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1.
Drug Chem Toxicol ; 45(3): 1408-1416, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-33059469

RESUMO

Daidzein is a naturally occurring compound belonging to the class isoflavones and found in soya beans and other legumes. Acute oral toxicity was performed as per OECD guideline (TG 423) with slight modifications. A repeated dose toxicity study was carried out as per OECD guideline (TG 407). In-silico toxicity such as AMES toxicity, carcinogenicity, mutagenicity, immunotoxicity, hepatotoxicity, skin irritation, reproductive effect, rat and mouse toxicity, LD50, hERG I, II inhibitor and minnow toxicity were predicted using online servers and tools. In an acute oral toxicity study, daidzein did not show any mortality in experimental animals. The No Observed Adverse Effect Level (NOAEL) of daidzein was found to be above 5000 mg/kg. 28 days treatment of diadzein at all doses did not show changes in hematology parameters, clinical biochemistry and kidney function parameters. Gross necropsy or histopathology of important organs showed no signs of toxicity. In-silico predicted parameters also demonstrated risks ranging from low to a nontoxic level. Thus, daidzein was found to be safe in acute and repeated oral dose toxicity studies at all selected doses. In-silico study also indicated that daidzein is safe.


Assuntos
Isoflavonas , Animais , Isoflavonas/toxicidade , Camundongos , Nível de Efeito Adverso não Observado , Ratos , Reprodução , Soja/toxicidade
2.
J Ethnopharmacol ; 287: 114963, 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-34971733

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Glabridin, extracted from Glycyrrhiza glabra L., is widely used for the treatment of hyperpigmentation because of its anti-inflammatory and antioxidant activities and its ability to inhibit melanin synthesis. This led to the strict regulation of its quality and safety. However, traditional quality control methods used for plant extracts cannot reflect the product quality owing to multiple unknown impurities, which necessitates the further analysis of impurities. AIM OF THE STUDY: The study identified the toxic impurities of glabridin and their toxicological mechanism. MATERIALS AND METHODS: In total, 10 glabridin samples from different sources were quantified using high-performance liquid chromatography. Sample toxicities were evaluated using zebrafish and cell models. To identify impurities, samples with different toxicity were analyzed by ultra-high-performance liquid chromatography coupled with quadrupole-Orbitrap mass spectrometry. The toxicity of related impurities was verified in the zebrafish model. Phalloidin stain was used to evaluate subtle changes in myofibril alignment. RESULTS: Although glabridin content in the samples was similar, there were significant differences in toxicity. The results were verified using four different mammalian cell lines. Higher contents of glabrone and glabrol were identified in the sample with the highest toxicity. In the zebrafish model, the addition of glabrol reduced the LC50 of glabridin to 9.224, 6.229, and 5.370 µM at 48, 72, and 96 h post-fertilization, respectively, whereas glabrone did not have any toxic effect. Phalloidin staining indicated that a glabrol impurity exacerbates the myotoxicity of glabridin in zebrafish embryos. CONCLUSION: Glabrol, but not glabrone, was identified as a key impurity that increased glabridin toxicity. This finding indicates that controlling glabrol content is necessary during glabridin product production.


Assuntos
Flavonoides/toxicidade , Glycyrrhiza/química , Isoflavonas/toxicidade , Miofibrilas/efeitos dos fármacos , Fenóis/toxicidade , Animais , Linhagem Celular , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Embrião não Mamífero/efeitos dos fármacos , Feminino , Flavonoides/química , Humanos , Isoflavonas/química , Masculino , Espectrometria de Massas , Camundongos , Miofibrilas/patologia , Fenóis/química , Extratos Vegetais/química , Extratos Vegetais/toxicidade , Controle de Qualidade , Peixe-Zebra
3.
Molecules ; 26(17)2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34500814

RESUMO

The investigation of the constituents of the rhizomes of Dioscorea collettii afforded one new dihydroisocoumarin, named (-)-montroumarin (1a), along with five known compounds-montroumarin (1b), 1,1'-oxybis(2,4-di-tert-butylbenzene) (2), (3R)-3'-O-methylviolanone (3a), (3S)-3'-O-methylviolanone (3b), and (RS)-sativanone (4). Their structures were elucidated using extensive spectroscopic methods. To the best of our knowledge, compound 1a is a new enantiomer of compound 1b. The NMR data of compound 2 had been reported but its structure was erroneous. The structure of compound 2 was revised on the basis of a reinterpretation of its NMR data (1D and 2D) and the assignment of the 1H and 13C NMR data was given rightly for the first time. Compounds 3a-4, three dihydroisoflavones, were reported from the Dioscoreaceae family for the first time. The cytotoxic activities of all the compounds were tested against the NCI-H460 cell line. Two dihydroisocoumarins, compounds 1a and 1b, displayed moderate cytotoxic activities, while the other compounds showed no cytotoxicity.


Assuntos
Cumarínicos/química , Dioscorea/química , Isoflavonas/química , Rizoma/química , Derivados de Benzeno/química , Linhagem Celular Tumoral , Cumarínicos/toxicidade , Humanos , Isoflavonas/toxicidade , Extratos Vegetais/química
4.
Biomed Chromatogr ; 35(9): e5140, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33830528

RESUMO

Owing to the complexity of the composition of herbal and dietary supplements, it is a challenging problem to efficiently screen and identify active or toxic compounds. Psoralea corylifolia L. (PCL) was selected as the subbject to establish a methodology for rapid screening and identification of hepatotoxic compounds. High-content imaging, ultra-performance liquid chromatography and high-resolution mass spectrometry were used in this study to detect the hepatotoxicity and identify unknown compounds in PCL samples. Then, putative toxic compounds which are highly related to hepatotoxicity were screened by spectrum-toxicity correlation analysis, and the toxicity intensity verified by high-content imaging. The maximum nontoxic dose of processed samples with good detoxification effect reduced more than 9 times compared with unprocessed raw medicinal materials. Spectrum-toxicity correlation analysis showed that bavachinin A, bavachin, isobavachalcone and neobavaisoflavone had high correlation with the hepatotoxicity of PCL, and psoralen and isopsoralen had low correlation with hepatotoxicity. This study verified the hepatotoxicity of these six putative compound monomers, proving the results of spectrum-toxicity correlation analysis. Based on the correlation analysis of high-resolution mass spectrometry of detection compounds and high-content imaging of hepatocyte toxicity data, the potential toxic compound of herbal and dietary supplement products can be quickly and accurately screened.


Assuntos
Suplementos Nutricionais/toxicidade , Medicamentos de Ervas Chinesas/toxicidade , Hepatócitos/efeitos dos fármacos , Psoralea/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ficusina/toxicidade , Flavonoides/toxicidade , Humanos , Isoflavonas/toxicidade , Espectrometria de Massas/métodos , Imagem Molecular/métodos
5.
Food Chem Toxicol ; 144: 111644, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32763437

RESUMO

In this study, we hypothesized that anti-parkinsonian effect of puerarin is attributable to its antioxidant properties via Nrf2-dependent glutathione (GSH) biosynthesis mechanism. Experimentally, we found that puerarin attenuated 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress through elevating biosynthetic capacity of GSH in PC12 cells. Mechanistically, puerarin suppressed Fyn phosphorylation by GSK-3ß-dependent mechanism in MPP+-challenged PC12 cells. Furthermore, puerarin induced accumulation of Nrf2 in the nucleus via inhibiting its nuclear exclusion. In parallel, puerarin up-regulated antioxidant response element (ARE)-driven catalytic subunits from glutamate cysteine ligase (GCLc) expression at levels of transcription and translation. Most interestingly, pharmacological inhibitor of GSK-3ß or Fyn shRNA blocked puerarin-induced Nrf2 activation in MPP+-challenged PC12 cells. Concomitantly, puerarin ameliorated motor deficits and inhibited oxidative stress in the ventral midbrain in MPTP-intoxicated wild-type (WT) mice, but failed to attenuate MPTP neurotoxicity and up-regulate GCLc gene in Nrf2-knockout (Nrf2-/-) mice, suggesting that anti-parkinsonian effect of puerarin was dependent on Nrf2. Additionally, puerarin regulated Fyn and GSK-3ß phosphorylation in the ventral midbrain in MPTP-intoxicated WT mice. Collectively, the results of the study provide molecular insights into the potential therapeutic action of puerarin in Parkinson's disease, suggesting that puerarin may be a promising candidate for the treatment of Parkinson's disease.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Isoflavonas/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Células PC12 , Doença de Parkinson/prevenção & controle , Fosforilação , Ratos
6.
Biol Pharm Bull ; 43(5): 884-897, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32147624

RESUMO

Inflammation, and the pain that accompanies it, is a natural response of the body. The licorice plant (Glycyrrhiza glabra) have demonstrated anti-inflammatory, anti-edematous, and anti-nociceptive effects of its extracts. The effective ingredient remains unidentified; however, one possibility is the unique isoflavone glabridin. The anti-nociceptive, and anti-inflammatory effects of glabridin and its possible mechanism with focus on the large conductance Ca2+-activated K+ (BKCa) channels and L-arginine-nitric oxide (NO) pathway were examined by using different tests. In order to determine the anti-edematous, anti-nociceptive, and anti-oxidative effects of glabradin, some tests such as the tail flick, hotplate, carrageenan-induced paw edema, air pouch, acetic-acid-induced writhing, formalin, and capsaicin tests, as well as toxicity and open field tests were made. Glabridin was administered to rats (n = 8) or mice (n = 8) for 3 d at 3 doses (10, 20, and 40 mg/kg). Glabridin inhibited cytokine production and showed an anti-nociceptive response via the activating of BKCa channels and downregulating NO level and partially transient receptor potential vanilloid-1 pathways. It also demonstrated anti-inflammatory effects by inhibiting cyclooxygenase (COX) activity, while showing no cytotoxicity. Glabridin, however, showed no anti-nociceptive effect in the neurogenic phase. Glabridin is a promising substance in terms of its anti-nociceptive and anti-inflammatory effects by disrupting peripheral NO production, inhibiting cyclic guanosine monophosphate (cGMP) activation and activating BKCa channels and its lack of acute and subacute toxic effects.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Edema/tratamento farmacológico , Isoflavonas/uso terapêutico , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Dor/tratamento farmacológico , Fenóis/uso terapêutico , Analgésicos/farmacologia , Analgésicos/toxicidade , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/toxicidade , Citocinas/imunologia , Edema/imunologia , Edema/metabolismo , Isoflavonas/farmacologia , Isoflavonas/toxicidade , Dose Letal Mediana , Leucócitos/efeitos dos fármacos , Leucócitos/fisiologia , Masculino , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Dor/imunologia , Dor/metabolismo , Fenóis/farmacologia , Fenóis/toxicidade , Ratos Wistar
7.
Food Chem Toxicol ; 136: 111027, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31870919

RESUMO

The incubation system of CYP2E1 and CYP3A4 enzymes in rat liver microsomes was established to investigate the effects of psoralidin, isobavachalcone, neobavaisoflavone and daidzein from Fructus Psoraleae in vitro. The relevant metabolites were measured by the method of high performance liquid chromatography (HPLC), after probe substrates of 4-nitrophenol, testosterone and the drugs at different concentrations were added to the incubation systems. In addition, real-time RT-PCR was performed to determine the effect of psoralidin, neobavaisoflavone and daidzein on the mRNA expression of CYP3A4 in rat liver. The results suggested that psoralidin, isobavachalcone and neobavaisoflavone were Medium-intensity inhibitors of CYP2E1 with Ki values of 2.58, 1.28 and 19.07 µM, respectively, which could inhibit the increase of CYP2E1 and reduce diseases caused by lipid peroxidation. Isobavachalcone (Ki = 37.52 µM) showed a weak competitive inhibition on CYP3A4. Psoralidin and neobavaisoflavone showed obvious induction effects on CYP3A4 in the expression level of mRNA, which could accelerate the effects of drug metabolism and lead to the risk of inducing DDIs and serious adverse reactions. The results could be used for guideline of Fructus Psoraleae in clinic, which aimed to calculate the drug toxicity by studying the drug-drug interactions caused by the induction and inhibition of CYP450.


Assuntos
Benzofuranos/toxicidade , Chalconas/toxicidade , Cumarínicos/toxicidade , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A/metabolismo , Isoflavonas/toxicidade , Microssomos Hepáticos/metabolismo , Animais , Benzofuranos/metabolismo , Chalconas/metabolismo , Cumarínicos/metabolismo , Inibidores do Citocromo P-450 CYP2E1/metabolismo , Inibidores do Citocromo P-450 CYP2E1/toxicidade , Inibidores do Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/toxicidade , Interações Medicamentosas , Isoflavonas/metabolismo , Ratos Sprague-Dawley
8.
Food Chem Toxicol ; 135: 110863, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31604113

RESUMO

Breast cancer is one of the most common causes of mortality in women. Lupiwighteone has anticancer effects in prostate cancer cells and neuroblastoma cells. However, the molecular and cellular mechanisms of lupiwighteone effects on human breast cancer cells are not as well known. In the present study, we investigated the effects of lupiwighteone on the proliferation and apoptosis of two different human cancer cells; MCF-7, an estrogen receptor (ER)-positive human breast cancer cell, and MDA-MB-231, a triple negative human breast cancer cell. Lupiwighteone treatment decreased the viability of MCF-7 and MDA-MB-231 cells. Lupiwighteone treatment resulted in apoptotic cell death in breast cancer cells, which was characterized by DNA fragmentation, accumulation of apoptotic cells, and nuclear condensation. We also showed that treatment with lupiwighteone induced caspase-dependent apoptosis (up-regulation of caspase-3, -7, -8, -9, PARP, and Bax or down-regulation of Bid, Bcl-2), induction of caspase-independent apoptosis (up-regulation of AIF and Endo G on cytosol), and inhibition of the PI3K/Akt/mTOR signaling pathway (down-regulation of PI3K, p-Akt, and p-mTOR) in both MCF-7 and MDA-MB-231 cells. These results suggest that lupiwighteone induces caspase-dependent and -independent apoptosis in both breast cancer cell lines via inhibiting PI3K/Akt/mTOR pathway.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Caspases/metabolismo , Isoflavonas/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática , Humanos
9.
Chem Res Toxicol ; 32(10): 2125-2134, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31515991

RESUMO

Auriculasin has a wide range of pharmacological effects, including anticancer and anti-inflammatory effects. In this work, we explored the metabolic characteristics and inhibitory effect of auriculasin against cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes in vitro. Auriculasin inhibited UGT1A6, UGT1A8, UGT1A10, UGT2B7, CYP2C9, and CYP3A4 strongly at a concentration of 100 µM. Different species showed significant differences in auriculasin metabolism, and metabolic characteristics were similar between pig and human. We identified seven metabolites, and hydroxylated auriculasin was the main metabolite. In addition, CYP2D6, CYP2C9, CYP2C19, and CYP2C8 were the major CYP isoforms involved in the metabolism of auriculasin. Molecular docking studies showed that noncovalent interactions between auriculasin and the CYPs are dominated by hydrogen bonding, π-π stacking, and hydrophobic interactions. Our in vitro study provides insights into the pharmacological and toxicological mechanisms of auriculasin.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/toxicidade , Glucuronosiltransferase/antagonistas & inibidores , Isoflavonas/metabolismo , Isoflavonas/toxicidade , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Glucuronosiltransferase/metabolismo , Humanos , Isoflavonas/química , Isoflavonas/farmacologia , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade
10.
Histol Histopathol ; 34(8): 875-887, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30729492

RESUMO

Phytochemicals are widely present in the aquatic environment and they are derived from many anthropogenic activities. The isoflavone daidzein is a natural compound that is found in the soya products used as habitual constituents of aquafeeds. Nevertheless, this isoflavone possesses oestrogenic and apoptotic properties. The present study determined the effects of daidzein (at 20 mg/L) during the first month and a half of life (from 7 to 44 days post-hatching -dph-) of the flatfish Senegalese sole, Solea senegalensis, focusing at the metamorphosis. We have analysed different gene expression levels and immunohistochemical protein patterns implicated in some oestrogenic, apoptosis and enzymatic pathways. In general, the oestrogen receptor (ERß) and stimulating apoptosis death receptor factor (Fas) transcript levels showed similar baseline patterns and transcriptional responses induced by daidzein. Both ERß and Fas were up-regulated by this isoflavone at the pre-metamorphosis and metamorphosis, and they were down-regulated in post-metamorphosed stages. The expression pattern of the apoptotic effector caspase (Casp6) was exclusively up-regulated at the pre-metamorphic phase. The Birc5 transcripts (i.e. anti-apoptosis, Survivin) were down-regulated by daidzein during certain metamorphic and post-metamorphosed stages. Besides, daidzein showed an up-regulating effect on both enzymatic complexes, the haemoprotein CYP1A and the acetylcholinesterase (AChE), except for a temporary AChE down-regulation in some post-metamorphosed stages. Immunostaining analysis only showed increased CYP1A signals in the liver of daidzein exposed fish. Overall, a majority of the transcriptional oestrogenic and apoptotic imbalances could be gradually and/or temporarily stabilised. Most controls and exposed larvae (70-80%) developed and grew following normal ontogenetic developmental patterns.


Assuntos
Receptor beta de Estrogênio/metabolismo , Linguados/metabolismo , Inibidores do Crescimento/toxicidade , Isoflavonas/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linguados/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Metamorfose Biológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
11.
Nat Prod Res ; 33(12): 1727-1733, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29457519

RESUMO

A new homoisoflavonoid, (3R)-5,7-dihydroxy-6-methyl-3-(2'-hydroxy-4'-methoxybenzyl)-chroman-4-one (1), namely polygonatone H, in addition to fourteen known homoisoflavones (2-15) were isolated from the rhizome of Polygonatum Cyrtonema Hua. The structures were identified with the aid of 1D/2D NMR spectroscopic technologies. Compounds 2, 6, 8, 10, 11, 13, and 15 were isolated from P. Cyrtonema for the first time. Compound 1 showed cytotoxicities to human cancer cell lines with IC50 values to comparable those of cisplatin.


Assuntos
Antineoplásicos/isolamento & purificação , Isoflavonas/isolamento & purificação , Isoflavonas/toxicidade , Polygonatum/química , Rizoma/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular , Citotoxinas/química , Citotoxinas/isolamento & purificação , Citotoxinas/farmacologia , Humanos , Concentração Inibidora 50 , Isoflavonas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular
12.
Mol Cells ; 41(5): 476-485, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29764006

RESUMO

Although tectorigenin (TG), a major compound in the rhizome of Belamcanda chinensis, is conventionally used for the treatment of inflammatory diseases, its effects on osteogenesis and osteoclastogenesis have not been reported. The objective of this study was to investigate the effects and possible underlying mechanism of TG on in vitro osteoblastic differentiation and in vivo bone formation, as well as in vitro osteoclast differentiation and in vivo bone resorption. TG promoted the osteogenic differentiation of primary osteoblasts and periodontal ligament cells. Moreover, TG upregulated the expression of the BMP2, BMP4, and Smad-4 genes, and enhanced the expression of Runx2 and Osterix. In vivo studies involving mouse calvarial bone defects with µCT and histologic analysis revealed that TG significantly increased new bone formation. Furthermore, TG treatment inhibited osteoclast differentiation and the mRNA levels of osteoclast markers. In vivo studies of mice demonstrated that TG caused the marked attenuation of bone resorption. These results collectively demonstrated that TG stimulated osteogenic differentiation in vitro, increased in vivo bone regeneration, inhibited osteoclast differentiation in vitro, and suppressed inflammatory bone loss in vivo. These novel findings suggest that TG may be useful for bone regeneration and treatment of bone diseases.


Assuntos
Reabsorção Óssea/prevenção & controle , Consolidação da Fratura/efeitos dos fármacos , Isoflavonas/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Transformada , Células Cultivadas , Feminino , Humanos , Isoflavonas/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Ligamento Periodontal/citologia , Cultura Primária de Células , Ligante RANK/fisiologia , Células RAW 264.7 , Crânio/efeitos dos fármacos , Crânio/lesões , Crânio/cirurgia , Fatores de Transcrição/metabolismo
13.
J Appl Toxicol ; 38(6): 801-809, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29350786

RESUMO

Calycosin-7-O-ß-d-glucoside (CG) is an important active isoflavone compound in Radix Astragali that has many bioactivities. However, the toxicological effects and related toxicological mechanism of CG have been rarely documented. The purpose of the present study was to evaluate the toxicity effects of CG on the model organism Caenorhabditis elegans. Some characteristics of the nematode, including lifespan, movement behavior and reproductive capacity, were used to detect the toxic effects of CG on C. elegans. The results showed that CG could shorten the lifespan of C. elegans by up to 25.3% and severely damage the movement of N2 larvae compared with the control group. Moreover, CG could prolong the generation times and reduce the brood sizes. Furthermore, CG promoted the formation of reactive oxygen species (ROS), which caused oxidative stress, increased the mRNA expression of sod-1, sod-2, sod-3, sod-5, ctl-1, ctl-2 and ctl-3, and induced the antioxidant enzymes activities of superoxide dismutase and catalase to scavenge free radicals. However, antioxidant treatment experiments showed that Trolox could reduce the level of ROS caused by CG to the normal state of the control. These results suggested that the generation and elimination of ROS could not restore normal homeostasis in C. elegans treated by CG. These findings indicated that the activation of oxidative damage is one of the most important toxic mechanisms of CG in C. elegans.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Glucosídeos/toxicidade , Isoflavonas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Catalase/genética , Catalase/metabolismo , Regulação Enzimológica da Expressão Gênica , Longevidade/efeitos dos fármacos , Movimento/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fatores de Tempo
14.
Environ Toxicol ; 33(2): 248-255, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29119715

RESUMO

Oral submucous fibrosis (OSF) has been recognized as one of the oral potentially malignant disorders. Areca nut chewing is implicated in this pathological fibrosis, and it causes chronic inflammation and persistent activation of myofibroblasts. As yet, existing treatments only provide temporary symptomatic relief and there is a lack of an effective intervention to cure OSF. Therefore, development of approaches to ameliorate myofibroblast activities becomes a crucial objective to prevent the malignant progression of OSF. In this study, we examined the inhibitory effect of glabridin, an isoflavane extracted from licorice root, on the myofibroblast characteristics in human fibrotic buccal mucosal fibroblasts (fBMFs). Our results showed that myofibroblast activities, including collagen gel contractility, migration, invasion and wound healing abilities were reduced after exposure of glabridin in a dose-dependent manner. Most importantly, we demonstrated that the arecoline-induced myofiroblast activities were abolished by glabridin treatment. Additionally, the expression of the myofibroblast marker α-smooth muscle actin and other fibrogenic marker, type I collagen, in fBMFs were dose-dependently downregulated. Moreover, we showed that the production of TGF-ß was suppressed by glabridin in fBMFs and the protein expression of phospho-Smad2 was decreased as well. In summary, our data suggested that glabridin repressed the myofibroblast features in fBMFs via TGF-ß/Smad2 signaling pathway. Glabridin also prevented the arecoline-increased myofibroblast activities, and could serve as a natural anti-fibrosis compound for OSF.


Assuntos
Isoflavonas/toxicidade , Fenóis/toxicidade , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Actinas/metabolismo , Arecolina/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Humanos , Isoflavonas/química , Mucosa Bucal/citologia , Miofibroblastos/citologia , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Fenóis/química
15.
Cell Physiol Biochem ; 44(5): 1775-1784, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29241196

RESUMO

BACKGROUND/AIMS: Calycosin, a phytoestrogenic compound, has recently emerged as a promising antitumor drug. It has been shown that calycosin suppresses growth and induces apoptosis of breast cancer cells. However, the effect of calycosin on migration and invasion of breast cancer cells and the underlying molecular mechanisms have not been elucidated. METHODS: Human breast cancer cells MCF-7 and T47D were treated with, or without, different doses (0, 6.25, 12.5, 25, 50, 100 or 150 µM) of calycosin, and the viability of different groups was determined by MTT assay. Next, the inhibitory effect of higher doses (50, 100 or 150 µM) of calycosin on migration and invasion of the two cell lines was determined by wound healing and transwell assay. The relative expression levels of forkhead box P3 (Foxp3), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) in MCF-7 and T47D cells were determined by quantitative RT-PCR and Western blot. RESULTS: Treatment with lower doses (6.25 or 12.5 µM) promoted proliferation of breast cancer cells, but with higher doses significantly reduced the viability of MCF-7 and T47D cells. Furthermore, higher doses of calycosin were found to inhibit migration and invasion of the two cell lines in a dose-dependent manner. Additionally, treatment with a higher dose of calycosin significantly reduced the expression levels of Foxp3, followed by down-regulation of VEGF and MMP-9 in both MCF-7 and T47D breast cancer cells. CONCLUSION: Treatment with a higher dose of calycosin tends to reduce migration and invasion capacity of human breast cancer cells, by targeting Foxp3-mediated VEGF and MMP-9 expression.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Isoflavonas/toxicidade , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/toxicidade , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Células MCF-7 , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Environ Toxicol Pharmacol ; 52: 83-89, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28384516

RESUMO

Puerarin is a natural compound and has been used as herb medication in a number of countries, especially in Asia. The effect of puerarin on Ca2+ signaling is unknown in renal cells. This study examined whether puerarin affected Ca2+ physiology in MDCK renal tubular cells. Cytosolic free Ca2+ levels ([Ca2+]i) were measured using the fluorescent dye fura-2. Cell viability was examined by using WST-1 assay. Puerarin induced [Ca2+]i rises and the response was reduced by removing extracellular Ca2+. Puerarin-induced Ca2+ entry was not altered by protein kinase C (PKC) activity, but was inhibited by nifedipine. In Ca2+-free medium, treatment with the endoplasmic reticulum Ca2+ pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) or thapsigargin partly inhibited puerarin-evoked [Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122 did not change puerarin-induced [Ca2+]i rises. Puerarin at 25-50µM caused cytotoxicity, which was not reversed by pretreatment with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Collectively, in MDCK cells, puerarin induced [Ca2+]i rises by evoking PLC-independent Ca2+ release from the endoplasmic reticulum and other unknown stores, and Ca2+ entry via nifedipine-sensitive, PKC-insensitive Ca2+ entry pathways. Puerarin also caused Ca2+-independent cell death.


Assuntos
Cálcio/metabolismo , Isoflavonas/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Cães , Túbulos Renais/citologia , Células Madin Darby de Rim Canino
17.
Regul Toxicol Pharmacol ; 86: 374-378, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28408196

RESUMO

As part of a safety evaluation, we evaluated the potential genotoxicity of sodium formononetin-3'-sulphonate (Sul-F) using bacterial reverse mutation assay, chromosomal aberrations detection, and mouse micronucleus test. In bacterial reverse mutation assay using five strains of Salmonella typhimurium (TA97, TA98, TA100, TA102 and TA1535), Sul-F (250, 500, 1000, 2000, 4000 µg/plate) did not increase the number of revertant colonies in any tester strain with or without S9 mix. In a chromosomal assay using Chinese hamster lung fibroblast (CHL) cells, there were no increases in either kind of aberration at any dose of Sul-F (400, 800, and 1600 µg/mL) treatment groups with or without S9 metabolic activation. In an in vivo bone marrow micronucleus test in ICR mice, Sul-F at up to 2000 mg/kg (intravenous injection) showed no significant increases in the incidence of micronucleated polychromatic erythrocytes, and the proportion of immature erythrocytes to total erythrocytes. The results demonstrated that Sul-F does not show mutagenic or genotoxic potential under these test conditions.


Assuntos
Aberrações Cromossômicas/induzido quimicamente , Isoflavonas/toxicidade , Salmonella typhimurium/efeitos dos fármacos , Animais , Cricetinae , Cricetulus , Eritrócitos/efeitos dos fármacos , Eritrócitos Anormais , Fibroblastos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Testes para Micronúcleos , Testes de Mutagenicidade , Mutação , Salmonella typhimurium/genética , Sódio
18.
Bioorg Med Chem Lett ; 27(11): 2454-2458, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28408225

RESUMO

Phenoxodiol is an isoflavene with potent anti-tumor activity. In this study, a series of novel mono- and di-substituted phenoxodiol-thiosemicarbazone hybrids were synthesized via the condensation reaction between phenoxodiol with thiosemicarbazides. The in vitro anti-proliferative activities of the hybrids were evaluated against the neuroblastoma SKN-BE(2)C, the triple negative breast cancer MDA-MB-231, and the glioblastoma U87 cancer cell lines. The mono-substituted hybrids exhibited potent anti-proliferative activity against all three cancer cell lines, while the di-substituted hybrids were less active. Selected mono-substituted hybrids were further investigated for their cytotoxicity against normal MRC-5 human lung fibroblast cells, which identified two hybrids with superior selectivity for cancer cells over normal cells as compared to phenoxodiol. This suggests that mono-substituted phenoxodiol-thiosemicarbazone hybrids have promising potential for further development as anti-cancer agents.


Assuntos
Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Isoflavonas/farmacologia , Tiossemicarbazonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Benzopiranos/síntese química , Benzopiranos/toxicidade , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoflavonas/síntese química , Isoflavonas/toxicidade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/toxicidade
19.
Drug Chem Toxicol ; 40(3): 256-262, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27461151

RESUMO

Phenolic compounds not only contribute to the sensory qualities of fruits and vegetables but also exhibit several health protective properties. Galangin, puerarin, and ursolic acid are commonly used plant phenolics in folk medicine. In this study, the antioxidant capacities of galangin, puerarin, and ursolic acid by the trolox equivalent antioxidant capacity (TEAC) assay and the cytotoxic effects by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in V79 cells were investigated. The genotoxic potentials of galangin, puerarin, and ursolic acid were evaluated by micronucleus (MN) and alkaline COMET assays in human lymphocytes and in V79 cells. Galangin, puerarin, and ursolic acid (10, 100, 500, 1000, 2000, 5000, 10 000, and 20 000 µM) were found to have antioxidant activities at the studied concentrations. IC50 values of galangin, puerarin, and ursolic acid in V79 cells were found to be 275.48 µM, 2503.712 µM, and 224.85 µM, respectively. Galangin, puerarin, and ursolic acid, at the all concentrations, have not exerted genotoxic effects and galangin, puerarin, and ursolic acid revealed a reduction in the frequency of MN and DNA damage induced by H2O2.


Assuntos
Antimutagênicos/farmacologia , Antioxidantes/farmacologia , Flavonoides/farmacologia , Isoflavonas/farmacologia , Triterpenos/farmacologia , Animais , Antimutagênicos/toxicidade , Antioxidantes/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Cricetulus , Dano ao DNA , Relação Dose-Resposta a Droga , Flavonoides/toxicidade , Humanos , Isoflavonas/toxicidade , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Testes para Micronúcleos , Triterpenos/toxicidade
20.
Toxicol Lett ; 262: 39-48, 2016 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-27506417

RESUMO

There is increasing concern about possible adverse effects of soy based infant formulas (SBIF) due to their high amount of isoflavones (ISO). The aim of the present study was to investigate effects of neonatal exposure to ISO on reproductive system of female Wistar rats. Animals were exposed to an ISO depleted diet or a diet enriched with an ISO extract (IRD; 508mg ISO/kg) during embryogenesis and adolescence. Pups of each group were fed daily by pipette with ISO-suspension (ISO+; 32mg ISO/kg bw) or placebo from postnatal day (PND) 1 until PND23 resulting in plasma concentrations similar to levels reported in infants fed SBIF. The visceral fat mass was reduced by long-term IRD. Vaginal epithelial height was increased at PND23 and vaginal opening was precocious in ISO+ groups. Later in life, more often irregular estrus cycles were observed in rats of ISO+ groups. In addition, FSH levels and uterine epithelial heights were increased at PND80 in ISO+ groups. In summary, the results indicate that neonatal ISO intake, resulting in plasma concentrations achievable through SBIF, has an estrogenic effect on prepubertal rats and influences female reproductive tract later in life.


Assuntos
Estrogênios não Esteroides/toxicidade , Isoflavonas/toxicidade , Reprodução/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Desenvolvimento Embrionário/efeitos dos fármacos , Estrogênios não Esteroides/sangue , Ciclo Estral/efeitos dos fármacos , Feminino , Genitália Feminina/efeitos dos fármacos , Genitália Feminina/crescimento & desenvolvimento , Crescimento/efeitos dos fármacos , Humanos , Lactente , Alimentos Infantis , Gordura Intra-Abdominal/efeitos dos fármacos , Isoflavonas/sangue , Ratos , Ratos Wistar , Maturidade Sexual/efeitos dos fármacos , Soja , Vagina/anatomia & histologia , Vagina/efeitos dos fármacos
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