), 3ß-hydroxy-11α-methoxyurs-12-ene (18), 6-hydroxystigmast-4,22-diene-3-one (19), 6-hydroxystigmast-4-ene-3-one (20), 11α,21α-dihydroxy-3ß-acetoxy-urs-12-ene (21), and ß-sitosterol-3-O-ß-D-glucopyranoside (22). Compound 21 is reported for the first time from a natural source. The structures of the 20 compounds were elucidated on the basis of IR, 1D ((1)H and (13)C), 2D ((1)H-(1)H COSY, HSQC, HMBC and NOESY) NMR and MS spectroscopic data, in addition to comparison with literature data. The isolated compounds were evaluated for their anti-microbial, anti-malarial, anti-leishmanial, and cytotoxic activities. In addition, their radioligand displacement affinity on opioid and cannabinoid receptors was assessed. Compounds 4, 11, and 15 exhibited good affinity towards the CB2 receptor, with displacement values of 69.7, 62.5 and 86.5 %, respectively. Furthermore, the binding mode of the active compounds in the active site of the CB2 cannabinoid receptors was investigated through molecular modelling.


Assuntos
Ficus , Extratos Vegetais/metabolismo , Receptores de Canabinoides/metabolismo , Receptores Opioides/metabolismo , Triterpenos/metabolismo , Animais , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Frutas , Humanos , Extratos Vegetais/isolamento & purificação , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores de Canabinoides/química , Receptores Opioides/química , Triterpenos/química , Triterpenos/isolamento & purificação , Células Vero
12.
Biosci Biotechnol Biochem ; 79(7): 1155-63, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25704646

RESUMO

We investigated the ameliorative effect of freshwater clam extract (FCE) on fatty liver, hypercholesterolemia, and liver injury in rats exposed to chloretone. Furthermore, we examined the effects of major FCE components (fat and protein fractions) to determine the active components in FCE. Chloretone increased serum aminotransferase activities and led to hepatic lipid accumulation. Serum aminotransferase activities and hepatic lipid content were lower in rats fed total FCE or fat/protein fractions of FCE. Expression of fatty acid synthase and fatty acid desaturase genes was upregulated by chloretone. Total FCE and fat/protein fractions of FCE suppressed the increase in gene expression involved in fatty acid synthesis. Serum cholesterol levels increased twofold upon chloretone exposure. Total FCE or fat/protein fractions of FCE showed hypocholesterolemic effects in rats with hypercholesterolemia induced by chloretone. These suggest that FCE contains at least two active components against fatty liver, hypercholesterolemia, and liver injury in rats exposed to chloretone.


Assuntos
Anticolesterolemiantes/farmacologia , Clorobutanol/efeitos adversos , Corbicula/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Extratos de Tecidos/farmacologia , Animais , Anticolesterolemiantes/química , Colesterol/sangue , Suplementos Nutricionais , Fezes , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Ratos Wistar , Extratos de Tecidos/química , Transaminases/metabolismo
13.
J Agric Food Chem ; 62(38): 9279-85, 2014 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-25195619

RESUMO

Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) is a powerful technique for visualizing the distribution of a wide range of biomolecules within tissue sections. However, methodology for visualizing a bioactive ellagitannin has not yet been established. This paper presents a novel in situ label-free MALDI-MSI technique for visualizing the distribution of strictinin, a bioactive ellagitannin found in green tea, within mammalian kidney after oral dosing. Among nine representative matrix candidates, 1,5-diaminonaphthalene (1,5-DAN), harmane, and ferulic acid showed higher sensitivity to strictinin spotted onto a MALDI sample plate. Of these, 1,5-DAN enables visualization of a two-dimensional image of strictinin directly spotted on mouse kidney sections with the highest sensitivity. Furthermore, 1,5-DAN-based MALDI-MSI could detect the unique distribution of orally dosed strictinin within kidney sections. This in situ label-free imaging technique will contribute to the localization analysis of strictinin and its biological mechanisms.


Assuntos
Camellia sinensis/metabolismo , Rim/química , Fenóis/química , Fenóis/metabolismo , Extratos Vegetais/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Animais , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Fenóis/administração & dosagem , Extratos Vegetais/administração & dosagem , Extratos Vegetais/metabolismo , Espectrometria de Massas em Tandem/métodos
14.
Sci Rep ; 3: 2749, 2013 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-24067358

RESUMO

We investigated the effects of extracts of Benifuuki (a tea cultivar that contains methylated catechins such as epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3"Me)) in mice fed a high-fat/high-sucrose (HF/HS) diet. This tea cultivar was then compared with an extract of Yabukita (a popular tea cultivar that lacks methylated catechins). For 6 weeks, C57BL/6J mice were fed either HF/HS diet with or without tea extracts from tea cultivars, which contained almost identical ingredients except for methylated catechins (i.e., Yabukita (0.2% and 1%) or Benifuuki (0.2% and 1%) extract powders). Supplementation with Benifuuki 0.2% markedly lowered plasma levels of TG and NEFAs compared with mice supplemented with Yabukita 0.2%. The diet containing Benifuuki 1% decreased adipose tissue weights, liver TG, and expression of lipogenic genes in the liver. These results suggested that Benifuuki had much greater lipid-lowering effects than Yabukita. Taken together, these data suggest that methylated catechins direct the strong lipid-lowering activity of Benifuuki.


Assuntos
Catequina/uso terapêutico , Transtornos do Metabolismo dos Lipídeos/tratamento farmacológico , Transtornos do Metabolismo dos Lipídeos/prevenção & controle , Extratos Vegetais/uso terapêutico , Chá/química , Absorção , Tecido Adiposo/efeitos dos fármacos , Animais , Catequina/farmacologia , Colesterol/metabolismo , Dieta Hiperlipídica , Sacarose Alimentar , Ácidos Graxos não Esterificados/sangue , Comportamento Alimentar/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Transtornos do Metabolismo dos Lipídeos/sangue , Transtornos do Metabolismo dos Lipídeos/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , Fitoterapia , Extratos Vegetais/farmacologia , Triglicerídeos/sangue
15.
PLoS One ; 7(5): e37942, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22666419

RESUMO

BACKGROUND: We previously identified the 67-kDa laminin receptor (67LR) as the cell-surface receptor conferring the major green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) responsiveness to cancer cells. However, the underlying mechanism for interaction between EGCG and 67LR remains unclear. In this study, we investigated the possible role of EGCG-67LR interaction responsible for its bioactivities. METHODOLOGY/PRINCIPAL FINDINGS: We synthesized various peptides deduced from the extracellular domain corresponding to the 102-295 region of human 67LR encoding a 295-amino acid. The neutralizing activity of these peptides toward EGCG cell-surface binding and inhibition of cancer cell growth were assayed. Both activities were inhibited by a peptide containing the 10-amino acid residues, IPCNNKGAHS, corresponding to residues 161-170. Furthermore, mass spectrometric analysis revealed the formation of a EGCG-LR161-170 peptide complex. A study of the amino acid deletion/replacement of the peptide LR161-170 indicated that the 10-amino acid length and two basic amino acids, K(166) and H(169), have a critical role in neutralizing EGCG's activities. Moreover, neutralizing activity against the anti-proliferation action of EGCG was observed in a recombinant protein of the extracellular domain of 67LR, and this effect was abrogated by a deletion of residues 161-170. These findings support that the 10 amino-acid sequence, IPCNNKGAHS, might be the functional domain responsible for the anti-cancer activity of EGCG. CONCLUSIONS/SIGNIFICANCE: Overall, our results highlight the nature of the EGCG-67LR interaction and provide novel structural insights into the understanding of 67LR-mediated functions of EGCG, and could aid in the development of potential anti-cancer compounds for chemopreventive or therapeutic uses that can mimic EGCG-67LR interactions.


Assuntos
Catequina/análogos & derivados , Polifenóis/metabolismo , Receptores de Laminina/química , Receptores de Laminina/metabolismo , Proteínas Ribossômicas/química , Proteínas Ribossômicas/metabolismo , Chá/química , Motivos de Aminoácidos , Sequência de Aminoácidos , Catequina/metabolismo , Catequina/farmacologia , Proliferação de Células/efeitos dos fármacos , Espaço Extracelular/metabolismo , Células Hep G2 , Humanos , Dados de Sequência Molecular , Polifenóis/farmacologia , Ligação Proteica , Estrutura Terciária de Proteína
16.
Biochem J ; 443(2): 525-34, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22257159

RESUMO

EGCG [(-)-epigallocatechin-3-O-gallate], the major polyphenol of green tea, has cancer chemopreventive and chemotherapeutic activities. EGCG selectively inhibits cell growth and induces apoptosis in cancer cells without adversely affecting normal cells; however, the underlying molecular mechanism in vivo is unclear. In the present study, we show that EGCG-induced apoptotic activity is attributed to a lipid-raft clustering mediated through 67LR (67 kDa laminin receptor) that is significantly elevated in MM (multiple myeloma) cells relative to normal peripheral blood mononuclear cells, and that aSMase (acid sphingomyelinase) is critical for the lipid-raft clustering and the apoptotic cell death induced by EGCG. We also found that EGCG induces aSMase translocation to the plasma membrane and PKCδ (protein kinase Cδ) phosphorylation at Ser664, which was necessary for aSMase/ceramide signalling via 67LR. Additionally, orally administered EGCG activated PKCδ and aSMase in a murine MM xenograft model. These results elucidate a novel cell-death pathway triggered by EGCG for the specific killing of MM cells.


Assuntos
Apoptose/efeitos dos fármacos , Catequina/análogos & derivados , Microdomínios da Membrana/efeitos dos fármacos , Mieloma Múltiplo/metabolismo , Proteína Quinase C-delta/metabolismo , Receptores de Laminina/metabolismo , Esfingomielina Fosfodiesterase/metabolismo , Animais , Caspase 3/metabolismo , Catequina/farmacologia , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Humanos , Microdomínios da Membrana/metabolismo , Camundongos , Peso Molecular , Mieloma Múltiplo/patologia , Chá/química
17.
PLoS One ; 6(8): e23426, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21853132

RESUMO

BACKGROUND: Green tea has various health promotion effects. Although there are numerous tea cultivars, little is known about the differences in their nutraceutical properties. Metabolic profiling techniques can provide information on the relationship between the metabolome and factors such as phenotype or quality. Here, we performed metabolomic analyses to explore the relationship between the metabolome and health-promoting attributes (bioactivity) of diverse Japanese green tea cultivars. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the ability of leaf extracts from 43 Japanese green tea cultivars to inhibit thrombin-induced phosphorylation of myosin regulatory light chain (MRLC) in human umbilical vein endothelial cells (HUVECs). This thrombin-induced phosphorylation is a potential hallmark of vascular endothelial dysfunction. Among the tested cultivars, Cha Chuukanbohon Nou-6 (Nou-6) and Sunrouge (SR) strongly inhibited MRLC phosphorylation. To evaluate the bioactivity of green tea cultivars using a metabolomics approach, the metabolite profiles of all tea extracts were determined by high-performance liquid chromatography-mass spectrometry (LC-MS). Multivariate statistical analyses, principal component analysis (PCA) and orthogonal partial least-squares-discriminant analysis (OPLS-DA), revealed differences among green tea cultivars with respect to their ability to inhibit MRLC phosphorylation. In the SR cultivar, polyphenols were associated with its unique metabolic profile and its bioactivity. In addition, using partial least-squares (PLS) regression analysis, we succeeded in constructing a reliable bioactivity-prediction model to predict the inhibitory effect of tea cultivars based on their metabolome. This model was based on certain identified metabolites that were associated with bioactivity. When added to an extract from the non-bioactive cultivar Yabukita, several metabolites enriched in SR were able to transform the extract into a bioactive extract. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that metabolic profiling is a useful approach for nutraceutical evaluation of the health promotion effects of diverse tea cultivars. This may propose a novel strategy for functional food design.


Assuntos
Suplementos Nutricionais/análise , Metabolômica/métodos , Chá/química , Cromatografia Líquida , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Japão , Espectrometria de Massas , Modelos Biológicos , Cadeias Leves de Miosina/metabolismo , Fosforilação/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/isolamento & purificação , Análise de Regressão , Trombina/farmacologia
18.
J Ethnopharmacol ; 137(1): 231-5, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21619924

RESUMO

AIM OF THE STUDY: Herbs, as food or medicine, can strengthen the body and increase its resistance to illnesses by acting on various components of the immune system. For example, Echinacea is noted for its ability to enhance immune function, primarily through activation of the innate immune responses. Here, we investigated the potential for two herbs commonly found in India, Ashwagandha (Withania somnifera) and Brahmi (Bacopa monnieri), to enhance immune function and compared their effects to that of Echinacea. MATERIALS AND METHODS: Sprague Dawley rats were fed a diet supplemented with 1% (w/w) Echinacea, Ashwagandha, or Brahmi for 4 weeks to examine their effects on immune function. RESULTS: The Brahmi diet stimulated more secretion of IgA and IgG in the serum compared to Echinacea or Ashwagandha. Whether or not lectin was present in the diet, the production of IgA, IgG and IgM in spleen lymphocytes increased with herbal supplements. The concentrations of IFN-γ and IL-2 treated with LPS and ConA were significantly higher in the dietary herb than in the control. On the contrary, TNF-α production in rats receiving dietary herbal supplements was significantly lower compared to the control animals. CONCLUSION: Herbal remedies based on Echinacea, Brahmi, or Ashwagandha can enhance immune function by increasing immunoglobulin production. Furthermore, these herbal medicines might regulate antibody production by augmenting both Th1 and Th2 cytokine production.


Assuntos
Bacopa , Echinacea , Linfócitos/efeitos dos fármacos , Baço/efeitos dos fármacos , Withania , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Células Cultivadas , Concanavalina A/farmacologia , Dieta , Ingestão de Alimentos/efeitos dos fármacos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Interferon gama/sangue , Interleucina-2/sangue , Lipopolissacarídeos/farmacologia , Linfócitos/imunologia , Masculino , Extratos Vegetais , Plantas Medicinais , Ratos , Ratos Sprague-Dawley , Baço/imunologia , Fator de Necrose Tumoral alfa/sangue
19.
FEBS Lett ; 585(5): 814-20, 2011 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-21320497

RESUMO

Here we show the molecular basis for the inhibition of peptidoglycan (PGN)-induced TLR2 signaling by a major green tea polyphenol epigallocatechin-3-gallate (EGCG). Recently, we identified the 67-kDa laminin receptor (67LR) as the cell-surface EGCG receptor. Anti-67LR antibody treatment or silencing of 67LR resulted in abrogation of the inhibitory action of EGCG on PGN-induced production of pro-inflammatory mediators and activation of mitogen-activated protein kinases. Silencing of Toll-interacting protein (Tollip), a negative regulator of TLR signaling impaired the TLR2 signaling inhibitory activity of EGCG, suggesting that TLR2 response could be inhibited by EGCG via 67LR and Tollip.


Assuntos
Catequina/análogos & derivados , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptidoglicano/farmacologia , Receptores de Laminina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Chá/química , Receptor 2 Toll-Like/metabolismo , Animais , Catequina/farmacologia , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Flavonoides/farmacologia , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos , Peso Molecular , Fenóis/farmacologia , Polifenóis
20.
PLoS One ; 5(6): e11051, 2010 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-20548792

RESUMO

BACKGROUND: Green tea consumption has been shown to have cancer preventive qualities. Among the constituents of green tea, (-)-Epigallocatechin-3-O-gallate (EGCG) is the most effective at inhibiting carcinogenesis. However, the concentrations of EGCG that are required to elicit the anticancer effects in a variety of cancer cell types are much higher than the peak plasma concentration that occurs after drinking an equivalent of 2-3 cups of green tea. To obtain the anticancer effects of EGCG when consumed at a reasonable concentration in daily life, we investigated the combination effect of EGCG and food ingredient that may enhance the anticancer activity of EGCG on subcutaneous tumor growth in C57BL/6N mice challenged with B16 melanoma cells. METHODOLOGY/PRINCIPAL FINDINGS: All-trans-retinoic acid (ATRA) enhanced the expression of the 67-kDa laminin receptor (67LR) and increased EGCG-induced cell growth inhibition in B16 melanoma cells. The cell growth inhibition seen with the combined EGCG and ATRA treatment was abolished by treatment with an anti-67LR antibody. In addition, the combined EGCG and ATRA treatment significantly suppressed the melanoma tumor growth in mice. Expression of 67LR in the tumor increased upon oral administration of ATRA or a combined treatment of EGCG and ATRA treatment. Furthermore, RNAi-mediated silencing of the retinoic acid receptor (RAR) alpha attenuated the ATRA-induced enhancement of 67LR expression in the melanoma cells. An RAR agonist enhanced the expression levels of 67LR and increased EGCG-induced cell growth inhibition. CONCLUSIONS/SIGNIFICANCE: Our findings provide a molecular basis for the combination effect seen with dietary components, and indicate that ATRA may be a beneficial food component for cancer prevention when combined with EGCG.


Assuntos
Antineoplásicos/farmacologia , Flavonoides/farmacologia , Melanoma Experimental/patologia , Fenóis/farmacologia , Receptores de Laminina/metabolismo , Chá/química , Regulação para Cima/efeitos dos fármacos , Vitamina A/farmacologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Polifenóis
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