RESUMO
Benign prostatic hypertrophy (BPH) is an intractable chronic inflammatory disease. We studied the efficacy of two ellagitannins, namely camptothin B (1) and cornusiin A (2) that were isolated from Cornus alba (CA) for the treatment of BPH, which is a common health issue in older men. The ellagitannins (1 and 2) were evaluated on its inhibitory activities of the enzyme 5α-reductase and tumor necrosis factor (TNF)-α, its interleukin (IL)-1ß, IL-6, and IL-8 production, and its anti-proliferation and apoptosis induction in prostate cells that show hypertrophy (RWPE-1 cell). In inhibition of 5α-reductase, the ellagitannins (1 and 2) showed potential effects, compared to the positive control, finasteride. In the case of IL-1ß, IL-6, IL-8, and TNF-α, 1 and 2 showed good inhibitory effects as compared to the control group treated with LPS. The ellagitannins (1 and 2) were also shown to inhibit proliferation of, and induce apoptosis in, the RWPE-1 cell. These results suggest that the ellagitannins (1 and 2) may be good candidates for the treatment of BPH.
Assuntos
Colestenona 5 alfa-Redutase/metabolismo , Cornus/química , Taninos Hidrolisáveis/farmacologia , Interleucinas/metabolismo , Hiperplasia Prostática/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Taninos Hidrolisáveis/química , Taninos Hidrolisáveis/isolamento & purificação , Masculino , Estrutura Molecular , Hiperplasia Prostática/tratamento farmacológico , Ratos , Células Th1RESUMO
The adhesion of cancer cells to the extracellular matrix (ECM) is crucial for cell proliferation, survival, and metastasis. Thus, it is necessary to inhibit cell-ECM adhesion by blocking the activation of the associated signaling to control cancer. Here, we identify erybraedin A (EBA) as a potential Src inhibitor that blocks cell adhesion and viability in non-small-cell lung cancer (NSCLC). EBA significantly inhibited the adhesion of NSCLC cells to fibronectin. EBA also markedly inhibited the activation of Src and its downstream targets, including FAK and Akt. The interaction between integrin ß1 or integrin ß3 and Src was inhibited by EBA treatment. A docking study revealed the bindings of EBA to the ATP-binding pocket and the allosteric regulatory site of the Src kinase. Additionally, EBA markedly inhibited the viability and the colony formation of NSCLC cells and induced apoptotic cell death. These results describe novel biological properties of EBA, which can block the Src-mediated adhesion and survival of NSCLC cells, suggesting the potential of EBA as an anticancer Src inhibitor that warrants further development in advanced preclinical and clinical settings.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pterocarpanos/farmacologia , Quinases da Família src/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Quinases da Família src/metabolismoRESUMO
Activity-guided isolation of 80% acetone extract of Cornus alba, which is traditionally used as an anti-inflammatory, hemostatic and diuretic in Korea, yielded one novel compound, tentatively designated cornusiin H (13), together with 12 known compounds. The known compounds included four flavonoids (catechin (1), quercetin-3-O-ß-D-glucuronide (2), quercetin-3-O-ß-D-glucopyranoside (3), kaempferol-3-O-ß-D-glucopyranoside (4)) and eight hydrolysable tannins (gallic acid (5), 2,6-di-O-galloyl-hamamelofuranoside (6), 2-galloyl-4-caffeoyl-L-threonic acid (7) 2,3-di-O-galloyl-4-caffeoyl-L-threonic acid (8), 1,2,3,4,6-penta-O-galloyl-ß-D-glucopyranoside (9), cornusiin B (10), cornusiin A (11) and camptothin B (12)). All compounds exhibited potent 1,1-diphenyl-2-picrylhydrazyl (DPPH)-free radical scavenging activity. Especially, the radical scavenging activities of 6 and 9-13 were higher than that of vitamin C. Compounds 9, 11, 12 and 13 inhibited the production of nitric oxide (NO) in lipopolysaccharide-stimulated RAW264.7 cells to the same degree as N(G)-Monomethyl-L-arginine (L-NMMA). When the antiproliferative effects of the isolated compounds were assessed in prostate cancer cells, the dimeric ellagitannins (11-13) selectively inhibited LNCaP hormone-dependent prostate cancer cells. Flow cytometry analysis indicated that the dimeric ellagitannins induced apoptosis and S-phase arrest. These results suggest that dimeric ellagitannins from Cornus alba can be developed as functional materials or herbal medicines for prostate tumors such as benign prostate hyperplasia and early-stage prostate cancer.
Assuntos
Antioxidantes/farmacologia , Cornus/química , Citostáticos/farmacologia , Taninos Hidrolisáveis/farmacologia , Neoplasias da Próstata/metabolismo , Animais , Antioxidantes/química , Apoptose , Linhagem Celular Tumoral , Citostáticos/química , Citostáticos/isolamento & purificação , Humanos , Taninos Hidrolisáveis/química , Taninos Hidrolisáveis/isolamento & purificação , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Células RAW 264.7 , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacosRESUMO
The roots of Rosa multiflora THUNB. (RM) has been used in oriental traditional medicines as remedies for scabies, rheumatic arthralgia and stomatitis which were practicably related with today's inflammatory and allergic diseases. In the present study, we evaluated whether RM root extract (RME) and its major constituent, 2-(3,4-dihydroxyphenyl)-6-(4-hydroxyphenyl)-8-(2,4-dihydroxyphenyl)-2,3-trans-6,7-cis-7,8-trans-3,4,7,8-tetrahydro-2H,6H-pyrano[2,3-f] chromene-3,7,9-triol (RM-3) belongs to condensed tannins, improve atopic dermatitis (AD)-like skin lesions in NC/Nga mice induced by mite antigen. Topical application of RME as well as RM-3 improved skin severity and suppressed mRNA levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) on skin tissues, in addition, significantly reduced T helper 2 (Th2) immune responses via interleukin 10 (IL-10) up-regulation. Thus, RME, contains lots of condensed tannins such as RM-3 which possesses potent anti-inflammtory and immune-modulatory effects, may be useful for treatment of skin allergies and can be developed as new alternative herbal therapy against AD.
Assuntos
Dermatite Atópica/tratamento farmacológico , Ácaros/imunologia , Fitoterapia , Extratos Vegetais/uso terapêutico , Proantocianidinas/uso terapêutico , Rosa/química , Pele/efeitos dos fármacos , Administração Tópica , Animais , Antígenos , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Feminino , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos , Óxido Nítrico Sintase Tipo II/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Proantocianidinas/isolamento & purificação , Proantocianidinas/farmacologia , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Pele/metabolismo , Pele/patologia , Células Th2/metabolismo , Regulação para CimaRESUMO
Three new orcinol (3-hydroxy-5-methylphenol)-conjugated hydrolysable tannins, together with two known compounds were isolated from the leaves of Cleyera japonica (CJ), and have been tentatively named cleyeratannin A (1), cleyeratannin B (2) and cleyeratannin C (3). The chemical structures of these compounds were elucidated using 1 dimensional (1D)/2D NMR and high resolution FAB-MS, and the absolute configuration was confirmed by circular dichroism (CD). To evaluate their anti-oxidative activities, 1,1-diphenyl-2-picrylhydrazyl (DPPH)/free radical scavenging activity and nitroblue tetrazolium (NBT)/superoxide anion scavenging activity were determined.
Assuntos
Antioxidantes/química , Sequestradores de Radicais Livres/química , Taninos Hidrolisáveis/química , Extratos Vegetais/química , Resorcinóis/química , Theaceae/química , Nitroazul de Tetrazólio/química , Superóxidos/químicaRESUMO
Isolation of compounds from the root of Rhodiola sachalinensis (RRS) yielded tyrosol (1), salidroside (2), multiflorin B (3), kaempferol-3,4'-di-O-ß-D-glucopyranoside (4), afzelin (5), kaempferol (6), rhodionin (7), and rhodiosin (8). Quantification of these compounds was performed by high-performance liquid chromatography (HPLC). To investigate the antioxidant and anti-inflammatory effects of the compounds, DPPH radical scavenging, NBT superoxide scavenging and nitric oxide production inhibitory activities were examined in LPS-stimulated Raw 264.7 cells. We suggest that the major active components of RRS are herbacetin glycosides, exhibiting antioxidant activity, and kaempferol, exhibiting anti-inflammatory activity.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Fenóis/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Rhodiola/química , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Óxido Nítrico/biossíntese , Picratos/antagonistas & inibidores , Superóxidos/antagonistas & inibidoresRESUMO
The roots of Rhododendron mucronulatum Turzaninov have been used in Oriental traditional medicine for the treatment of dysuria, fever, increase of digestive activity and tonics in China and Korea. Activity guided isolation of the roots of Rhododendron mucronulatum Turzaninov has led to the isolation of three flavonoids, one flavan 3-ol and one proanthocyanidin. Chemical investigation of the 80% Me2 CO extract from the roots of Rhododendron mucronulatum led to the isolation and identification of five compounds: taxifolin (1), taxifolin 3-O-ß-D-glucopyranoside (2), quercetin 3-O-α-L-arabinofuranoside (3), (-)-epicatechin (4), procyanidin B-3 (5). To investigate the antioxidative and antiinflammatory effects of these compounds, their 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities and the protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated HaCaT cells were also quantified by western blotting and their end products, nitric oxide (NO) and prostaglandin E2 (PGE2 ), respectively. Compounds (1-5) showed potent DPPH radical scavenging compared with positive controls (L-ascorbic acid). Also, compounds 1 and 2 dose-dependently inhibited the expressions of inflammatory mediators, NO and PGE2 , suggesting they are promising candidates as antiinflammatory agents.
Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Extratos Vegetais/farmacologia , Rhododendron/química , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Arabinose/análogos & derivados , Arabinose/farmacologia , Biflavonoides/farmacologia , Catequina/farmacologia , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Glucosídeos/farmacologia , Humanos , Óxido Nítrico/metabolismo , Raízes de Plantas/química , Proantocianidinas/farmacologia , Quercetina/análogos & derivados , Quercetina/farmacologiaRESUMO
Recently, the isolation of several condensed tannins from the roots of Rosa multiflora Thunberg, a traditional herbal therapy in oriental medicine for rheumatoid arthritis and scabies, was described. Two of the major condensed tannins - procyanidin B-3 (ProB3) and ent-guibourtinidol-(4ß â 6)-catechin (RM-1) - were then applied topically to atopic dermatitis-like skin lesions on NC/Nga mice in order to assess their immunomodulatory properties. Both ProB3 and RM-1 significantly reduced the serum levels of eosinophils, IgE and certain Th2 cytokines (IL-4, 5 and 13) (p < 0.05 or 0.01). Additionally, ProB3 and RM-1 significantly reduced both the mRNA and protein expression of COX-2 and iNOS in mouse skin tissues (p < 0.01). Such results strongly suggest that ProB3 and RM-1 may be useful in the treatment allergic skin conditions, most notably atopic dermatitis.
Assuntos
Biflavonoides/uso terapêutico , Catequina/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Fatores Imunológicos/farmacologia , Fitoterapia , Extratos Vegetais/uso terapêutico , Proantocianidinas/uso terapêutico , Rosa/química , Administração Tópica , Animais , Biflavonoides/farmacologia , Catequina/análogos & derivados , Catequina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/uso terapêutico , Citocinas/sangue , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Eosinófilos/metabolismo , Feminino , Imunoglobulina E/sangue , Fatores Imunológicos/uso terapêutico , Camundongos , Camundongos Endogâmicos , Óxido Nítrico Sintase Tipo II/metabolismo , Extratos Vegetais/farmacologia , Raízes de Plantas , Proantocianidinas/farmacologia , RNA Mensageiro/metabolismo , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Células Th2/metabolismoRESUMO
Atopic dermatitis (AD) is a common inflammatory skin disease. The increasing prevalence and severity of AD have prompted the developments of safer, more effective drugs. Although topical corticosteroids have been used as first line therapy for AD, their potential side effects limit their clinical applications. To investigate the effect of hirsutenone (HIR), a diarylheptanoid compound, on AD-like skin lesions and other factors related to immune response is the aim of this paper Th2-related cytokines (IL-4, IL-5, IL-13), eosinophil, IgE inflammatory factors (COX-2, iNOS) levels were reduced in blood, lymphocytes, and tissue after HIR treatment. These results suggest that HIR might be an effective treatment for AD.
Assuntos
Catecóis/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Diarileptanoides/uso terapêutico , Pele/patologia , Administração Cutânea , Animais , Catecóis/administração & dosagem , Catecóis/síntese química , Ciclo-Oxigenase 2/sangue , Diarileptanoides/administração & dosagem , Diarileptanoides/síntese química , Diarileptanoides/isolamento & purificação , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Feminino , Imunoglobulina E/sangue , Injeções Intraperitoneais , Interleucinas/sangue , Camundongos , Camundongos Endogâmicos , Óxido Nítrico Sintase Tipo II/sangueRESUMO
Increased levels of eosinphils, IgE, IL-4, 5, and 13 and pro-inflammatory factors (COX-2, iNOS) are observed in patients with atopic dermatitis (AD). Taxifolin 3-O-beta-D-glucopyranoside (TAX) from the roots of Rhododendron mucronulatum (RM) was examined to determine whether its immunomodulatory effect was applicable for treating atopic dermatitis.A total of 7 groups of NC/Nga mice with AD were treated by topical application or intraperitoneal injection of TAX for 4 weeks. Follow-up evaluations were done to assess the changes in clinical observations, eosinophil counts, and levels of IgE, cytokines, COX-2 and iNOS.In the clinical observation during the experimental period, TAX treatment significantly reduced the severity of AD-like lesions induced in NC/Nga mice. Eosinophil and IgE levels decreased after treatment of the animals with TAX. TAX may thus be associated with improvement of eosinophil-related allergic diseases. The expression of cytokines (IL-4, 5 and 13) was significantly inhibited in the TAX-treated group, suggesting that TAX might play an immunoregulatory role associated with AD. In RT-PCR, iNOS and COX-2 expression levels were reduced in the TAX-treated group. In western blotting, the expression levels of iNOS and COX-2 were also reduced in the TAX-treated group.These findings suggest that TAX is effective for the treatment of AD by preventing the production of inflammatory cytokines and by reducing skin inflammation.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Dermatite Atópica/tratamento farmacológico , Glicosídeos/farmacologia , Quercetina/análogos & derivados , Pele/efeitos dos fármacos , Animais , Ciclo-Oxigenase 2/análise , Ciclopropanos , Citocinas/sangue , Modelos Animais de Doenças , Eosinófilos/imunologia , Feminino , Imunoglobulina E/sangue , Inflamação/tratamento farmacológico , Inflamação/patologia , Camundongos , Óxido Nítrico Sintase Tipo II/análise , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Quercetina/farmacologia , Rhododendron/química , Pele/patologiaRESUMO
Three new stereoisomers of condensed tannins (1-3), and four known phenolic compounds (4-7) were isolated from the 80% acetone extract of the roots of Rosa multiflora Thunberg. The structures of these compounds were elucidated using 1D/2D NMR, high resolution (HR)-MS, and circular dichroism (CD) spectra. In order to evaluate their anti-oxidative and anti-inflammatory activities, their 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity and inhibitory activity on nitric oxide (NO) production were determined.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Proantocianidinas/química , Proantocianidinas/farmacologia , Rosa/química , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Compostos de Bifenilo/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Radicais Livres/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Óxido Nítrico/imunologia , Picratos/metabolismo , Raízes de Plantas/química , Proantocianidinas/isolamento & purificação , EstereoisomerismoRESUMO
BACKGROUND/AIM: Despite the Warburg effect, mitochondria play an essential role in the survival and maintenance of cancer cells. Thus, mitochondria have been considered a target for anticancer agents. Here, we identified a mitochondria-targeting anticancer agent from natural products. MATERIALS AND METHODS: Morphological and functional changes in mitochondria were determined by a fluorescence-based High Content Imaging System. Using human non-small cell lung cancer (NSCLC) cell lines (H1299, H226B, and A549), cell viability and colony formation assays, cell cycle analysis, and immunoblotting were performed to determine cytotoxic and proapoptotic effects of papuamine. RESULTS: Using a natural product chemical library, we identified papuamine as an active compound to inhibit viability and ATP production of NSCLC cells. Papuamine depleted intracellular ATP by causing mitochondrial dysfunction, as indicated by the loss of the mitochondrial membrane potential and increased mitochondrial superoxide generation. Papuamine significantly inhibited viability and colony formation of NSCLC cells by inducing apoptosis. CONCLUSION: Papuamine has a potential as a novel mitochondria-targeting anticancer agent.
Assuntos
Alcaloides/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mitocôndrias/patologia , Células A549 , Trifosfato de Adenosina/metabolismo , Adenilato Quinase/metabolismo , Alcaloides/química , Alcaloides/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Mitocôndrias/efeitos dos fármacos , Ensaio Tumoral de Célula-Tronco , Regulação para Cima/efeitos dos fármacosRESUMO
Activity guided fractionation of Aconitum koreanum root extract (RAK), a traditional medicine in Korea, afforded four caffeoyl derivatives, caffeic acid (1), 4,5-dicaffeoylquinic acid (2), 3,5-dicaffeoylquinic acid (3) and 3,5-dicaffeoylquinic acid methyl ester (4). In order to evaluate the anti-oxidative and anti-inflammatory effects of these compounds, their 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities and abilities to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 were examined. And the protein and mRNA levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated HaCaT cells were also quantified by Western blotting and reverse transcription-polymerase chain reaction (RT-PCR). Compounds (1-4) showed potent DPPH radical scavenging and NO inhibitory activities as compared with positive controls (L-ascorbic acid and N(G)-monomethyl-L-arginine (L-NMMA), respectively). Also, these compounds dose-dependently inhibited the expressions of iNOS and COX-2 as well as their mRNA levels.
Assuntos
Aconitum/química , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Ácidos Cafeicos/farmacologia , Óxido Nítrico/antagonistas & inibidores , Extratos Vegetais/farmacologia , Animais , Compostos de Bifenilo , Western Blotting , Técnicas de Cultura de Células , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Humanos , Queratinócitos/efeitos dos fármacos , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Camundongos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Picratos , Extratos Vegetais/química , Raízes de Plantas , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Mitochondria play a pivotal role in cancer bioenergetics and are considered a potential target for anticancer therapy. Considering the limited efficacy and toxicity of currently available mitochondria-targeting agents, it is necessary to develop effective mitochondria-targeting anticancer drugs. By screening a large chemical library consisting of natural products with diverse chemical entities, we identified gracillin, a steroidal saponin, as a mitochondria-targeting antitumor drug. Gracillin displayed broad-spectrum inhibitory effects on the viability of a large panel of human cancer cell lines, including those carrying acquired resistance to chemotherapy or EGFR-targeting drugs, by inducing apoptosis. We show that gracillin attenuates mitochondria-mediated cellular bioenergetics by suppressing ATP synthesis and by producing reactive oxygen species (ROS). Mechanistically, gracillin disrupts complex II (CII) function by abrogating succinate dehydrogenase (SDH) activity without affecting the succinate:ubiquinone reductase. The gracillin-induced cell death was potentiated by 3-nitropropionic acid (3-NPA) or thenoyltrifluoroacetone (TTFA), which inhibit CII by binding to the active site of SDHA or to the ubiquinone-binding site, respectively. Finally, we show that gracillin effectively suppressed the mutant-Kras-driven lung tumorigenesis and the growth of xenograft tumors derived from cell lines or patient tissues. Gracillin displayed no obvious pathophysiological features in mice. Collectively, gracillin has potential as a CII-targeting antitumor drug.
Assuntos
Carcinogênese/genética , Morte Celular/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Espirostanos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Morte Celular/genética , Complexo II de Transporte de Elétrons/genética , Xenoenxertos , Humanos , Neoplasias Pulmonares/genética , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Nitrocompostos/metabolismo , Oxirredução , Propionatos/metabolismo , Espécies Reativas de Oxigênio , Tenoiltrifluoracetona/metabolismoRESUMO
Chemical investigation of the 80% Me(2)CO extract from the seeds of Prunus tomentosa led to the isolation and identification of six flavonoids: kaempferol (1), kaempferol 3-O-alpha-L-rhamnopyranoside (2; afzelin), kaempferol 3-O-beta-D-(6-acetyl)-glucopyranosyl(1-->4)-alpha-L-rhamnopyranoside (3; multiflorin A), kaempferol 3-O-beta-D-glucopyranosyl(1-->4)-alpha-L-rhamnopyranoside (4; multiflorin B), quercetin 3-O-alpha-L-rhamnopyranoside (5; quercitrin), and quercetin 3-O-beta-D-glucopyranosyl (1-->4)-alpha-L-rhamnopyranoside (6; multinoside A). Anti-oxidative and inhibitory activities on nitric oxide (NO) and prostaglandin E(2) production in interferon-gamma (INF-gamma) and lipopolysaccharide (LPS)-activated RAW 264.7 cells in vitro (COX-2) of the isolated compounds were evaluated. Compounds 1, 5, and 6 exhibited potent anti-oxidative activity in the DPPH radical scavenging assay with IC(50) values of 57.2, 59.4, and 54.3 microg/mL respectively. The positive control, ascorbic acid, had an IC(50) of 55.5 mug/mL. Compounds 1, 5, and 6 also reduced COX-2 levels in a dose dependent manner with IC(50) values of 10.2, 8.7, and 9.6 microg/mL respectively, with the positive control, indomethacin, having an IC(50) of 5.1 microg/mL. All six compounds inhibited NO production in a dose dependent manner with IC(50) values of 35.1, 42.8, 40.0, 44.8, 43.7, and 43.9 microg/mL respectively, while the positive control, L-NMMA, had an IC(50) of 42.1 microg/mL.
Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Sequestradores de Radicais Livres/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico/metabolismo , Prunus , Animais , Sobrevivência Celular/efeitos dos fármacos , Cromonas/farmacologia , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/isolamento & purificação , Flavonoides/isolamento & purificação , Sequestradores de Radicais Livres/isolamento & purificação , Glicosídeos/farmacologia , Indometacina/farmacologia , Interferon gama/metabolismo , Quempferóis/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Manosídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico Sintase/metabolismo , Proantocianidinas/farmacologia , Prunus/química , Quercetina/análogos & derivados , Quercetina/farmacologia , Sementes , ômega-N-Metilarginina/farmacologiaRESUMO
Chromatographic isolation of the 80% MeOH extract of Acer ginnala (AG) yielded seven galloyl derivatives: gallic acid (1), ginnalin B (2), acertannin (3), maplexin D (4), maplexin E (5), quercetin-3-O-(2''-galloyl)-α-L-rhamnopyranoside (6), and kaempferol-3-O-(2''-galloyl)-α-L-rhamnopyranoside (7). This is the first study to report the isolation of compounds 4 and 5 from AG. Galloyl derivatives 3-7 exhibited potent radical scavenging activities, with 5 and 7 showing particularly strong inhibitory activities against nitric oxide production in lipopolysaccharides- (LPS-) stimulated RAW264.7 cells. In addition, oral administration of AG extract (500 mg/kg b.w.) improved symptoms of hyperglycemia and blunted the increases in serum GOT/GPT levels in a rat model of streptozotocin-induced diabetes. These results suggest that galloyl derivatives (1-7) are antioxidant and anti-inflammatory agents and that AG extract has potential as a functional material or novel herbal medicine for treating diabetes mellitus.
RESUMO
Purpose: Histone deacetylase inhibitors (HDI) are promising anticancer therapies; however, drug resistance limits their efficacy. Here, we investigated the molecular mechanisms underlying HDI resistance, focusing on the mechanism of HDI-mediated induction of insulin-like growth factor 2 (IGF2) based on our previous study.Experimental Design: The methylation status of CCCTC-binding factor (CTCF)-binding sites in the IGF2/H19 imprinting control region (ICR) were determined by methylation-specific PCR and bisulfite sequencing. The effectiveness of single or combinatorial blockade of DNA methyltransferase 1 (DNMT1) and histone deacetylase (HDAC) was evaluated using cell viability assay and patient-derived tumor xenograft (PDX) model.Results: HDAC inhibition by vorinostat increased acetylated STAT3 (K685), resulting in transcriptional upregulation of DNMT1 DNMT1-mediated hypermethylation of CTCF-binding sites in the IGF2/H19 ICR decreased CTCF insulator activity, leading to a transcriptional upregulation of IGF2 and activation of the insulin-like growth factor 1 receptor (IGF-1R) pathway in cells with acquired or de novo vorinostat resistance. Strategies targeting DNMT1 diminished the IGF2 expression and potentiated vorinostat sensitivity in preclinical models of lung cancer with hypermethylation in the H19/IGF2 ICR. The degree of ICR hypermethylation correlated with vorinostat resistance in patient-derived lung tumors and in patients with hematologic malignancies.Conclusions: DNMT1-mediated transcriptional upregulation of IGF2 is a novel mechanism of resistance to HDIs, highlighting the role of epigenetic deregulation of IGF2 in HDI resistance and the potential value of the H19/IGF2 ICR hypermethylation and DNMT1 expression as predictive biomarkers in HDI-based anticancer therapies. Clin Cancer Res; 23(5); 1299-311. ©2016 AACR.
Assuntos
DNA (Citosina-5-)-Metiltransferase 1/genética , Neoplasias Hematológicas/tratamento farmacológico , Fator de Crescimento Insulin-Like II/genética , Neoplasias Pulmonares/genética , RNA Longo não Codificante/genética , Animais , Fator de Ligação a CCCTC/genética , Metilação de DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Inibidores de Histona Desacetilases/efeitos adversos , Histona Desacetilases/genética , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Camundongos , Fator de Transcrição STAT3/genética , Vorinostat , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Two new phenolic compounds, 4-O-glucopyranosyl-5-O-caffeoylshikimic acid (1) and 2,3-digalloyl oregonin (2), were isolated along with eight known phenolic compounds (3-10) from an 80% acetone extract of Alnus sibirica leaves. The chemical structures of these compounds were elucidated using 1D/2D nuclear magnetic resonance and high resolution-MS. The anti-oxidative activities of these compounds were determined by assaying their 1,1-diphenyl-2-picrylhydrazyl radical and nitroblue tetrazolium superoxide anion scavenging activity. All of the isolated phenolic compounds (1-10) exhibited potent anti-oxidative activities. In particular, 2 and 4, which are diarylheptanoids, and 10 which is ellagitannin exhibited excellent anti-oxidative activities with almost the same potency as that of the positive controls L-ascorbic acid and allopurinol.
Assuntos
Alnus/química , Antioxidantes/química , Antioxidantes/farmacologia , Diarileptanoides/química , Ácido Gálico/análogos & derivados , Glucosídeos/química , Folhas de Planta/química , Ácido Chiquímico/análogos & derivados , Ácido Ascórbico/farmacologia , Compostos de Bifenilo/química , Diarileptanoides/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Ácido Gálico/química , Ácido Gálico/farmacologia , Glucosídeos/farmacologia , Taninos Hidrolisáveis/farmacologia , Espectroscopia de Ressonância Magnética , Fenóis/química , Picratos/química , Extratos Vegetais/química , Ácido Chiquímico/química , Ácido Chiquímico/farmacologia , Superóxidos/químicaRESUMO
The Hsp90 facilitates proper folding of signaling proteins associated with cancer progression, gaining attention as a target for therapeutic intervention. The natural rotenoid deguelin was identified as an Hsp90 inhibitor, but concerns about neurotoxicity have limited prospects for clinical development. In this study, we report progress on deguelin analogues that address this limitation, focusing on the novel analogue SH-1242 as a candidate to broadly target human lung cancer cells, including those that are chemoresistant or harboring KRAS mutations. In a KRAS-driven mouse model of lung cancer, SH-1242 administration reduced tumor multiplicity, volume, and load. Similarly, in human cell line-based or patient-derived tumor xenograft models, SH-1242 induced apoptosis and reduced tumor vasculature in the absence of detectable toxicity. In contrast to deguelin, SH-1242 toxicity was greatly reduced in normal cells and when administered to rats did not produce obvious histopathologic features in the brain. Mechanistic studies revealed that SH-1242 bound to the C-terminal ATP-binding pocket of Hsp90, disrupting the ability to interact with its co-chaperones and clients and triggering a degradation of client proteins without affecting Hsp70 expression. Taken together, our findings illustrate the superior properties of SH-1242 as an Hsp90 inhibitor and as an effective antitumor and minimally toxic agent, providing a foundation for advancing further preclinical and clinical studies.
Assuntos
Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Quercetin-3-O-(2â³-gallate)-α-l-rhamnopyranoside (QGR) is a new quercetin derivative which is isolated from the leaves of Acer ginnala Maxim, a native plant of Korea. Quercetin has several biological effects including antioxidative, anti-inflammatory, and anti-allergic effects. However, the topical effect of QGR on atopic dermatitis (AD) like skin lesion in NC/Nga mice has not been studied. OBJECTIVE: To evaluate the anti-inflammatory and anti-allergic effect of QGR in a murine model of atopic dermatitis. METHODS: We measured inducible nitric oxide synthase (iNOS) and cyclooxygenase -2(COX-2) level in RAW264.7 cell with QGR treatment. And after induction of AD like skin lesions with Dermatophagoides farina (Df) ointment, mice were treated with QGR and control drugs. Clinical scores, interleukin (IL) 4, 5, and 13, serum IgE, eosinophil levels, iNOS and COX-2 level were evaluated. RESULTS: Results show that mRNA level of iNOS and COX-2 in vitro were decreased after QGR treatment. Topical QGR markedly decreased the iNOS and COX-2 mRNA expressions in the skin. QGR also significantly suppressed the increase in the level of total plasma IgE and eosinophils. In addition, topical application of QGR down-regulated the expressions of the cytokines, IL-4,5 and 13, which were induced by Df ointment stimulation. CONCLUSIONS: In the present study, we showed that topical application of QGR ameliorated Df-induced AD-like inflammatory responses in NC/Nga mice. These results demonstrate that QGR might be beneficial in the treatment of AD.