RESUMO
Myocardial fibrosis following acute myocardial infarction (AMI) seriously affects the prognosis and survival rate of patients. This study explores the role and regulation mechanism of storax, a commonly used traditional Chinese medicine for treatment of cardiovascular diseases, on myocardial fibrosis and cardiac function. The AMI rat model was established by subcutaneous injection of Isoproterenol hydrochloride (ISO). Storax (0.1, 0.2, 0.4 g/kg) was administered by gavage once/d for 7 days. Electrocardiogram, echocardiography, hemodynamic and cardiac enzyme in AMI rats were measured. HE, Masson, immunofluorescence and TUNEL staining were used to observe the degree of pathological damage, fibrosis and cardiomyocyte apoptosis in myocardial tissue, respectively. Expression of AT1R, CARP and their downstream related apoptotic proteins were detected by WB. The results demonstrated that storax could significantly improve cardiac electrophysiology and function, decrease serum cardiac enzyme activity, reduce type I and III collagen contents to improve fibrosis and alleviate myocardial pathological damage and cardiomyocyte apoptosis. It also found that storax can significantly down-regulate expression of AT1R, Ankrd1, P53, P-p53 (ser 15), Bax and cleaved Caspase-3 and up-regulate expression of Mdm2 and Bcl-2. Taken together, these findings indicated that storax effectively protected cardiomyocytes against myocardial fibrosis and cardiac dysfunction by inhibiting the AT1R-Ankrd1-P53 signaling pathway.
Assuntos
Medicamentos de Ervas Chinesas , Infarto do Miocárdio , Animais , Ratos , Apoptose , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Fibrose , Proteínas Musculares/efeitos dos fármacos , Proteínas Musculares/metabolismo , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Nucleares/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Proteínas Repressoras/efeitos dos fármacos , Proteínas Repressoras/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismoRESUMO
Increased activity of the lysine methyltransferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma and acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present the first antagonists that block the protein-protein interaction between the N-terminal PWWP domain of NSD2 and H3K36me2. Using virtual screening and experimental validation, we identified the small-molecule antagonist 3f, which binds to the NSD2-PWWP1 domain with a Kd of 3.4 µM and abrogates histone H3K36me2 binding to the PWWP1 domain in cells. This study establishes an alternative approach to targeting NSD2 and provides a small-molecule antagonist that can be further optimized into a chemical probe to better understand the cellular function of this protein.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Proteínas Repressoras/antagonistas & inibidores , Simulação por Computador , Cristalografia por Raios X , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Histona-Lisina N-Metiltransferase/efeitos dos fármacos , Humanos , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Domínios Proteicos , Proteínas Repressoras/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-AtividadeRESUMO
Flavaglines are cyclopenta[b]benzofurans found in plants of the genus Aglaia, several species of which are used in traditional Chinese medicine. These compounds target the initiation factor of translation eIF4A and the scaffold proteins prohibitins-1 and 2 (PHB1/2) to exert various pharmacological activities, including antiviral effects against several types of viruses, including coronaviruses. This review is focused on the antiviral effects of flavaglines and their therapeutic potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Assuntos
Aglaia/química , Antivirais/uso terapêutico , Produtos Biológicos/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fator de Iniciação 4A em Eucariotos/genética , Pneumonia Viral/tratamento farmacológico , Proteínas Repressoras/genética , Animais , COVID-19 , Fator de Iniciação 4A em Eucariotos/efeitos dos fármacos , Humanos , Medicina Tradicional Chinesa , Pandemias , Proibitinas , Proteínas Repressoras/efeitos dos fármacosRESUMO
The increasing incidence of antimicrobial-resistant bacterial pathogens has focused researchers on quorum sensing inhibition strategies instead of those conventional approaches to fight bacterial infections. Anti-quorum sensing (QS) activity of aqueous extract from Forsythia suspense (FSE) was assessed, and its potential QS inhibition mechanisms were also analyzed. The minimal inhibitory concentration (MIC) of FSE to Chromobacterium violaceum 12472 is 0.5 mg mL-1. Inhibition of QS-regulated violacein production and biofilm formation in C. violaceum 12472 by FSE occurred in a concentration-dependent manner at sub-MIC, with > 70.12 and > 85.31% inhibition at 0.25 mg mL-1, respectively. N-Acyl homoserine lactones (AHLs) extracted from cultures of C. violaceum 31532 grown in the presence of FSE could not change the violacein production in C. violaceum 026, which indicated that FSE did not inhibit AHL synthesis. We also found that FSE cannot degrade AHLs. Finally, in silico molecular docking was conducted. The computed binding energy data suggested that components of F. suspense have a tendency to inhibit CviR with varying binding affinities and the energy score of Pinoresinol (- 26.02 kcal/mol) is higher than that of C6-HSL (- 16.09 kcal mol-1). We concluded that FSE acts as an antagonist of bacterial quorum sensing by competing with AHL receptor binding site.
Assuntos
Chromobacterium/efeitos dos fármacos , Forsythia , Extratos Vegetais/farmacologia , Percepção de Quorum/efeitos dos fármacos , 4-Butirolactona/análogos & derivados , 4-Butirolactona/metabolismo , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Indóis/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular/métodos , Extratos Vegetais/química , Proteínas Repressoras/efeitos dos fármacos , Proteínas Repressoras/metabolismo , Transativadores/efeitos dos fármacos , Transativadores/metabolismoRESUMO
Dysregulated human monocytes/macrophages can synthesize and secrete matrix metalloproteinases (MMPs), which play important roles in the progression of sepsis. In this study, we investigated the effects and mechanism of a novel histone deacetylase (HDAC8) inhibitor, (E)-N-hydroxy-4-methoxy-2-(biphenyl-4-yl)cinnamide (WK2-16), on MMP-9 production and activation in stimulated human monocytic THP-1 cells. Our results demonstrated that the acetylation level of structural maintenance of chromosomes 3 (SMC3) was up-regulated by WK2-16 in THP-1 cells. Consistently, an in vitro enzyme study demonstrated that WK2-16 selectively inhibited HDAC8 activity. Moreover, the WK2-16 concentration dependently suppressed MMP-9-mediated gelatinolysis induced by tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS). Additionally, WK2-16 significantly inhibited both MMP-9 protein and mRNA expression without cellular toxicity. Nevertheless, WK2-16 suppressed the extracellular levels of interleukin (IL)-6 from LPS-stimulated THP-1 cells. For the signaling studies, WK2-16 had no effect on LPS/TLR4 downstream signaling pathways, such as the NF-κB and ERK/JNK/P38 MAPK pathways. On the other hand, WK2-16 enhanced the recruitment of acetylated Yin Yang 1 (YY1) with HDAC1. Finally, in vivo studies indicated that WK2-16 could reduce the serum levels of TNF-α and IL-6 in endotoxemic mice. These results suggested that HDAC8 inhibition might provide a novel therapeutic strategy of hypercytokinemia in sepsis.
Assuntos
Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/efeitos dos fármacos , Histona Desacetilases/metabolismo , Lipopolissacarídeos/farmacologia , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Repressoras/efeitos dos fármacos , Proteínas Repressoras/metabolismo , Acetilação , Animais , Proteínas de Ciclo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Ciclo-Oxigenase 2/efeitos dos fármacos , Regulação para Baixo , Endotoxemia , Histona Desacetilase 1/efeitos dos fármacos , Humanos , Interleucina-6 , Proteínas Quinases JNK Ativadas por Mitógeno/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , NF-kappa B/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/efeitos dos fármacos , Sepse/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Células THP-1/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Fator de Transcrição YY1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacosRESUMO
BACKGROUND: The scope of this work was to study synergism between human papillomavirus (HPV) infection and tobacco in vitro, both known to be independent risk factors for oral cancer. METHODS: HPV-positive and HPV-negative oral keratinocytes and oral HPV-negative fibroblasts were exposed to smokeless tobacco extract (STE) prepared from the Scandinavian (STE1) and US-type (STE2) snuff. Cell cycle profiles were determined with flow cytometry, and HPV E6/E7 mRNA expression in HPV-positive cells was assayed using RT-qPCR. RESULTS: The exposure of HPV-positive keratinocytes with STE2 increased the number of aneuploid cells from 27% to 80% of which 44% were in S-phase, while none of the diploid cells were in S-phase. The changes after STE1 exposure were less than seen after STE2: from 27% to 31% of which 34% were in S-phase. STE had no effect on HPV16 E6/E7 expression in HPV-positive keratinocytes. In oral spontaneously transformed, HPV-negative keratinocytes, the number of aneuploid cells at G2-M stage increased after STE1 and STE2 exposure from 3% to 9% and 7%, respectively. In HPV-negative oral fibroblasts, the number of cells at G2-M phase increased from 11% to 21% after STE1 and 29% after STE2 exposure. CONCLUSIONS: The effect of STE varied in the cell lines studied. STE2 increased significantly the proportion of aneuploid cells in HPV-positive oral keratinocytes, but not HPV16 E6/E7 expression. This indicates that tobacco products may enhance the effects of HPV 16 and the risk of DNA aneuploidy increasing risk to malignant transformation.
Assuntos
Aneugênicos/efeitos adversos , Aneuploidia , Transformação Celular Viral/fisiologia , Papillomavirus Humano 16/fisiologia , Queratinócitos/efeitos dos fármacos , Mucosa Bucal/efeitos dos fármacos , Extratos Vegetais/efeitos adversos , Tabaco sem Fumaça/efeitos adversos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Transformada , Diploide , Fibroblastos/efeitos dos fármacos , Fibroblastos/virologia , Fase G2/efeitos dos fármacos , Gengiva/citologia , Gengiva/virologia , Humanos , Queratinócitos/virologia , Mucosa Bucal/citologia , Mucosa Bucal/virologia , Nicotina/efeitos adversos , Proteínas Oncogênicas Virais/análise , Proteínas Oncogênicas Virais/efeitos dos fármacos , Proteínas E7 de Papillomavirus/análise , Proteínas E7 de Papillomavirus/efeitos dos fármacos , Proteínas Repressoras/análise , Proteínas Repressoras/efeitos dos fármacos , Fase S/efeitos dos fármacos , Pele/citologia , Pele/virologia , TetraploidiaRESUMO
Quorum sensing (QS) is a process by which bacteria use small molecules or peptidic signals to assess their local population densities. At sufficiently high density, bacteria can alter gene expression levels to regulate group behaviors involved in a range of important and diverse phenotypes, including virulence factor production, biofilm formation, root nodulation, and bioluminescence. Gram-negative bacteria most commonly use N-acylated l-homoserine lactones (AHLs) as their QS signals. The AHL lactone ring is hydrolyzed relatively rapidly at biological pH, and the ring-opened product is QS inactive. We seek to identify AHL analogues with heightened hydrolytic stability, and thereby potentially heightened activity, for use as non-native modulators of bacterial QS. As part of this effort, we probed the utility of thiolactone analogues in the current study as QS agonists and antagonists in Gram-negative bacteria. A focused library of thiolactone analogs was designed and rapidly synthesized in solution. We examined the activity of the library as agonists and antagonists of LuxR-type QS receptors in Pseudomonas aeruginosa (LasR), Vibrio fischeri (LuxR), and Agrobacterium tumefaciens (TraR) using bacterial reporter strains. The thiolactone library contained several highly active compounds, including some of the most active LuxR inhibitors and the most active synthetic TraR agonist reported to date. Analysis of a representative thiolactone analog revealed that its hydrolysis half-life was almost double that of its parent AHL in bacterial growth medium.
Assuntos
Acil-Butirolactonas/síntese química , Bactérias Gram-Negativas/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Percepção de Quorum/efeitos dos fármacos , Proteínas Repressoras/efeitos dos fármacos , Transativadores/efeitos dos fármacos , Acetilação , Acil-Butirolactonas/química , Acil-Butirolactonas/farmacocinética , Acil-Butirolactonas/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Genes Reporter/efeitos dos fármacos , Bactérias Gram-Negativas/genética , Bactérias Gram-Negativas/metabolismo , Hidrólise , Terapia de Alvo Molecular , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Percepção de Quorum/fisiologia , Proteínas Repressoras/agonistas , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/fisiologia , Transativadores/agonistas , Transativadores/antagonistas & inibidores , Transativadores/fisiologiaRESUMO
Quorum sensing (QS) is a cell-cell signaling mechanism that allows bacteria to monitor their population size and alter their behavior at high cell densities. Gram-negative bacteria use N-acylated L-homoserine lactones (AHLs) as their primary signals for QS. These signals are susceptible to lactone hydrolysis in biologically relevant media, and the ring-opened products are inactive QS signals. We have previously identified a range of non-native AHLs capable of strongly agonizing and antagonizing QS in Gram-negative bacteria. However, these abiotic AHLs are also prone to hydrolysis and inactivation and thereby have a relatively short time window for use (â¼12-48 h). Non-native QS modulators with reduced or no hydrolytic instability could have enhanced potencies and would be valuable as tools to study the mechanisms of QS in a range of environments (for example, on eukaryotic hosts). This study reports the design and synthesis of two libraries of new, non-hydrolyzable AHL mimics. The libraries were screened for QS modulatory activity using LasR, LuxR, and TraR bacterial reporter strains, and several new, abiotic agonists and antagonists of these receptors were identified.
Assuntos
Acil-Butirolactonas/metabolismo , Desenho de Fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Percepção de Quorum/efeitos dos fármacos , Proteínas Repressoras/efeitos dos fármacos , Transativadores/efeitos dos fármacos , Acil-Butirolactonas/síntese química , Acil-Butirolactonas/química , Acil-Butirolactonas/farmacologia , Proteínas de Bactérias/agonistas , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/efeitos dos fármacos , Proteínas de Bactérias/genética , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Genes Reporter/efeitos dos fármacos , Bactérias Gram-Negativas/fisiologia , Lactonas/metabolismo , Terapia de Alvo Molecular , Proteínas Repressoras/agonistas , Proteínas Repressoras/genética , Proteínas Repressoras/fisiologia , Transativadores/agonistas , Transativadores/antagonistas & inibidores , Transativadores/genética , Transativadores/fisiologiaAssuntos
Catequina/análogos & derivados , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Neoplasias Cutâneas/genética , Animais , Anticarcinógenos , Catequina/farmacologia , Dieta , Epiderme/química , Epigênese Genética , Humanos , Camundongos , Proteínas Nucleares/efeitos dos fármacos , Proteínas Nucleares/fisiologia , Complexo Repressor Polycomb 1 , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Repressoras/efeitos dos fármacos , Proteínas Repressoras/fisiologia , Neoplasias Cutâneas/prevenção & controle , Chá/químicaRESUMO
Jaceosidin (4',5,7-trihydroxy-3',6-dimethoxyflavone) was isolated from Artemisia argyi as a putative oncogene inhibitor. Jaceosidin inhibited binding between oncoprotein E6 of the human papillomavirus and the p53 tumor suppressor protein. In addition, jaceosidin inhibited binding between the E7 oncoprotein and the Rb tumor suppressor protein, and also inhibited the function of HPV-16 harboring cervical cancer cells, including SiHa and CaSki. Collectively, jaceosidin inhibited the functions of the E6 and E7 oncoproteins of the human papillomavirus, suggesting that this compound might be used as a potential drug for the treatment of cervical cancers associated with the human papillomavirus.
Assuntos
Artemisia , Flavonoides/farmacologia , Proteínas Oncogênicas Virais/efeitos dos fármacos , Proteínas Repressoras/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos dos fármacos , Neoplasias do Colo do Útero , Sobrevivência Celular/efeitos dos fármacos , Feminino , Flavonoides/isolamento & purificação , Humanos , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus , Folhas de Planta , Proteínas Repressoras/metabolismoRESUMO
The development of skeletal muscle in mammals is promoted by the muscle-specific basic helix-loop-helix transcription factors of the MyoD family. Evidence also suggests that there are basic helix-loop-helix proteins that specifically inhibit skeletal myogenesis, including Mtwist, Mist1, and the most recently described, MyoR. It has been suggested that MyoR expression is limited to the precursors of the skeletal muscle lineage and acts as a transcriptional repressor of the muscle differentiation program. However, our results demonstrate that MyoR is expressed in several different, nonmuscle adult tissues. Furthermore, MyoR is expressed in the embryonic ectoderm of blastocyst stage mouse embryos, well before skeletal muscle specification and even before delineation of the mesodermal germ layer. Using embryonic ectoderm analogous stem cells, we demonstrate that in these nonmuscle cells, as in skeletal muscle precursor cells, expression of MyoR is inversely correlated with the extent of cellular differentiation as induced by retinoic acid. Our preliminary results indicate that overexpression of exogenous MyoR inhibits retinoic-acid-induced differentiation in EC cells and is lethal to early mouse embryos. Our results suggest a much broader role for MyoR in the repression and/or determination of embryonic cell differentiation.
Assuntos
Diferenciação Celular/fisiologia , Ectoderma/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Camundongos/embriologia , Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/fisiologia , DNA Complementar/análise , DNA Complementar/genética , Ectoderma/citologia , Feto , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Genes Letais/efeitos dos fármacos , Genes Letais/genética , Genes Reguladores/efeitos dos fármacos , Genes Reguladores/fisiologia , Camundongos/metabolismo , Camundongos Transgênicos/genética , Camundongos Transgênicos/metabolismo , Dados de Sequência Molecular , Proteínas Musculares , Proteínas Repressoras/efeitos dos fármacos , Proteínas Repressoras/metabolismo , Homologia de Sequência de Aminoácidos , Homologia de Sequência do Ácido Nucleico , Especificidade da Espécie , Células-Tronco/citologia , Fatores de Transcrição/genética , Fatores de Transcrição/isolamento & purificação , Tretinoína/farmacologiaRESUMO
Ayurveda, the ancient Indian system of health care and medicine, has a well-organized materia medica in which plants form a dominant part. A key illustration of the exploitation of this knowledge toward the development of a modern drug is the isolation and characterization of two antihyperlipidemic compounds, Z-, and E-guggulsterone from the tree Commiphora mukul, the exudate of which has been traditionally used for mitigating lipid disorders. Here, we demonstrate that Z-guggulsterone and an analog, 80-574 currently in clinical trials, act as antagonists of the bile acid receptor (BAR), a member of the intracellular receptor superfamily. These compounds antagonize the activity of BAR in vitro, and in cell culture systems on promoters and endogenous target genes. In biochemical assays, they are able to displace coactivator peptides from the receptor in a dose-dependent manner. The mechanism by which they act as BAR antagonists is likely through their inability to recruit coactivator proteins, failure to release corepressor proteins from unliganded receptor, and ability to compete with BAR agonists to block coactivator recruitment. Our data suggest these compounds may mediate at least some of their effects via the BAR.
Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Hidroxiesteroide Desidrogenases , Hipolipemiantes/farmacologia , Glicoproteínas de Membrana , Pregnenodionas/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Células Cultivadas , Colesterol 7-alfa-Hidroxilase/efeitos dos fármacos , Colesterol 7-alfa-Hidroxilase/genética , Proteínas de Ligação a DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Isoxazóis/farmacologia , Ligantes , Fígado/efeitos dos fármacos , Fígado/metabolismo , Subunidade 1 do Complexo Mediador , Proteínas Nucleares/efeitos dos fármacos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Correpressor 1 de Receptor Nuclear , Pregnadienos/farmacologia , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores dos Hormônios Tireóideos/efeitos dos fármacos , Receptores dos Hormônios Tireóideos/metabolismo , Proteínas Repressoras/efeitos dos fármacos , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/metabolismoRESUMO
Tea catechins exert many biological effects, including anticancer and antibacterial activities. Also, it is reported that some plant flavonoids exhibit estrogenic activity. In this study, we investigated estrogenic or antiestrogenic activities of catechins in HeLa cells transiently transfected with an estrogen response element (ERE)-regulated luciferase reporter and an estrogen receptor (ER) alpha or ERbeta expression vector. Catechins alone did not induce luciferase (luc) activity in either of the ERs. Addition of 17beta-estradiol (E2) plus epicatechin gallate (ECG) or epigallocatechin gallate (EGCG) at 5 x 10(-6) M resulted in significant decreases in the ERalpha-mediated luc activity compared with that of E2 alone. On the contrary, lower concentrations significantly increased the E2-induced luc activity. Similar effects were observed with tamoxifen. The ERbeta-mediated estrogenic activities were stimulated by catechins. In conclusion, some catechins, particularly EGCG, were antiestrogenic for ERalpha at higher doses, and co-estrogenic for ERalpha at lower doses and for ERbeta. The lower doses were found in human plasma after tea-drinking. In addition, some catechins may be antiendocrine disruptors because they suppressed bisphenol A-induced luc activities.