RESUMO
It has been well established that estrogen plays an important role in the progression and treatment of breast cancer. However, the role of triiodothyronine (T3) remains controversial. We have previously shown its capacity to stimulate the development of positive estrogen receptor breast carcinoma, induce the expression of genes (PR, TGF-alpha) normally stimulated by estradiol (E2), and suppress genes (TGF-beta) normally inhibited by E2. Since T3 regulates growth hormones, metabolism, and differentiation, it is important to verify its action on other genes normally induced by E2. Therefore, we used DNA microarrays to compare gene expression patterns in MCF-7 breast adenocarcinoma cells treated with E2 and T3. Several genes were modulated by both E2 and T3 in MCF-7 cells (Student's t-test, P < 0.05). Specifically, we found eight genes that were differentially expressed after treatment with both E2 and T3, including amphiregulin, fibulin 1, claudin 6, pericentriolar material 1, premature ovarian failure 1B, factor for adipocyte differentiation-104, sterile alpha motif domain containing 9, and likely ortholog of rat vacuole membrane protein 1 (fold change > 2.0, pFDR < 0.05). We confirmed our microarray results by real-time PCR. Our findings reveal that certain genes in MCF-7 cells can be regulated by both E2 and T3.
Assuntos
Neoplasias da Mama/genética , Carcinoma/genética , Estrogênios/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Tri-Iodotironina/farmacologia , Feminino , Humanos , Células MCF-7 , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Coumarins, also known as benzopyrones, are plant-derived products with several pharmacological properties, including antioxidant and anti-inflammatory activities. Based on the wide distribution of coumarin derivatives in plant-based foods and beverages in the human diet, our objective was to evaluate both the antioxidant and intestinal anti-inflammatory activities of six coumarin derivatives of plant origin (scopoletin, scoparone, fraxetin, 4-methyl-umbeliferone, esculin and daphnetin) to verify if potential intestinal anti-inflammatory activity was related to antioxidant properties. METHODS: Intestinal inflammation was induced by intracolonic instillation of TNBS in rats. The animals were treated with coumarins by oral route. The animals were killed 48 h after colitis induction. The colonic segments were obtained after laparotomy and macroscopic and biochemical parameters (determination of glutathione level and myeloperoxidase and alkaline phosphatase activities) were evaluated. The antioxidant properties of these coumarins were examined by lipid peroxidation and DPPH assays. RESULTS: Treatment with esculin, scoparone and daphnetin produced the best protective effects. All coumarin derivatives showed antioxidant activity in the DPPH assay, while daphnetin and fraxetin also showed antioxidant activity by inhibiting lipid peroxidation. Coumarins, except 4-methyl-umbeliferone, also showed antioxidant activity through the counteraction of glutathione levels or through the inhibition of myeloperoxidase activity. DISCUSSION: The intestinal anti-inflammatory activity of coumarin derivatives were related to their antioxidant properties, suggesting that consumption of coumarins and/or foods rich in coumarin derivatives, particularly daphnetin, esculin and scoparone, could prevent intestinal inflammatory disease.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Colite/metabolismo , Colo/efeitos dos fármacos , Cumarínicos/farmacologia , Fitoterapia , Extratos Vegetais/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Compostos de Bifenilo/metabolismo , Colite/etiologia , Colite/prevenção & controle , Colo/metabolismo , Cumarínicos/uso terapêutico , Esculina/farmacologia , Esculina/uso terapêutico , Glutationa/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/prevenção & controle , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Picratos/metabolismo , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Umbeliferonas/farmacologia , Umbeliferonas/uso terapêuticoRESUMO
Baccharis dracunculifolia DC (Asteraceae) is a Brazilian medicinal plant popularly used for its antiulcer and anti-inflammatory properties. This plant is the main botanical source of Brazilian green propolis, a natural product incorporated into food and beverages to improve health. The present study aimed to investigate the chemical profile and intestinal anti-inflammatory activity of B. dracunculifolia extract on experimental ulcerative colitis induced by trinitrobenzenosulfonic acid (TNBS). Colonic damage was evaluated macroscopically and biochemically through its evaluation of glutathione content and its myeloperoxidase (MPO) and alkaline phosphatase activities. Additional in vitro experiments were performed in order to test the antioxidant activity by inhibition of induced lipid peroxidation in the rat brain membrane. Phytochemical analysis was performed by HPLC using authentic standards. The administration of plant extract (5 and 50 mg kg(-1)) significantly attenuated the colonic damage induced by TNBS as evidenced both macroscopically and biochemically. This beneficial effect can be associated with an improvement in the colonic oxidative status, since plant extract prevented glutathione depletion, inhibited lipid peroxidation and reduced MPO activity. Caffeic acid, p-coumaric acid, aromadendrin-4-O-methyl ether, 3-prenyl-p-coumaric acid, 3,5-diprenyl-p-coumaric acid and baccharin were detected in the plant extract.
RESUMO
OBJECTIVE: To better understand the estrogen (E2) agonist action of triiodothyronine (T3) the effects of these hormones on ER negative MDA-MB-231 breast cancer cells were compared with those on S30, a clone of MDA-MB-231 stably transfected with ERalpha cDNA, in terms of proliferation and modulation of hormone receptors. RESULTS: Growth experiments showed that MDA-MB-231 was not modulated by any hormone or tamoxifen (TAM). Treatment with E2, 10(-8)M or 10(-9)M had little effect on S30 proliferation. T3 at 10(-8)M significantly inhibited proliferation. This effect was not reverted by TAM. Treatments with 10(-8)M concentration of E2 or T3 reduced ERalpha gene expression in S30, an effect partially blocked by association with TAM, with no effect on TR expression. These results suggest that, in S30, 10(-8)M T3 has a similar action to E2 relative to ERalpha gene modulation. CONCLUSIONS: Such results emphasize the need of determining T3 levels, before the introduction of antiestrogenic forms of treatment in breast cancer patients.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Estradiol/farmacologia , Receptores de Estrogênio/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Tri-Iodotironina/farmacologia , Análise de Variância , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Células Clonais , Antagonistas de Estrogênios/farmacologia , Feminino , Humanos , Receptores de Estrogênio/genética , Receptores dos Hormônios Tireóideos/genética , Tamoxifeno/farmacologiaRESUMO
OBJECTIVE: To better understand the estrogen (E2) agonist action of triiodothyronine (T3) the effects of these hormones on ER negative MDA-MB-231 breast cancer cells were compared with those on S30, a clone of MDA-MB-231 stably transfected with ERα cDNA, in terms of proliferation and modulation of hormone receptors. RESULTS: Growth experiments showed that MDA-MB-231 was not modulated by any hormone or tamoxifen (TAM). Treatment with E2, 10-8M or 10-9M had little effect on S30 proliferation. T3 at 10-8M significantly inhibited proliferation. This effect was not reverted by TAM. Treatments with 10-8M concentration of E2 or T3 reduced ERα gene expression in S30, an effect partially blocked by association with TAM, with no effect on TR expression. These results suggest that, in S30, 10-8M T3 has a similar action to E2 relative to ERα gene modulation. CONCLUSIONS: Such results emphasize the need of determining T3 levels, before the introduction of antiestrogenic forms of treatment in breast cancer patients.
OBJETIVO: Para compreender melhor a ação da triiodotironina (T3) agonista de estrógeno (E2), foram comparados os efeitos destes hormônios em células de câncer de mama MDA-MB-231 ER negativas com um clone de MDA-MB-231, transfectado estavelmente com o cDNA de ERα (S30), em termos de proliferação e modulação dos receptores hormonais. RESULTADOS: Experimentos de crescimento mostraram que MDA-MB-231 não foi modulada por qualquer hormônio ou pelo tamoxifeno (TAM). O crescimento de S30 foi essencialmente inalterado por tratamento com E2 10-9M ou 10-8M, mas T3 10-8M inibiu significativamente a proliferação quando comparada a ambas concentrações de E2. Esse efeito não foi revertido pelo TAM, sugerindo um resultado não genômico, independente de ERE. Tratamentos com 10-8M de E2 ou de T3 reduziram a expressão do gene ERα em S30, efeito parcialmente impedido pela associação com TAM, sem efeito na expressão de TR. Os resultados sugerem que, em S30, T3 10-8M tem ação semelhante ao E2 com relação à modulação do gene ERα. CONCLUSÕES: Esses resultados enfatizam a necessidade de dosagem de T3 circulante antes da introdução do tratamento antiestrogênico no câncer de mama.
Assuntos
Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Estradiol/farmacologia , Receptores de Estrogênio/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Tri-Iodotironina/farmacologia , Análise de Variância , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Células Clonais , Antagonistas de Estrogênios/farmacologia , Receptores de Estrogênio/genética , Receptores dos Hormônios Tireóideos/genética , Tamoxifeno/farmacologiaRESUMO
Coumarins represent an important class of phenolic compounds with multiple biological activities, including inhibition of lipidic peroxidation and neutrophil-dependent anion superoxide generation, anti-inflammatory and immunosuppressor actions. All of these proprieties are essential for that a drug may be used in the treatment of inflammatory bowel disease. The present study examined intestinal anti-inflammatory activity of coumarin and its derivative, the 4-hydroxycoumarin on experimental ulcerative colitis in rats. This was performed in two different experimental settings, i.e. when the colonic mucosa is intact or when the mucosa is in process of recovery after an initial insult. The results obtained revealed that the coumarin and 4-hydroxycoumarin, at doses of 5 and 25 mg/kg, significantly attenuated the colonic damage induced by trinitrobenzenesulphonic acid (TNBS) in both situations, as evidenced macroscopically, microscopically and biochemically. This effect was related to an improvement in the colonic oxidative status, since coumarin and 4-hydroxycoumarin prevented the glutathione depletion that occurred as a consequence of the colonic inflammation.