Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 544
Filtrar
1.
J Med Chem ; 63(15): 8157-8178, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32610904

RESUMO

Triple-negative breast cancer (TNBC) is one of the most highly invasive and metastatic breast cancers without safe and effective therapeutic drugs. The natural product oridonin is reported to be a potential anti-TNBC agent. However, its moderate activity and complex structure hampered its clinical application. In this study, the novel oridonin analogues were first identified by removal of multiple hydroxyl groups and structural simplification of oridonin. The representative analogue 20 exhibited potent anticancer effects. Further structural modification on 20 generated the most potent derivative 56, which possessed 120-fold more potent antiproliferative activity than oridonin in the TNBC cell line HCC1806. Importantly, compound 56 exhibited more potent anticancer activity than paclitaxel in TNBC xenograft nude mice. Moreover, 56 could attenuate the expression of MMP-2, MMP-9, p-FAK, and integrin ß1 to inhibit TNBC cell metastasis. All results suggest that compound 56 may warrant further investigation as a promising candidate agent for the treatment of TNBC.


Assuntos
Diterpenos de Caurano/química , Diterpenos de Caurano/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
2.
Food Chem ; 331: 127262, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32563799

RESUMO

Stevioside is the main and the sweetest glycoside of stevia plant. It is attractive as a natural sweetener to diabetics and others on carbohydrate-controlled diets. This paper discusses the stability of stevioside under food processing conditions. It was found that stevioside was transformed not only to rubusoside, steviolbioside, steviol monoside and steviol but also to previously unknown stevioside α-anomer and rubusoside α-anomer. Those two identified stevioside transformation products are formed not only during the heating of acidic, neutral and alkaline stevioside standard solutions and stevia leaves suspensions in water and ethanol/water solvents but also during the processing of foods containing stevia. Apart from presenting the new compounds, the paper additionally shows that the recombination of sugar moiety with steviolbioside molecule in MS/ESI source can occur. The effect of molecule recombination in the MS source is known from the literature; however, it has not been reported previously in relation to stevioside derivatives.


Assuntos
Diterpenos de Caurano/química , Manipulação de Alimentos/métodos , Glucosídeos/química , Edulcorantes/química , Cromatografia Líquida de Alta Pressão , Concentração de Íons de Hidrogênio , Hidrólise , Espectrometria de Massas por Ionização por Electrospray , Temperatura
3.
Molecules ; 25(3)2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32013210

RESUMO

This paper reports the isolation and structural characterization of four new ent-kaurane derivatives from the Lamiaceae plant Sideritis hyssopifolia. Planar structures and relative configurations were determined using both mass spectrometry and nuclear magnetic resonance (1D and 2D). Absolute configurations were determined by comparing experimental and theoretical electronic circular dichroism spectra. The cytotoxic and microbial activities of all new compounds were tested. Compounds that were non-cytotoxic were further evaluated for anti-inflammatory activity.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Diterpenos de Caurano/farmacologia , Extratos Vegetais/farmacologia , Sideritis/química , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Diterpenos de Caurano/química , Diterpenos de Caurano/isolamento & purificação , Humanos , Modelos Moleculares , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Análise Espectral
4.
Int J Mol Sci ; 21(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32070065

RESUMO

Croton is an extensive flowering plant genus in the spurge family, Euphorbiaceae. Three croton compounds with the common ent-kaurane skeleton have been purified from Croton tonkinensis. METHODS: We examined any modifications of croton components (i.e., croton-01 [ent-18-acetoxy-7α-hydroxykaur-16-en-15-one], croton-02 [ent-7α,14ß-dihydroxykaur-16-en-15-one] and croton-03 [ent-1ß-acetoxy-7α,14ß-dihydroxykaur-16-en-15-one] on either hyperpolarization-activated cation current (Ih) or erg-mediated K+ current identified in pituitary tumor (GH3) cells and in rat insulin-secreting (INS-1) cells via patch-clamp methods. RESULTS: Addition of croton-01, croton-02, or croton-03 effectively and differentially depressed Ih amplitude. Croton-03 (3 µM) shifted the activation curve of Ih to a more negative potential by approximately 11 mV. The voltage-dependent hysteresis of Ih was also diminished by croton-03 administration. Croton-03-induced depression of Ih could not be attenuated by SQ-22536 (10 µM), an inhibitor of adenylate cyclase, but indeed reversed by oxaliplatin (10 µM). The Ih in INS-1 cells was also depressed effectively by croton-03. CONCLUSION: Our study highlights the evidence that these ent-kaurane diterpenoids might conceivably perturb these ionic currents through which they have high influence on the functional activities of endocrine or neuroendocrine cells.


Assuntos
Croton/química , Diterpenos de Caurano/farmacologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/antagonistas & inibidores , Neoplasias Hipofisárias/tratamento farmacológico , Adenilil Ciclases/genética , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Diterpenos de Caurano/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/química , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Estrutura Molecular , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Ratos
5.
Food Chem ; 317: 126359, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32097820

RESUMO

High content of steviol glycosides in stevia leaves is a cause of their high popularity as. a natural sweetener of various sugar-free food products. Stevioside (13-[(2-O-ß-d-glucopyranosyl-ß-d-glucopyranosyl)oxy]-ent-kaur-16-en-19-oic acid ß-d-glucopyranosyl ester) is one of the main steviol glycosides in stevia leaves known for its hydrolytic instability responsible for the formation of simple steviol glucosides (steviolbioside, rubusoside, steviol monoside) and steviol. However, the formation of hydroxy and alkoxy adducts of stevioside and of its hydrolysis products has not yet been reported. The performed experiments prove that water and alkoxy adducts are formed not only during temperature processing of stevioside but also of stevia and stevia-containing food products. Their quantities depend on environment pH, water concentration and food composition. Although they are formed in small amounts their biological activity is unknown and should be recognized.


Assuntos
Diterpenos de Caurano/química , Glucosídeos/química , Stevia/química , Análise de Alimentos , Concentração de Íons de Hidrogênio , Hidrólise , Metanol/química , Folhas de Planta/química , Folhas de Planta/metabolismo , Stevia/metabolismo , Edulcorantes/química , Temperatura , Água/química
6.
J Chromatogr A ; 1620: 460978, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32106966

RESUMO

To explore the retention and separation of stevioside polar compounds on a sulfonic acid-functionalized cation exchange column, the effects of different organic solvent-water mobile phases on the retention behavior of polar rebaudioside A (RA) and its analogues on the column were investigated over a wide range of organic solvent contents. The obtained U-shape curves hinted that the retention of the compounds on the same column transitioned from a reversed-phase liquid chromatography (RPLC) mode to a hydrophilic interaction liquid chromatography (HILIC) mode when the water-rich state in the mobile phases changed to an organic solvent-rich state. Under the RPLC mode, no separation of RA from its analogues was observed. The HILIC mode was beneficial to the retention and separation of RA and its analogues. Compared with polar protic solvents, aprotic solvents were more conducive to the retention and separation of the polar compounds based on the HILIC mode in organic solvent-rich mobile phases. Three models were used to evaluate and discuss the HILIC retention and separation of the compounds on the column. In the aprotic solvent-rich mobile phase, the HILIC retention of RA and its analogues was effectively described by a mixed-mode model; in the polar proton solvent-rich mobile phase, the retention of analytes was best described by an linear solvation strength (LSS) model. The content and composition of the organic solvent in the mobile phase were determined to be important influencing factors that regulated the retention time for the RA and its analogues, and even the separation mechanism for HILIC. The present work provides a theoretical basis for guiding one to prepare high-purity RA from its analogues by predicting the retention time.


Assuntos
Diterpenos de Caurano/análise , Glucosídeos/análise , Ácidos Sulfônicos/química , Cromatografia de Fase Reversa , Diterpenos de Caurano/química , Glucosídeos/química , Interações Hidrofóbicas e Hidrofílicas , Troca Iônica , Compostos Orgânicos/química , Solventes/química , Água/química
7.
Molecules ; 25(2)2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31947574

RESUMO

Oridonin (ORI), an ent-kaurene tetracyclic diterpenoid compound, is isolated from Chinese herb Rabdosia rubescens with various biological and pharmacological activities including anti-tumor, anti-microbial and anti-inflammatory effects. However, the clinical application of ORI is limited due to its low solubility and poor bioavailability. In order to overcome these shortcomings, many strategies have been explored such as structural modification, new dosage form, etc. This review provides a detailed discussion on the research progress to increase the solubility and bioavailability of ORI.


Assuntos
Anti-Inflamatórios/química , Antineoplásicos Fitogênicos/química , Diterpenos de Caurano/química , Diterpenos de Caurano/farmacocinética , Anti-Inflamatórios/farmacocinética , Antineoplásicos Fitogênicos/farmacocinética , Disponibilidade Biológica , Humanos , Solubilidade , Distribuição Tecidual
8.
J Agric Food Chem ; 68(6): 1579-1587, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31760750

RESUMO

Organic anion transporter 3 (OAT3) plays a critical role in the renal excretion of many xenobiotics. Because steviol acyl glucuronide (SVAG), an OAT3 substrate, is the major circulating metabolite after oral ingestion of steviol glycosides and is excreted into the urine, inhibition of OAT3 activity may alter pharmacokinetic profiles of SVAG. The present study showed that drugs such as probenecid and glimepiride displayed potent inhibition toward the OAT3-mediated SVAG transport, with IC50 values of 4.9 and 0.8 µM, respectively. No species differences were observed. Probenecid and glimepiride could significantly elevate plasma concentrations of SVAG after oral administration of rebaudioside A, with significant increases in plasma maximum (Cmax) and area under the plasma time-concentration curve values. The inhibitory effect on the OAT3-mediated SVAG transport exemplified a unique case between drugs and the metabolite of a food additive. Our data suggest that caution should be exercised when giving steviol glycoside products to human subjects with compromised renal function.


Assuntos
Diterpenos de Caurano/metabolismo , Glucosídeos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Probenecid/metabolismo , Compostos de Sulfonilureia/metabolismo , Animais , Transporte Biológico , Diterpenos de Caurano/química , Glucosídeos/química , Células HEK293 , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Probenecid/administração & dosagem , Probenecid/química , Ratos , Ratos Sprague-Dawley , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/química
9.
Prostaglandins Other Lipid Mediat ; 146: 106402, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31841664

RESUMO

Although C6-Ceramide has attracted much attention as a possible tumor suppressor, the delivery of C6-Ceramide is still challenging due to its inherent hydrophobicity and insolubility. In this study we explored the use of a natural compound rubusoside (RUB) as a solubilizer to enhance the solubility of a fluorescence-labeled C6-Ceramide (NBD C6-Ceramide) and to characterize its pharmacokinetics and tissue distribution in an animal model. RUB significantly enhanced the solubility of NBD C6-Ceramide by forming nanomicelles, and efficiently delivered NBD C6-Ceramide in rats by oral and intravenous administration. RUB loaded 1.96 % of NBD C6-Ceramide in the nanomicelles and solubilized it to a concentration of 3.6 mg/mL in water. NBD C6-Ceramide in nanomicelles remained stable in aqueous solutions, allowing intravenous administration without the use of any organic solvents or surfactants. After oral administration, NBD C6-Ceramide rapidly rose to peak plasma concentrations within the first 90 min, distributed to tissues, and remained in vivo for more than 24 h. Tissular levels of NBD C6-Ceramide from high to low were associated with heart, lung, cerebellum, testicle, spleen, liver, kidney, and brain. Altogether, our study demonstrated that RUB-assisted nanomicelles can serve as an efficient and convenient delivery system for short-chain C6-Ceramide and enable in vivo evaluation of potential new cancer treatments.


Assuntos
Ceramidas , Diterpenos de Caurano , Glucosídeos , Animais , Ceramidas/química , Ceramidas/farmacocinética , Ceramidas/farmacologia , Diterpenos de Caurano/química , Diterpenos de Caurano/farmacocinética , Diterpenos de Caurano/farmacologia , Glucosídeos/química , Glucosídeos/farmacocinética , Glucosídeos/farmacologia , Masculino , Especificidade de Órgãos , Projetos Piloto , Ratos , Ratos Sprague-Dawley , Solubilidade , Distribuição Tecidual
10.
Eur J Med Chem ; 187: 111978, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31877536

RESUMO

Hydrogen sulfide (H2S) has been recognized as the third endogenous signaling gasotransmitter following nitric oxide (NO) and carbon monoxide (CO), and exhibits antiproliferative activity against several cancer cells. In order to stably and controllably release H2S, H2S donating compound (ADT-OH) was used in the present study and 18H2S releasing natural ent-kaurane diterpenoid oridonin derivatives were designed and synthesized. Most derivatives showed more potent antiproliferative activities than oridonin against HepG2 and K562 cell lines, while they were lack of sensitivity to HCT-116 and B16 cells. In particular, 12b showed the most potent antiproliferative activities against HepG2, HCT-116 and K562 cells with IC50 values of 2.57, 5.81 and 0.95 µM, respectively. Through cell cycle analysis, 12b caused cell cycle arrest at S phase in K562 cells and G1 phase in HepG2 cells. In Hoechst 33258 staining assay, cell shrinkage and fragmentation of cell nuclei indicated apoptotic morphological changes. Considering the decline of mitochondrial membrane potential and changes in the levels of apoptosis-related proteins, 12b was shown to induce apoptosis through extrinsic and intrinsic apoptosis pathways.


Assuntos
Apoptose/efeitos dos fármacos , Diterpenos de Caurano/farmacologia , Sulfeto de Hidrogênio/farmacologia , Diterpenos de Caurano/síntese química , Diterpenos de Caurano/química , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Sulfeto de Hidrogênio/química , Células K562 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade
11.
Food Chem ; 308: 125569, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31644967

RESUMO

In this study, the solubility of phloretin (PT) was enhanced via steviol glycoside (STE)-based micelle (MC) and solid dispersion (SD). Computer simulation, characterization, interaction with serum albumin (SA) and in vitro release were carried out to investigate the solubilization mechanisms and the difference in their solubilization capacities. For PT-loaded MC (STE-PT MC), PT was encapsulated into the hydrophobic core of a spherical micelle with a droplet diameter of 5 nm. For PT-loaded SD (STE-PT SD), PT was completely dispersed with the amorphous state in STE. Most of those PTs were directly dissolved in water, and few were encapsulated by STE micelles. The amorphous state combined with relatively large micelles contributed to the high solubilization capacity of STE-PT SD. In addition, PT of STE-PT SD exhibited a higher dissolution rate and more effective interaction with SA than that of STE-PT MC. No undesirable chemical interaction between PT and STE occurred.


Assuntos
Diterpenos de Caurano/química , Glucosídeos/química , Floretina/química , Interações Hidrofóbicas e Hidrofílicas , Micelas , Floretina/análise , Solubilidade , Água/química
12.
Food Chem ; 304: 125444, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31491712

RESUMO

Poor aqueous solubility of some minor steviol glycosides (SGs) has prevented their potential widespread usage as non-nutritional high intensity sweeteners in beverage industry. Rebaudioside B (reb B) is one of the minor SGs found in stevia leaf, and has a better taste quality than many of the major SGs. However, reb B suffers from poor aqueous solubility and low dissolution rate, which greatly limits its application, especially in beverages. In our effort to enhance its solubility by using natural means, we discovered that under certain conditions reb B forms hemihydrate crystal, which has much lower solubility and dissolution rate than commercial powder reb B product. The crystal was characterized by Fourier Transform Infrared spectroscopy (FT-IR), Scanning Electron Microscopy (SEM), and X-ray Diffraction (XRD). This may offer more insight into the interaction of SGs with water at molecular level, and therefore provide new guidance on current efforts to enhance the solubility of SGs.


Assuntos
Glucosídeos/química , Glicosídeos/química , Edulcorantes/química , Diterpenos de Caurano/química , Microscopia Eletrônica de Varredura , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Água/química , Difração de Raios X
13.
Enzyme Microb Technol ; 132: 109412, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31731958

RESUMO

Transglycosylation is one of enzymatic methods to improve the physical and biochemical properties of various functional compounds. In this study, stevioside glucosides were synthesized using sucrose as a substrate, stevioside (Ste) as an acceptor, and dextransucrase from Leuconostoc mesenteroides B-512 F/KM. The highest Ste conversion yield of 98% was obtained with 50 mg/mL Ste, 800 mM sucrose, and dextransucrase 4 U/mL at 28 °C for 6 h. The concentration of Ste was unchanged while of Ste-G1 was increased from 7.7 mM to 9.1 mM as the Ste acceptor reaction digest was treated with dextranase from Lipomyces starkeyi. Ste-G1 (13-O-ß-sophorosyl-19-O-ß-isomaltosyl-steviol), Ste-G2 (13-O-(ß-(1→6) glucosyl)-ß-glucosylsophorosyl-19-O-ß-isomaltosyl-steviol), and Ste-G2' (13-O-ß-sophorosyl-19-O-ß-isomaltotriosyl-steviol) were determined by NMR. These glucosylated Ste showed increased stabilities at pH 2, 60 °C for 48 h as compared to Ste. Ste-G1, Ste-G2, and Ste-G2' inhibited the insoluble glucan synthesis from sucrose by mutansucrase from Streptococcus muntans by the transfer of the glucosyl group of sucrose to Ste-G1, Ste-G2, and Ste-G2'. The relative water solubility of curcumin, pterostilbene or idebenone was increased by Ste or Ste glucosides treatment. Ste and Ste-G1 restored cell viability in RAW264.7 cells at concentrations up to 8 mg/mL and inhibited nitric oxide production in LPS-induced RAW264.7 cells with IC50 of 3.29 and 1.87 mg/mL.


Assuntos
Dextranase/metabolismo , Diterpenos de Caurano/química , Glucosídeos/química , Glucosiltransferases/metabolismo , Sacarose/química , Edulcorantes/química , Leuconostoc mesenteroides/enzimologia , Espectroscopia de Ressonância Magnética , Polimerização , Solubilidade
14.
World J Microbiol Biotechnol ; 36(1): 8, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31858273

RESUMO

The application of chemical fertilizers to enhance crop production is a major concern due to associated environmental pollution and health hazards. Hence, there is an urgent need to develop an eco-friendly solution to improve crop production and promote sustainable agriculture simultaneously. Stevia rebaudiana is an important medicinal crop being substitute for sugar, superior flavor outline, extensive medicinal properties, and also of agronomic interest. In the present study, bacterium STJP isolated from the rhizospheric soil of S. rebaudiana and identified as Bacillus safensis on the basis of 16S rRNA gene sequencing, showed good amount of zinc (4.4 mg/L) and potassium (5.4 mg/L) solubilization. Paneer-whey (a dairy waste) based bioformulation (P-WBF) was developed utilizing isolate B. safensis STJP (accession number NAIMCC TB-2833) and inspected for the quality and ability to enhance the growth, nutrients uptake, and stevioside content in S. rebaudiana. The application of P-WBF displayed a significantly higher concentration (153.12%) of stevioside in S. rebaudiana as compared to control. P-WBF treated Stevia plants showed significantly higher fresh and dry weight as well (as compared to control). Further, enhancement of phosphorous, nitrogen, potassium, and zinc uptake in plant tissue was also recorded by application of P-WBF. This study suggests the use of P-WBF based biofertilizer using B. safensis STJP to increase stevioside content in Stevia plant by a nutrient(s) linked mechanism. This novel approach can also be beneficial for utilization of a dairy waste in preparation of bioformulation and, for enhancement of crop yield by an ecofriendly manner leading to sustainable agriculture.


Assuntos
Bacillus/fisiologia , Diterpenos de Caurano/química , Fertilizantes/análise , Glucosídeos/química , Nutrientes/química , Desenvolvimento Vegetal , Stevia/crescimento & desenvolvimento , Agricultura , Bacillus/genética , Nitrogênio/análise , Fósforo/análise , RNA Ribossômico 16S/genética
15.
Food Funct ; 10(12): 7967-7972, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31750488

RESUMO

Efficient treatment of hypertension is vital. The inhibition of angiotensin-converting enzyme activity has been one of the major strategies for treating hypertension. The ethanol extract of stevia leaves, steviol glycosides (with 95% purity; natural sweeteners widely used in the food industry) isolated from the ethanol extract and stevia leaf protein hydrolysates inhibited 26.60%, 59.56% and 74.38% of angiotensin-converting enzyme activities, respectively. Their effect was dose-dependent, which can be beneficial for avoiding hypertension or hypotension just by the proper control of the amount of their intake, and it was found to be superior to that of pharmaceutical drugs. A sensory test indicated that the application of the mixtures of steviol glycosides and stevia protein hydrolysates to decaffeinated coffee or tea as well as a formulated peanut protein drink was found to be well accepted, and an animal test showed that they had a significantly antihypertensive effect in spontaneously hypertensive rats. Steviol glycosides and stevia leaf protein hydrolysates can be good ingredients for making functional or healthy food products or beverages targeted for the prevention or treatment of hypertension.


Assuntos
Diterpenos de Caurano/química , Inibidores Enzimáticos/química , Glucosídeos/química , Peptidil Dipeptidase A/química , Extratos Vegetais/química , Proteínas de Plantas/administração & dosagem , Stevia/química , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Diterpenos de Caurano/administração & dosagem , Diterpenos de Caurano/isolamento & purificação , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/isolamento & purificação , Feminino , Glucosídeos/administração & dosagem , Glucosídeos/isolamento & purificação , Humanos , Hipertensão/tratamento farmacológico , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Proteínas de Plantas/química , Proteínas de Plantas/isolamento & purificação , Hidrolisados de Proteína/administração & dosagem , Hidrolisados de Proteína/química , Hidrolisados de Proteína/isolamento & purificação , Ratos , Ratos Endogâmicos SHR , Paladar
16.
J Biol Chem ; 294(46): 17471-17486, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31594861

RESUMO

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) occurs in ∼70% of human cancers, and STAT3 is regarded as one of the most promising targets for cancer therapy. However, specific direct STAT3 inhibitors remain to be developed. Oridonin is an ent-kaurane plant-derived diterpenoid with anti-cancer and anti-inflammatory activities. Here, using an array of cell-based and biochemical approaches, including cell proliferation and apoptosis assays, pulldown and reporter gene assays, site-directed mutagenesis, and molecular dynamics analyses, we report that a thiazole-derived oridonin analogue, CYD0618, potently and directly inhibits STAT3. We found that CYD0618 covalently binds to Cys-542 in STAT3 and suppresses its activity through an allosteric effect, effectively reducing STAT3 dimerization and nuclear translocation, as well as decreasing expression of STAT3-targeted oncogenes. Remarkably, CYD0618 not only strongly inhibited growth of multiple cancer cell lines that harbor constitutive STAT3 activation, but it also suppressed in vivo tumor growth via STAT3 inhibition. Taken together, our findings suggest Cys-542 as a druggable site for selectively inhibiting STAT3 and indicate that CYD0618 represents a promising lead compound for developing therapeutic agents against STAT3-driven diseases.


Assuntos
Antineoplásicos/farmacologia , Diterpenos de Caurano/farmacologia , Neoplasias/tratamento farmacológico , Fator de Transcrição STAT3/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Diterpenos de Caurano/química , Diterpenos de Caurano/uso terapêutico , Feminino , Humanos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Neoplasias/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Fator de Transcrição STAT3/metabolismo , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/uso terapêutico
17.
J Food Sci ; 84(11): 3186-3193, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31589348

RESUMO

Rebaudioside A was modified via glucosylation by recombinant dextransucrase of Leuconostoc lactis EG001 in Escherichia coli BL21 (DE3), forming single O-α-D-glucosyl-(1″→6') rebaudioside A with yield of 86%. O-α-D-glucosyl-(1″→6') rebaudioside A was purified using HPLC and Diaion HP-20 and its properties were characterized for possible use as a food ingredient. Almost 98% of O-α-D-glucosyl-(1″→6') rebaudioside A was dissolved after 15 days of storage at room temperature, compared to only 11% for rebaudioside A. Compared to rebaudioside A, O-α-D-glucosyl-(1″→6') rebaudioside A showed similar or improved acidic or thermal stability in commercial drinks. Thus, O-α-D-glucosyl-(1″→6') rebaudioside A could be used as a highly pure and improved sweetener with high stability in commercial drinks. PRACTICAL APPLICATION: The proposed method can be used to generate glucosyl rebaudioside A by enzymatic glucosylation. Simple glucosyl rebaudioside A exhibited high acid/thermal stability and improved sweetener in commercialized drinks. This method can be applied to obtain high value-added bioactive compounds by enzymatic modification.


Assuntos
Proteínas de Bactérias/química , Diterpenos de Caurano/química , Glucosiltransferases/química , Leuconostoc/enzimologia , Edulcorantes/química , Biocatálise , Cromatografia Líquida de Alta Pressão
18.
Food Funct ; 10(11): 7453-7460, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31664284

RESUMO

The roots of Polygala tenuifolia Willd have a long history of being used as a traditional Chinese medicine for the treatment of insomnia, forgetfulness, sorrow and depression. Tenuifolin (TEN) has been isolated from Polygala tenuifolia Willd roots, and this study was carried out to investigate the potential beneficial effects of TEN on neuronal apoptosis and memory deficits in a mouse model of Alzheimer's disease (AD). TEN treatment reversed spatial learning and memory deficits, as well as neuronal apoptosis in hippocampal areas, in APP/PS1 transgenic AD mice. TEN treatment protected against Aß25-35-induced apoptosis, loss of mitochondria-membrane potential, and activation of caspases-3 and -9 in SH-SY5Y cells. TEN has potential benefit in treating learning and memory deficits in APP/PS1 transgenic AD mice, and its effects may be associated with reversing AD pathology-induced neuronal apoptosis. These insights pave the way for further analysis of the potential of TEN as an AD therapeutic agent.


Assuntos
Apoptose/efeitos dos fármacos , Diterpenos de Caurano/farmacologia , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Raízes de Plantas/química , Polygala/química , Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Andorra , Animais , Diterpenos de Caurano/química , Masculino , Aprendizagem em Labirinto , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Fragmentos de Peptídeos/metabolismo
19.
Molecules ; 24(18)2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527488

RESUMO

Oridonin (ORI) is a natural active ingredient with strong anticancer activity. But its clinical use is restricted due to its poor water solubility, short half-life, and low bioavailability. The aim of this study is to utilize the metal organic framework material MOF-5 to load ORI in order to improve its release characteristics and bioavailability. Herein, MOF-5 was synthesized by the solvothermal method and direct addition method, and characterized by Scanning Electron Microscopy (SEM), X-Ray Diffraction (XRD), Fourier Transform Infrared Spectrometer (FTIR), Thermogravimetric Analysis (TG), Brunauer-Emmett-Teller (BET), and Dynamic Light Scattering (DLS), respectively. MOF-5 prepared by the optimal synthesis method was selected for drug-loading and in vitro release experiments. HepG2 cells were model cells. MTT assay, 4',6-diamidino-2-phenylindole (DAPI) staining and Annexin V/PI assay were used to detect the biological safety of blank carriers and the anticancer activity of drug-loaded materials. The results showed that nano-MOF-5 prepared by the direct addition method had complete structure, uniform size and good biocompatibility, and was suitable as an ORI carrier. The drug loading of ORI@MOF-5 was 52.86% ± 0.59%. The sustained release effect was reliable, and the cumulative release rate was about 87% in 60 h. ORI@MOF-5 had significant cytotoxicity (IC50:22.99 µg/mL) and apoptosis effect on HepG2 cells. ORI@MOF-5 is hopeful to become a new anticancer sustained release preparation. MOF-5 has significant potential as a drug carrier material.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Diterpenos de Caurano/administração & dosagem , Diterpenos de Caurano/química , Portadores de Fármacos/química , Estruturas Metalorgânicas , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Análise Espectral , Termogravimetria
20.
Eur J Med Chem ; 183: 111722, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563807

RESUMO

Thrombosis is a pathological coagulation process and can lead to many serious thrombotic diseases. Here, we report a novel potent antithrombotic compound (6k) based on isosteviol with anticoagulant and antiplatelet activities. 6k selectively inhibited FXa (Ki = 0.015 µM) against a panel of serine proteases and showed excellent anticoagulant activity (significant prolongation of ex vivo PT and aPTT over the vehicle, p < 0.01). 6k also significantly inhibited ADP-induced platelet aggregation in rats relative to the vehicle (p < 0.01). Furthermore, 6k exhibited potent ex vivo and in vivo antithrombotic activity in rats relative to the vehicle (p < 0.01 and p < 0.0001, respectively). Novel structure 6k, with potent antithrombotic activity, is expected to lead a promising approach for the development of antithrombotic agents.


Assuntos
Diterpenos de Caurano/química , Diterpenos de Caurano/farmacologia , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Trombose/tratamento farmacológico , Animais , Descoberta de Drogas , Inibidores do Fator Xa/química , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Masculino , Tempo de Tromboplastina Parcial , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Wistar , Trombina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA