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1.
J Pharm Biomed Anal ; 177: 112856, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31521020

RESUMO

Daphne genkwa Sieb. et Zucc., as a traditional oriental herb, has been widely distributed and employed in China. The major bioactive components in D. genkwa are flavonoid compounds, which showed pharmacological activities such as anti-inflammatory, analgesic, anti-tumor and immunomodulatory activities. In this study, we analyzed total flavonoids in D. genkwa and their metabolites in normal and adjuvant arthritis (AA) rat plasma, urine and feces samples by liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS). A total of 4 metabolites in plasma, 9 metabolites in urine and 15 metabolites in feces were characterized respectively by LC-Q-TOF-MS technology in normal rat. And 9 of the metabolites were observed in the AA rat urine, while there was no prototype drug or its metabolites detected in plasma and fecal samples. The metabolic pathway mainly involves hydroxylation, methylation, glucuronide, sulfate conjugation, oxidation and reduction, during the phase I and phase II biotransformation pathway. All the information gained here will be greatly helpful in elucidating the potential biological and pharmacological mechanism of flavonoid in D. genkwa, thus providing new ideas for drug development.


Assuntos
Artrite Experimental/tratamento farmacológico , Daphne/química , Medicamentos de Ervas Chinesas/farmacocinética , Flavonoides/farmacocinética , Administração Oral , Animais , Artrite Experimental/sangue , Artrite Experimental/imunologia , Artrite Experimental/urina , Cromatografia Líquida de Alta Pressão , Sistema Enzimático do Citocromo P-450/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Fezes/química , Flavonoides/administração & dosagem , Flavonoides/química , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Glucuronosiltransferase/metabolismo , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Distribuição Tecidual
2.
Planta Med ; 85(16): 1275-1286, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31627219

RESUMO

Breast cancer is one of the most common cancers diagnosed among women worldwide. Estrogen receptor alpha (ERα) is a transcriptional factor that plays an important role in the development and progression of breast cancer. Yuanhuatine, a natural daphnane-type diterpenoid extracted from Daphne genkwa, was reported to exhibit significant cytotoxicity against breast cancer cells. However, the underlying mechanism is still unclear. In this study, we evaluated the cytotoxicity of yuanhuatine on two breast cancer cell lines that are ERα-positive and -negative. The results show that yuanhuatine inhibits the growth of ERα-positive cells (MCF-7) with much stronger inhibitory activity (IC50 = 0.62 µM) compared with positive control tamoxifen (IC50 = 14.43 µM). However, no obvious cytotoxicity was observed in ERα-negative cells (MDA-MB-231). Subsequent experiment also indicated that yuanhuatine markedly induced mitochondrial dysfunction, leading to apoptosis in MCF-7 cells. Molecular docking studies suggest the potential interactions between yuanhuatine and ERα. Immunofluorescence staining and Western blot analysis indicated that yuanhuatine down-regulated the expression of ERα in MCF-7 cells. MPP, a specific ERα inhibitor, significantly enhanced yuanhuatine-induced mitochondrial dysfunction and apoptosis in MCF-7 cells. On the contrary, the treatment with yuanhuatine causes no apoptosis in MM231 cells. Altogether, in vitro and in silico results suggested that ERα down-regulation was involved in yuanhuatine-induced mitochondrial dysfunction and apoptosis in ERα-positive breast cancer cells. Thus, yuanhuatine could be a potential candidate for treating ERα-positive breast cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Daphne/química , Tamoxifeno/farmacologia , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Mitocôndrias/metabolismo , Simulação de Acoplamento Molecular , Tamoxifeno/química
3.
Fitoterapia ; 138: 104352, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31476400

RESUMO

Five new guaiane-type sesquiterpenoids were obtained from the roots of Daphne genkwa. Their gross structures were established by extensive spectroscopic analyses. Attempts on the assignment of the relative configurations were unsuccessful when based on the NOESY correlations. Therefore, NMR chemical shift calculations based on the gauge independent atomic orbital (GIAO) method in combination with the statistical method DP4+ were employed to establish their relative configurations. Furthermore, the absolute configurations were determined by comparing the experimental and calculated electronic circular dichroism (ECD) using time-dependent density functional theory (TDDFT). The isolated compounds were screened for their cytotoxicity in vitro against two human hepatocellular carcinoma, HepG2 and Hep3B cell lines.


Assuntos
Daphne/química , Raízes de Plantas/química , Sesquiterpenos de Guaiano/química , China , Células Hep G2 , Humanos , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Sesquiterpenos de Guaiano/farmacologia
4.
J Ethnopharmacol ; 236: 136-146, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30851368

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice and Yuanhua are both famous herbs in Traditional Chinese Medicine (TCM), and their combination is used by some TCM doctors to treat renal and gastrointestinal diseases as well as tumors. On the other hand, the compatibility theory of TCM warns that toxic effects might be triggered by Licorice-Yuanhua combination. The usability of Licorice-Yuanhua combination has long been controversial due to lack of evidence and mechanism illustration. Colonic hydrogen sulfide (H2S) metabolism imbalance is closely related with colonic inflammation, tumor promotion and many other diseases. AIM OF THE STUDY: This study was carried out to investigate if licorice-Yuanhua combination could induce potential toxic effects in the aspect of colonic H2S metabolism. MATERIALS AND METHODS: Normal mice were treated with high or low doses of Licorice, Yuanhua and Licorice-Yuanhua combination. Fecal H2S concentration was measured by colorimetric method, colon sulfomucin production was compared through tissue staining, fecal microbiota and microbial metagenomes were analyzed by 16S rDNA sequencing and data mining. RESULTS: Data shows that although licorice cannot change colonic H2S concentration, it can exacerbate Yuanhua induced H2S rising. Licorice or Yuanhua increases colon sulfomucin production, and their combination further enhances this effect. 16S rDNA sequencing analysis revealed that licorice or Yuanhua has little influence on gut microbiota, however, licorice-Yuanhua combination can impact gut microbiota structural balance and increase the abundance of Desulfovibrio genus and other related genera. Moreover, the combination extensively changes microbial metagenomes, influencing 1172 genes that cannot be changed by individual licorice or Yuanhua. By searching in KEGG database, ten genes are annotated with H2S producing gene, and these genes are remarkably increased by licorice-Yuanhua combination, more significantly than licorice or Yuanhua. CONCLUSIONS: This study provides evidences and mechanisms for licorice induced risks, which is related with colonic H2S metabolism disturbance, gut microbiota and microbial metagenomes. More risk assessment should be evaluated when licorice was used in combination with foods, herbs or drugs. The study provides an example where healthy risks can be induced by combination of food additive, herbs or drugs, through regulating gut microbiota and its metagenomes.


Assuntos
Colo/efeitos dos fármacos , Daphne/química , Medicamentos de Ervas Chinesas/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Glycyrrhiza/química , Sulfeto de Hidrogênio/metabolismo , Animais , Colo/metabolismo , Colo/microbiologia , Desulfovibrio/efeitos dos fármacos , Desulfovibrio/genética , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/isolamento & purificação , Fezes/química , Flores/química , Microbioma Gastrointestinal/genética , Sulfeto de Hidrogênio/análise , Masculino , Medicina Tradicional Chinesa , Metagenoma/genética , Camundongos Endogâmicos ICR , Raízes de Plantas/química
5.
Fitoterapia ; 132: 68-74, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30496811

RESUMO

Nine new prenylated flavan compounds with multi-chiral centers including two pairs of epimers were isolated from the stem and root bark of Daphne giraldii. Their structures were established by extensive NMR and HR-ESIMS spectroscopic data analyses. The in vitro cytotoxicity experiments indicated that compound 6 showed the most significant cytotoxicity against Hep3B cells, with an IC50 value of 9.83 µM. Hoechst 33258 and Annexin V-FITC/PI staining suggested that 6 could induce apoptosis of Hep3B cells in a concentration-dependent manner. Further mechanism study indicated that the apoptosis was associated with the up-regulations of Bax, cl-PARP and a decrease in Bcl-2 expression.


Assuntos
Antineoplásicos Fitogênicos/química , Daphne/química , Polifenóis/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose , Linhagem Celular Tumoral , China , Humanos , Estrutura Molecular , Casca de Planta/química , Caules de Planta/química , Poli(ADP-Ribose) Polimerases/metabolismo , Polifenóis/isolamento & purificação , Prenilação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo
6.
Nat Prod Res ; 33(12): 1809-1812, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29431466

RESUMO

In this study, we investigated for the first time the anti-proliferative and antioxidant properties of D. mezereum and D. striata. The aerial parts were extracted by maceration with n-hexane, dichloromethane, and methanol. MPLC, GC, and GC-MS were used for the phytochemical study. The anti-proliferative activity was tested against MCF-7, A549, LNCaP, ACHN, and C32 cancer human cells. The antioxidant activity was measured by employing ß-carotene bleaching, ABTS, DPPH, and FRAP tests. The Relative Antioxidant Capacity Index (RACI) was applied from the perspective of statistics. D. mezereum dichloromethane extract showed a remarkable anti-proliferative with an IC50 of 6.08 µg/mL against LNCaP cells. Experimental data indicate that Daphne species have interesting anti-proliferative and antioxidant properties that deserve more investigations to develop novel antineoplastic drugs.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Daphne/química , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Componentes Aéreos da Planta/química , Extratos Vegetais/análise , Extratos Vegetais/química
7.
Xenobiotica ; 49(2): 216-226, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29325475

RESUMO

1. To investigate Genkwa Flos hepatotoxicity, a cell metabolomics strategy combined with serum pharmacology was performed on human HL-7702 liver cells in this study. 2. Firstly, cell viability and biochemical indicators were determined and the cell morphology was observed to confirm the cell injury and develop a cell hepatotoxicity model. Then, with the help of cell metabolomics based on UPLC-MS, the Genkwa Flos group samples were completely separated from the blank group samples in the score plots and seven upregulated as well as two down-regulated putative biomarkers in the loading plot were identified and confirmed. Besides, two signal molecules and four enzymes involved in biosynthesis pathway of lysophosphatidylcholine and the sphingosine kinase/sphingosine-1-phosphate pathway were determined to investigate the relationship between Genkwa Flos hepatotoxicity and these two classic pathways. Finally, the metabolic pathways related to specific biomarkers and two classic metabolic pathways were analyzed to explain the possible mechanism of Genkwa Flos hepatotoxicity. 3. Based on the results, lipid peroxidation and oxidative stress, phospholipase A2/lysophosphatidylcholine pathway, the disturbance of sphingosine-1-phosphate metabolic profile centered on sphingosine kinase/sphingosine-1-phosphate pathway and fatty acid metabolism might be critical participators in the progression of liver injury induced by Genkwa Flos.


Assuntos
Medicamentos de Ervas Chinesas/toxicidade , Fígado/efeitos dos fármacos , Animais , Células Cultivadas , Daphne/química , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Fígado/metabolismo , Masculino , Redes e Vias Metabólicas , Metabolômica , Estresse Oxidativo , Ratos Sprague-Dawley , Organismos Livres de Patógenos Específicos
8.
Nat Prod Res ; 33(23): 3454-3458, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29842791

RESUMO

Since plants are an important source of anticancer drugs, we have carried out a random screening for selective anticancer activity of 57 extracts from 45 plants collected in Grazalema Natural Park, an area in the South of Spain of high plant diversity and endemism. Using lung cancer cells (A549) and lung non-malignant cells (MRC-5), we found that several extracts were more cytotoxic and selective against the cancer cells than the standard anticancer agent cisplatin. Five active extracts were further tested in cancer and normal cell lines from other tissues, including three skin cell lines with increasing degree of malignancy. An extract from the leaves of Daphne laureola L. (Thymelaeaceae) showed a striking potency and selectivity on lung cancer cells and leukemia cells; the IC50 values against these cancer cells were approximately 10,000-fold lower than against the normal cells. Daphnane-type diterpene orthoesters may be responsible for this highly selective anticancer activity.


Assuntos
Antineoplásicos/isolamento & purificação , Daphne/química , Neoplasias Pulmonares/tratamento farmacológico , Extratos Vegetais/farmacologia , Células A549 , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Humanos , Leucemia/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Espanha , Thymelaeaceae/química
9.
Molecules ; 23(10)2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30248957

RESUMO

Daphnauranins C⁻E (compounds 1⁻3), two sesquiterpenoids and one monoterpenoid were isolated from the roots of Daphne aurantiaca Diels. Daphnauranin C is a 9-O-13 etherified and hydroperoxy-substituted guaiane sesquiterpenoid, daphnauranin D is a guaiane sesquiterpenoid ketal, and daphnauranin E is a monoterpenoid lactone. Their structures were elucidated by comprehensive analyses of MS, 1D NMR, and 2D NMR spectroscopic data. In an anti-feeding activities test, daphnauranins C⁻E showed activity against male fruit fly with anti-feeding indexes (AI) up to 39.1, 39.2, and 27.8% respectively, at 1 mM.


Assuntos
Daphne/química , Drosophila melanogaster/efeitos dos fármacos , Repelentes de Insetos/química , Sesquiterpenos/química , Animais , Drosophila melanogaster/fisiologia , Repelentes de Insetos/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Estrutura Molecular , Raízes de Plantas/química , Sesquiterpenos/farmacologia
10.
Biomed Pharmacother ; 107: 1426-1433, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30257359

RESUMO

Daphnegiravone D (DGD), a prenylated flavonoid from Daphne giraldii Nitsche, significantly inhibited cell growth of several cancer cell lines without cytotoxicity on human normal cells. Our previous study showed that DGD could induce apoptosis in hepatocellular carcinoma Hep3B and HepG2 cells, but the detailed mechanism was still unclear. The present study provides that DGD-induced oxidative and nitrosative stress contribute to apoptotic cell death in Hep3B and HepG2 cells. Furthermore, there is a positive loop between oxidative stress and p38 activation, similar result is observed between nitrosative stress and p38. N-Acetylcysteine (NAC), a reactive oxygen species scavenger, could relieve DGD-induced oxidative stress, but exerts little effect on nitrosative stress. In addition, carboxy-PTIO (PTIO, a well-known scavenger of reactive nitrogen species) down-regulates the induction of nitrosative stress without obvious effect on oxidative stress in DGD-treated cells. In conclusion, the induction of oxidative and nitrosative stress could enhance p38-mediated apoptosis in DGD-treated Hep3B and HepG2 cells. Moreover, we speculated that OS and NS could not ultimately affect each other in DGD-treated HCC cells. This study gives a new insight on the mechanism of DGD-induced apoptotic cell death via oxidative and nitrosative stress in HCC cells.


Assuntos
Carcinoma Hepatocelular/patologia , Daphne/química , Flavonoides/farmacologia , Neoplasias Hepáticas/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Acetilcisteína/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/enzimologia , Flavonoides/química , Flavonoides/isolamento & purificação , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Prenilação de Proteína , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo
11.
Planta ; 248(6): 1365-1381, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30116887

RESUMO

MAIN CONCLUSION: The results provide a significant verification of the activity of exogenously applied phytohormones: gibberellic acid, jasmonic acid, and brassinolide in the modulation of the plant's response to nickel treatment. The study investigated nickel accumulation and its toxicity to Daphne jasminea shoots cultured in vitro with or without exogenous supplementation with phytohormones: gibberellic acid (GA3), jasmonic acid (JA), and brassinolide (BL). The aim was to verify the modulatory effect of exogenous plant growth regulators (PGRs) on plant reaction to Ni excess. The combined action of Ni and PGRs was evaluated at the anatomical, ultrastructural, and biochemical levels. Nickel toxicity was manifested in decreased biomass accretion and growth tolerance index (83-53.6%), attributed to enhanced synthesis of growth inhibitors, mainly abscisic acid. As a defence reaction, endogenous gibberellins accumulated. Exogenous GA3 ameliorated the plant reaction to Ni stress, inducing proliferation and growth rate. Ni tolerance in the presence of GA3 was attributed to peroxisomal reactions that stimulated the synthesis of endogenous JA. In contrast, the application of BL caused enhanced Ni accumulation. Plants suffered from pronounced stress due to massive oxidation. The defence strategy of plants subjected to Ni and BL involved cell wall rearrangements. Exogenous JA stimulated the synthesis of active auxins and salicylic acid, contributing to enhanced mitotic activity within explants. However, JA disturbed the integrity of chloroplasts and lamellar compartments. Our study revealed that an action of exogenous PGRs may either enhance tolerance to Ni or increase metal toxicity in D. jasminea. Particularly in in vitro culture, where explants are subjected to external phytohormonal stimuli, the combined effects of supplemental PGRs may enhance stress and substantially affect plant development. Our results provide a significant verification of exogenous PGRs activity in the modulation of plant response to nickel.


Assuntos
Daphne/efeitos dos fármacos , Níquel/toxicidade , Reguladores de Crescimento de Planta/farmacologia , Ácido Abscísico/farmacologia , Brassinosteroides/farmacologia , Ciclopentanos/farmacologia , Daphne/química , Daphne/crescimento & desenvolvimento , Daphne/ultraestrutura , Giberelinas/farmacologia , Ácidos Indolacéticos/farmacologia , Níquel/metabolismo , Oxilipinas/farmacologia , Ácido Salicílico/farmacologia , Esteroides Heterocíclicos/farmacologia , Madeira
12.
Fitoterapia ; 130: 105-111, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30145333

RESUMO

Two new sesquiterpenoids (1-2), together with 30 known compounds including one sesquiterpenoid (3), six diterpenoids (4-9), fourteen lignans (10-23), and nine other kinds of compounds (24-32), were isolated from the stems of Daphne tangutica Maxim. Their structures were determined through extensive spectroscopic analyses, and the absolute configuration of daphnoid A (1) and B (2) were determined by the experimental and calculated electron circular dichroism (ECD) spectra. All the isolates were evaluated against two human nasopharyngeal carcinoma cells (HONE-1 and SUNE-1). Compound 25 (daphnenone) showed potent cytotoxicity toward HONE-1 and SUNE-1with IC50 values of 2.23 and 1.43 µM, respectively. Further studies indicated that compound 25 exhibited cytotoxic effects by inducing tumor cell apoptosis and arresting the cell cycle at G2/M phases in HONE-1 cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Daphne/química , Sesquiterpenos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose , Carcinoma/patologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , China , Humanos , Estrutura Molecular , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patologia , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Caules de Planta/química , Sesquiterpenos/isolamento & purificação
13.
PLoS One ; 13(8): e0201711, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30071090

RESUMO

In order to well identify the 93 wild Cortex Daphnes samples from different species and habitats in western China and develop a standard operating procedure (SOP) for the authentication and quality of them in the future, a comprehensive and efficient identification system based on DNA barcoding and HPLC fingerprint technologies has been developed. The result showed that only 17 samples (18%) were Daphne giraldii Nitsche (DG), which is recorded in Chinese Pharmacopeia, while the others (82%) might have safety hazards. Additionally, the result of HPLC fingerprint analysis indicated that samples in the same species origins and wild distributions could be clustered together, which was consistent with DNA barcoding analysis. The study can provide a significant system for the authentication and quality of commercial Cortex Daphnes herbs. Undoubtedly, this study undoubtedly confirmed that the chemical compositions of Cortex Daphnes herbs were affected by both species origins and ecological environments, which is required more in-depth research.


Assuntos
Código de Barras de DNA Taxonômico , Daphne/química , Daphne/classificação , Cromatografia Líquida de Alta Pressão , Daphne/genética , Ecossistema
14.
Curr Top Med Chem ; 18(9): 779-786, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29807517

RESUMO

BACKGROUND: Antimicrobial drug resistance is an emerging problem, which leads to a failure in the control of infectious diseases thereby, adversely affecting patient care and reducing effective management of infectious diseases globally. Thus, search for new and more effective alternatives is needed. Daphne retusa Hemsl. (Daphne) has medicinal values and is reported to be widely used in curing a variety of human ailments. OBJECTIVE: Current study assesses in-vitro antimicrobial activity of the crude extract of D.retusa (whole plant) and its derived fractions against clinically isolated human pathogenic bacteria and fungi. MATERIALS AND METHODS: Whole plant of D.retusa was powder dried and then extracted with methanol (E1). The resultant was fractionated to give Chloroform fraction (E2), Butanol fraction (E3) and Ethyl acetate fraction (E4). The crude extract and derived fractions were assessed for antimicrobial and antifungal activity by using agar well diffusion method and their MICs were found following Clinical and Laboratory Standard Institute (CLSI) guidelines. RESULT: Our study shows that D.retusa has very good inhibitory action against different bacterial and fungal strains. All of the extracts were active against almost every microorganism used in the study. E2 has the maximum percent of inhibition against bacterial growth while E1 has themaximum percent of inhibition against fungal growth. Streptococcus pneumonia was the most susceptible bacteria while among fungi, Gongronella butleri showed highest susceptibility. CONCLUSION: Results justify the use of D. retusa in the treatment of microbial infections. For the development of a novel antibiotic, the crude extract and its derived fractions need further exploration; with emphasis to isolate and identify the active constituents that are responsible for antibacterial and antifungal activity.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/patogenicidade , Daphne/química , Fungos/efeitos dos fármacos , Fungos/patogenicidade , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antifúngicos/química , Antifúngicos/isolamento & purificação , Humanos , Testes de Sensibilidade Microbiana
15.
J Nat Med ; 72(3): 675-685, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29680963

RESUMO

Rheumatoid arthritis (RA) is one of the most prevalent chronic inflammatory and angiogenic diseases. The aim of this study was to evaluate the anti-inflammatory and anti-angiogenic activities in vitro of eight diterpenoids isolated from Daphne genkwa. LC-MS was used to identify diterpenes isolated from D. genkwa. The anti-inflammatory and anti-angiogenic activities of eight diterpenoids were evaluated on LPS-induced macrophage RAW264.7 cells and TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) using hierarchical cluster analysis (HCA) and principal component analysis (PCA). The eight diterpenes isolated from D. genkwa were identified as yuanhuaphnin, isoyuanhuacine, 12-O-(2'E,4'E-decadienoyl)-4-hydroxyphorbol-13-acetyl, yuanhuagine, isoyuanhuadine, yuanhuadine, yuanhuaoate C and yuanhuacine. All the eight diterpenes significantly down-regulated the excessive secretion of TNF-α, IL-6, IL-1ß and NO in LPS-induced RAW264.7 macrophages. However, only 12-O-(2'E,4'E-decadienoyl)-4-hydroxyphorbol-13-acetyl markedly reduced production of VEGF, MMP-3, ICAM and VCAM in TNF-α-stimulated HUVECs. HCA obtained 4 clusters, containing 12-O-(2'E,4'E-decadienoyl)-4-hydroxyphorbol-13-acetyl, isoyuanhuacine, isoyuanhuadine and five other compounds. PCA showed that the ranking of diterpenes sorted by efficacy from highest to lowest was 12-O-(2'E,4'E-decadienoyl)-4-hydroxyphorbol-13-acetyl, yuanhuaphnin, isoyuanhuacine, yuanhuacine, yuanhuaoate C, yuanhuagine, isoyuanhuadine, yuanhuadine. In conclusion, eight diterpenes isolated from D. genkwa showed different levels of activity in LPS-induced RAW264.7 cells and TNF-α-stimulated HUVECs. The comprehensive evaluation of activity by HCA and PCA indicated that of the eight diterpenes, 12-O-(2'E,4'E-decadienoyl)-4-hydroxyphorbol-13-acetyl was the best, and can be developed as a new drug for RA therapy.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Daphne/química , Diterpenos/uso terapêutico , Análise de Componente Principal/métodos , Inibidores da Angiogênese/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Humanos , Camundongos
16.
Chem Biol Interact ; 289: 1-8, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29698619

RESUMO

Hepatocellular carcinoma (HCC) is a primary malignant tumor with very poor prognosis. To search for more effective compounds for HCC treatment, two new pairs of flavan enantiomers, daphnegiranol C1/C2 (1a/1b) and daphnegiranol D1/D2 (2a/2b), were isolated from the stem bark and roots of Daphne giraldii by using chiral chromatography. MTT assay was applied to evaluate their cytotoxicity against three hepatocarcinoma cell lines (Hep3B, MHCC97H, HepG2) as well as a normal liver cell line L02. The results showed that these compounds preferred to inhibit the growth of Hep3B cells (p53 null). Among them, 2a/2b (the IC50 value was 4.87 and 3.35 µM, respectively) exhibited a stronger cytotoxic effect than sorafenib (IC50 = 6.59 µM) in Hep3B cells. A further study demonstrated that 2a/2b could induce apoptotic cell death with an increase in reactive oxygen species (ROS) in Hep3B cells. In addition, the IC50 values of 2a/2b in HepG2 and MHCC97H cells (both harbored p53 gene) were more than 10-folds greater when compared with Hep3B cells, indicating that 2a/2b selectively exhibited cytotoxicity in p53-null hepatocarcinoma cells. Moreover, inhibition of p53 increased the inhibitory effect in p53-wild hepatocarcinoma cells, as well as apoptotic cells and ROS generation. Taken together, flavan enantiomers 2a/2b selectively induced apoptosis in Hep3B cells because of p53 deficiency.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Daphne/química , Flavonoides/química , Flavonoides/farmacologia , Neoplasias Hepáticas/patologia , Proteína Supressora de Tumor p53/deficiência , Benzotiazóis/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Humanos , Concentração Inibidora 50 , Neoplasias Hepáticas/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Espécies Reativas de Oxigênio/metabolismo , Sorafenibe , Estereoisomerismo , Tolueno/análogos & derivados , Tolueno/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos
17.
Biomed Chromatogr ; 32(7): e4233, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29500935

RESUMO

A selective and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for investigating the pharmacokinetics of umbelliferone, apigenin, genkwanin and hydroxygenkwanin after oral administration of Daphne genkwa extract. Plasma samples were treated by protein precipitation with acetonitrile. Analytes were detected by triple-quadrupole MS/MS with an ESI source in negative selection reaction monitoring mode. The transitions of m/z 161 → 133 for umbelliferone, m/z 269 → 117 for apigenin, m/z 283 → 268 for genkwanin and m/z 299 → 284 for hydroxygenkwanin were confirmed for quantification. Chromatographic separation was conducted using an Eclipse XDB-C18 column, and the applied isocratic elution program allowed for simultaneous determination of the four analytes for a total run time of 2.5 min. The linearity was validated over the plasma concentration ranges of 1.421-1421 ng/mL for umbelliferone, 0.845-845 ng/mL for apigenin, 1.025-1025 ng/mL for genkwanin and 0.845-845 ng/mL for hydroxygenkwanin. The extraction recovery rate was >82.7% for each analyte. No apparent matrix effect was observed during the bioanalysis. After full validation, the proposed method was successfully applied to compare the pharmacokinetics of these analytes between normal and arthritic rats.


Assuntos
Artrite Experimental/metabolismo , Cromatografia Líquida/métodos , Cumarínicos/sangue , Daphne/química , Flavonoides/sangue , Administração Oral , Animais , Cumarínicos/química , Cumarínicos/farmacocinética , Estabilidade de Medicamentos , Flavonoides/química , Flavonoides/farmacocinética , Modelos Lineares , Masculino , Extratos Vegetais/administração & dosagem , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos
18.
Bioorg Chem ; 77: 619-624, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29501029

RESUMO

One new 1,3-diphenylpropane (1) together with six known analogues (2-7) were firstly isolated from the stem and root bark of Daphne giraldii. Their structures were determined by comprehensive NMR and HRESIMS spectroscopic data analyses. All the isolates were evaluated for their cytotoxicity against two hepatocellular carcinoma cell lines (HepG2 and Hep3B). Among them, compound 5 showed the most significant cytotoxicity against Hep3B cells, with an IC50 value of 17.21 µM. A further study demonstrated that 5 obviously induced apoptotic cell death as well as the inactivation of nuclear factor kappa B p65 (NF-κB p65) in Hep3B cells. In addition, BAY 11-7082 (BAY), a NF-кB inhibitor, was used to determine the role of NF-кB signaling in 5-treated Hep3B cells. The results suggested that BAY could enhance 5-induced apoptosis of Hep3B cells. In conclusion, the data provided that 5 might be a potential candidate for the treatment of hepatocellular carcinoma through NF-κB inhibition.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Daphne/química , Neoplasias Hepáticas/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Propano/análogos & derivados , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Estrutura Molecular , NF-kappa B/metabolismo , Propano/química , Propano/isolamento & purificação , Propano/farmacologia , Relação Estrutura-Atividade
19.
Artigo em Inglês | MEDLINE | ID: mdl-29428673

RESUMO

A sensitive UHPLC-MS/MS approach was developed and validated for the quantification of genkwanin, 3'-hydroxygenkwanin, apigenin, luteolin, yuanhuacine and genkwadaphnin in biological samples after oral administration of raw and vinegar-processed Daphne genkwa. Liquiritin and glycyrrhetinic acid were employed as internal standards. Six components were extracted by using protein precipitation with acetonitrile. Chromatographic separation was achieved on a Waters BEH C18 column (50 mm × 2.1 mm, 1.7 µm) by using a mobile phase composed of water (containing 0.1% formic acid) and acetonitrile. Mass spectrometric detection was conducted using multiple reaction monitoring (MRM). The intra- and inter-day precisions of the six analytes were below 4.87%, and the accuracies were within ±5.0%. The extraction recoveries of the six constituents were determined between 97.5% and 105.4% and the matrix effects ranged from 97.3% to 103.7%. All the samples showed satisfactory precision and accuracy after various stability tests. The established approach was successfully applied to the comparative pharmacokinetic study. Compared to the raw group, the parameters of Cmax and AUC0-t of genkwanin, 3'-hydroxygenkwanin, apigenin and luteolin elevated remarkably (p < 0.05) after oral delivery of vinegar-processed Daphne genkwa while the parameters of Cmax and AUC0-t of yuanhuacine and genkwadaphnin decreased significantly (p < 0.05). The results revealed that vinegar-processing could enhance bioavailability of genkwanin, 3'-hydroxygenkwanin, apigenin and luteolin but reduce the bioavailability of yuanhuacine and genkwadaphnin.


Assuntos
Ácido Acético/química , Daphne/química , Extratos Vegetais/química , Administração Oral , Animais , Apigenina/análise , Apigenina/química , Disponibilidade Biológica , Diterpenos/análise , Diterpenos/química , Flavonas/análise , Flavonas/química , Flavonoides/análise , Flavonoides/química , Extração Líquido-Líquido , Masculino , Extratos Vegetais/farmacocinética , Raízes de Plantas/química , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Água/química
20.
Biomed Chromatogr ; 32(3)2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29110318

RESUMO

A simple sensitive LC-MS/MS method has been developed for the simultaneous determination of giraldoid A and giraldoid B in rat plasma. The method was applied to pharmacokinetics studies of the two compounds from Daphne giraldii Nitsche. Chromatographic separation was accomplished on an Acquity UPLC™ BEH C18 column (100 × 2.1 mm, 1.7 mm) by gradient elution with a flow rate of 0.2 mL min-1. The method was linear over the concentration range of 1.0-1000 ng mL-1 , and the lower limits of quantification were 1.04 ± 0.10 and 1.04 ± 0.09 ng mL-1 , respectively. The intra- and inter-day precisions (RSD) were <10.14 and 9.96%. The extraction recovery of the analytes was acceptable. Stability studies demonstrated that the two compounds were stable in the preparation and analytical process. The maximum plasma concentration was 687.78 ± 243.62 ng mL-1 for giraldoid A and 952.38 ± 131.99 ng mL-1 for giraldoid B. The time to reach the maximum plasma concentration was 0.50 ± 0.37 h for giraldoid A and 0.50 ± 0.66 h for giraldoid B. The validated method was successfully applied to investigate the concentration-time profiles of giraldoid A and giraldoid B.


Assuntos
Cromatografia Líquida/métodos , Daphne/química , Flavonoides/sangue , Extratos Vegetais , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Flavonoides/química , Flavonoides/farmacocinética , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley
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