RESUMO
Two new aminocyclitol amide derivatives, nabscessins A (1) and B (2), were isolated from the culture broth of a pathogenic actinomycete species, Nocardia abscessus IFM 10029T. The structures of nabscessins A and B were elucidated by spectral studies, and the compounds showed antifungal activity against Cryptococcus neoformans, with IC50 values of 32 and 16 µg/mL, respectively.
Assuntos
Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Ciclitóis/isolamento & purificação , Nocardia/química , Actinobacteria/química , Antifúngicos/química , Cryptococcus neoformans/efeitos dos fármacos , Ciclitóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Filogenia , RNA Ribossômico 16S/químicaRESUMO
B-Cell-specific Moloney murine leukemia virus insertion region 1 (BMI1) is a core component of the polycomb repressive complex 1 (PRC1). Abnormal expression of BMI1 is associated with a number of human malignances and cancer stem cells (CSCs), which cause chemotherapy resistance. Therefore, small molecules that inhibit BMI1 expression are potential candidates for cancer therapy. In this study, a cell-based reporter gene assay was developed that allowed BMI1 promoter activity to be measured in 293T human embryonic kidney cells based on luciferase expression levels. Using this screening assay, the methanol-soluble extracts of Beaumontia murtonii and Eugenia operculata were selected as leads. Bioassay-guided fractionation of the extracts led to the isolation of three known cardenolides (1-3) and one new compound (4) from B. murtonii and two known triterpenoids (5 and 6) and one new compound (7) from E. operculata. These seven compounds inhibited BMI1 promoter activity (IC50 range 0.093-23.0 µM), and the most active compound, wallichoside (1), was further evaluated. Western blot analysis revealed that wallichoside (1) decreases BMI1 protein levels in HCT116 human colon carcinoma cells, and flow cytometry analysis showed that it significantly reduced levels of the CSC biomarker epithelial cell adhesion molecule. Wallichoside (1) also inhibited sphere formation of Huh7 human hepatocellular carcinoma cells, indicating that it diminished the self-renewal capability of CSCs.
Assuntos
Apocynaceae/química , Eugenia/química , Complexo Repressor Polycomb 1/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Western Blotting , Carcinoma Hepatocelular/tratamento farmacológico , Cardenolídeos/química , Cardenolídeos/isolamento & purificação , Cardenolídeos/farmacologia , Linhagem Celular Tumoral , Células HCT116 , Células HEK293 , Humanos , Concentração Inibidora 50 , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Estrutura Molecular , Células-Tronco Neoplásicas/efeitos dos fármacos , Folhas de Planta/química , Tailândia , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologiaRESUMO
Hairy and enhancer of split 1 (Hes1) is a transcription factor that acts in neural stem cells to inhibit differentiation. We recently developed target protein oriented natural products isolation (TPO-NAPI) using Hes1-immobilized beads to identify activators of neural stem cells. Isomicromonolactam (1), staurosporin (2), and linarin (3) were isolated as Hes1-binding compounds using the TPO-NAPI method. Of these, compound 1 enhanced neural stem cell differentiation. Using truncated Hes1 proteins, the binding region of Hes1 for 1 was estimated to be in the C-terminal half that includes a TLE/Grg binding site. The differentiation-promoting activity of inohanamine (4) is also reported.
Assuntos
Produtos Biológicos/química , Lactamas/química , Componentes Aéreos da Planta/química , Fatores de Transcrição HES-1/metabolismo , Animais , Bangladesh , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Produtos Biológicos/metabolismo , Diferenciação Celular , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos , Estrutura Molecular , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Ressonância Magnética Nuclear BiomolecularRESUMO
Heronamides are a class of potent antifungal metabolites produced by marine-derived actinomycetes. The number of hydroxy groups and the stereochemistry of the two hydroxylated methine carbons are important for the activity of heronamide C, whereas the effect of the hydrocarbon chains is not known. In this study, the stereochemistry and the biological activity of BE-14106, another member of the heronamide class of antibiotics, isolated from an actinomycete Actinoalloteichus cyanogriseus IFM 11549 was investigated. Spectroscopic analysis coupled with photo- and O2-induced conversion revealed that BE-14106 and the heronamides had the same stereochemistry. BE-14106 showed potent growth inhibition against fission yeast cells with an MIC value of 0.50 µM (0.21 µg/mL), being 4 times less potent than heronamide C, which revealed the importance of the structure of the hydrocarbon tail for the activity.
Assuntos
Actinobacteria/química , Antibacterianos/isolamento & purificação , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Lactamas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Lactamas/química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Biologia Marinha , Estrutura Molecular , Schizosaccharomyces/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A new bis-aporphine alkaloid, cerasoidine (1), was isolated from the root extract of Polyalthia cerasoides together with the known bis-aporphine bidebiline E (2) during screening for compounds with Wnt signal inhibitory activities. The structure of cerasoidine (1) was established by X-ray analysis and shown by chiral HPLC analyses and electronic circular dichroism to be a 57:43 mixture of R(-)- and S(+)-atropisomers. Bidebiline E (2) exhibited inhibition of transcriptional activity of TCF/ß-catenin with an IC50 value of 20.2 µM and was also found to inhibit Wnt signaling by decreasing nuclear ß-catenin.
Assuntos
Alcaloides/isolamento & purificação , Aporfinas/isolamento & purificação , Aporfinas/farmacologia , Polyalthia/química , Proteínas Wnt/efeitos dos fármacos , Alcaloides/química , Alcaloides/farmacologia , Aporfinas/química , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Raízes de Plantas/química , Fator 1 de Transcrição de Linfócitos T/antagonistas & inibidores , Tailândia , beta Catenina/antagonistas & inibidoresRESUMO
TRAIL is a potent and selective inducer of apoptosis in most cancer cells while sparing normal cells, which makes it an attractive target for the development of new cancer therapies. In a screening program on natural resources with the ability to abrogate TRAIL resistance, the bioassay-guided fractionation of Boesenbergia pandurata rhizomes resulted in the isolation of 17 pimarane diterpenes and a monoterpene. Among these, compounds 1-8, named boesenberols A-H, are new pimarane diterpenes. All compounds exhibited TRAIL-resistance-overcoming activity in TRAIL-resistant AGS cells. Subtoxic doses of the major compound 9 sensitized AGS cells to TRAIL-induced apoptosis by up-regulating apoptosis-inducing proteins, such as DR4, DR5, p53, Fas, CHOP, Bak, and cleaved caspases-3, -8, and -9, and down-regulating the levels of cell survival proteins, such as Bcl-2, c-FLIP, and GSK-3ß, in TRAIL-resistant AGS cells. Furthermore, compound 9 did not decrease the viability of noncancerous (HEK293) cells at concentrations up to 30 µM.
Assuntos
Abietanos/isolamento & purificação , Abietanos/farmacologia , Monoterpenos/isolamento & purificação , Monoterpenos/farmacologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/efeitos dos fármacos , Abietanos/química , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Humanos , Estrutura Molecular , Monoterpenos/química , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Rizoma/química , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Tailândia , ZingiberaceaeRESUMO
The Wnt signal pathway modulates numerous biological processes, and its aberrant activation is related to various diseases. Therefore, inhibition of the Wnt signal may provide an effective (or efficient) strategy for these diseases. Cell-based luciferase assay targeting the Wnt signal (TOP assay) revealed that Hibiscus ficulneus extract inhibited the Wnt signal. The activity-guided isolation of the MeOH extract of H. ficulneus stems yielded four known (1-4) lignans along with myriceric acid (5). Compounds 1-4 potently inhibited the Wnt signal with TOPflash IC50 values of 1.0, 4.5, 6.3, and 1.9 µM, respectively. Compound 1 exhibited cytotoxicity against both Wnt-dependent (HCT116) and Wnt-independent (RKO) cells. Western blot analysis showed that 1 decreased the expression of full, cytosolic and nuclear ß-catenin along with c-myc in STF/293 cells. Our results suggested that 1 may have inhibited the Wnt signal by decreasing ß-catenin levels.
Assuntos
Hibiscus/metabolismo , Lignanas/farmacologia , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células HCT116 , Células HEK293 , Humanos , Lignanas/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , beta Catenina/metabolismoRESUMO
The ability of TRAIL to selectively induce apoptosis in cancer cells while sparing normal cells makes it an attractive target for the development of new cancer therapy. In search of bioactive natural products for overcoming TRAIL-resistance from natural resources, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionations of the extract of Xanthium strumarium led to the isolation of five sesquiterpene compounds (1-5). 11α,13-dihydroxanthinin (2) and 11α,13-dihydroxanthuminol (3) were first isolated from natural resources and xanthinosin (1), desacetylxanthanol (4), and lasidiol p-methoxybenzoate (5) were known compounds. All compounds (1-5) showed potent TRAIL-resistance overcoming activity at 8, 20, 20, 16, and 16 µM, respectively, in TRAIL-resistant AGS cells. Compounds 1 and 5 enhanced the levels of apoptosis inducing proteins DR4, DR5, p53, CHOP, Bax, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 and also decreased the levels of cell survival protein Bcl-2 in TRAIL-resistant AGS cells in a dose-dependent manner. Compound 1 also enhanced the levels of DR4 and DR5 proteins in a time-dependent manner. Thus, compounds 1 and 5 were found to induce both extrinsic and intrinsic apoptotic cell death. Compound 1 also exhibit TRAIL-resistance overcoming activity in DLD1, DU145, HeLa, and MCF7 cells but did not decrease viability in non-cancer HEK293 cells up to 8 µM.
Assuntos
Antineoplásicos Fitogênicos/química , Sesquiterpenos/química , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Xanthium/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Células HeLa , Humanos , Células MCF-7 , Espectroscopia de Ressonância Magnética , Conformação Molecular , Folhas de Planta/química , Folhas de Planta/metabolismo , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/toxicidade , Proteína Supressora de Tumor p53/metabolismo , Xanthium/metabolismoRESUMO
Facial skin blood flow (SkBF) has attracted attention as an autonomic indicator because it influences facial colour, which informs others of emotional states, and facial temperature related to social anxiety. Previous studies have examined the facial SkBF in people experiencing emotions; however, facial SkBF changes in the observers of emotions are poorly understood. Our study clarified facial SkBF changes related to observing others' emotions by comparing the changes with other physiological indices. Thirty healthy participants (24 females; mean age: 22.17) observed six types of facial expressions (neutral, angry, and embarrassed expressions with and without facial blushing) and rated the emotional intensity of the other person. We measured their facial SkBF, finger SkBF, and cardiac RR interval as they made their observations. Facial SkBF generally decreased in relation to observing emotional faces (angry and embarrassed faces) and significantly decreased for angry expressions with blushing. None of the participants noticed blushing of facial stimuli. For the RR interval and finger SkBF, there was no variation depending on the observed facial expressions, although there was a general increase related to observation. These results indicated that facial SkBF is sensitive and reactive to emotional faces-especially angry faces with blushing- compared with other autonomic indices. The facial SkBF changes were not related to either RR interval changes or the intensity rating, suggesting that facial SkBF changes may be caused by vasoconstriction and have potential functions for our emotions. The decrease in facial SkBF may have a role in calming observers by preventing them from adopting the same emotional state as a person with intense anger. These findings clarify daily facial SkBF fluctuations and their relationship with our emotional processing in interpersonal situations.
RESUMO
Although vaccines have been effective against the worldwide pandemic of Coronavirus Disease 19 (COVID-19), some case reports have described autoimmune hepatitis triggered by COVID-19 vaccination. Meanwhile, hepatitis C virus (HCV) is known to be related to autoimmune diseases. Here, we report a case of autoimmune hepatitis with history of HCV treatment triggered by COVID-19 vaccination. An 82-year-old woman was referred to our hospital for severe liver injury. She had received a COVID-19 vaccination 7 days prior. She had a history of HCV treatment with direct-acting antivirals 7 years previously. In her blood data, despite HCV antibody positivity, she was negative for HCV RNA by real-time RT-PCR. Anti-nuclear antibody was positive and IgG was elevated. Interface hepatitis and plasma cell infiltration were confirmed pathologically. She was diagnosed as autoimmune hepatitis and her liver injury quickly improved after initiation of steroid administration. This is a first case report of autoimmune hepatitis with history of HCV treatment triggered by COVID-19 vaccination.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Hepatite C Crônica , Hepatite Autoimune , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Feminino , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite Autoimune/etiologia , Humanos , Vacinação/efeitos adversosRESUMO
Neurons in the cerebral cortex are not homogeneous. However, neuronal types have been ignored in most previous work studying neuronal processes in behaving monkeys. We propose a new method to identify neuronal types in extracellular recording studies of behaving monkeys. We classified neurons as either bursting or non-bursting, and then classified the bursting neurons into three types: (i) neurons displaying a burst of many spikes (maximum number of spikes within a burst; NSB max > or = 8) at a high discharge rate (maximum interspike interval; ISI max < 5 ms); (ii) neurons displaying a burst of fewer spikes (NSB max < or = 5) at a high discharge rate (ISI max < 5 ms); and (iii) neurons displaying a burst of a few spikes (NSB max < or = 7) at relatively long ISIs (ISI max > 5 ms). We found that the discharge patterns of the four groups corresponded to those of regular spiking (RS), fast spiking (FS), fast rhythmic bursting (FRB) and intrinsic bursting (IB) neurons demonstrated in intracellular recording studies using in vitro slice preparations, respectively. In addition, we examined correlations with the task events for neurons recorded in the frontal eye field and neuronal interactions for pairs of neurons recorded simultaneously from a single electrode. We found that they were substantially different between RS and FS types. These results suggest that neurons in the frontal cortex of behaving monkeys can be classified into four types based on their discharge patterns, and that these four types contribute differentially to cortical operations.
Assuntos
Potenciais de Ação/fisiologia , Lobo Frontal/citologia , Neurônios/classificação , Neurônios/fisiologia , Vigília/fisiologia , Animais , Comportamento Animal , Movimentos Oculares/fisiologia , Macaca mulatta , Estimulação Luminosa/métodos , Recompensa , Estatística como Assunto , Estatísticas não ParamétricasRESUMO
A new amide, named dehydropropylpantothenamide (1), was obtained by a co-culture of Nocardia tenerifensis IFM 10554T in the presence of the mouse macrophage-like cell line J774.1 in modified Czapek-Dox (mCD) medium. Compound 1 was synthesized from D-pantothenic acid calcium salt in 6 steps. The absolute configuration of natural compound 1 was determined by comparisons of the optical rotation and CD spectra of synthetic 1. In the present study, a new method for producing secondary metabolites was demonstrated using a "co-culture" in which the genus Nocardia was cultured in the presence of an animal cell line.
Assuntos
Nocardia/metabolismo , Ácido Pantotênico/análogos & derivados , Ácido Pantotênico/isolamento & purificação , Animais , Proteínas de Bactérias/genética , Vias Biossintéticas , Linhagem Celular , Técnicas de Cocultura , Interações Hospedeiro-Patógeno , Macrófagos/microbiologia , Camundongos , Nocardia/genética , Nocardiose/metabolismo , Nocardiose/microbiologia , Ácido Pantotênico/biossíntese , Ácido Pantotênico/química , FilogeniaRESUMO
Chemical investigations of the ethyl acetate extract of Streptomyces sp. IFM 11490 have led to the isolation of six new angucycline metabolites, named elmenols C-H (1-6), along with the previously reported elmonin (7) and elmenols A (8) and B (9). The known LS1924A (10), 6-deoxy-8-methylrabelomycin (11), tetrangulol methyl ether (12) and angucyclinone (13) were additionally identified. The structures of the isolated compounds were elucidated by means of spectroscopic methods including UV, IR, HRESIMS, and 1D and 2D NMR. Compounds 1-6 were evaluated for their abilities to overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in human gastric adenocarcinoma (AGS) cells. Compounds 5 (10 µm) and 6 (50 µm) in combination with TRAIL showed moderate activity in sensitizing TRAIL-resistant AGS cells.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Streptomyces/metabolismo , Adenocarcinoma/patologia , Antraquinonas/química , Antraquinonas/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Análise Espectral/métodos , Neoplasias Gástricas/patologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologiaRESUMO
Gemcitabine hydrochloride (GEM) is a first-line therapeutic agent for advanced pancreatic cancer, but there is no established second-line treatment after GEM failure. We assessed the clinical benefit of systemic combined chemotherapy with 5-fluorouracil and cisplatin (FP therapy) in 19 patients compared with GEM in 32 patients, respectively. Tumor response rates were 10.5% and 15.6% for FP therapy and GEM, respectively. The median survival time in the FP therapy and GEM was 137 days and 241 days, respectively. Although clinical benefit was similar in both types of therapy, median survival time was more favorable for GEM, especially for Stage IVb. Nausea and vomiting were the most commonly observed toxicity in the FP therapy group. Our data indicate that FP therapy is not considered to be a useful second-line agent in patients with GEM pretreated pancreatic cancer.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , GencitabinaRESUMO
One new alkyl sulfonic acid derivative, sulfotanone (1), and the known panosialin wA (2) were isolated from the methanolic extract of mycelium of Streptomyces sp. 11694. The structure of the new compound (1) was established by a combination of spectroscopic techniques, including HRESIMS, IR, 1D and 2D NMR measurements. Compound 1 (40 µM) in combination with TRAIL showed synergistic activity in sensitizing TRAIL-resistance in human gastric adenocarcinoma cell lines.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Streptomyces/química , Ácidos Sulfônicos/uso terapêutico , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Derivados de Benzeno/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Ácidos Sulfônicos/química , Ácidos Sulfônicos/isolamento & purificação , Ácidos Sulfônicos/farmacologiaRESUMO
Two new phenazine derivatives, aotaphenazine (1) and 5,10-dihydrophencomycin (2), were isolated from the ethyl acetate extract of Streptomyces sp. IFM 11694. In addition, the known 1-phenazinecarboxylic acid (3), phencomycin (4) and 1,6-phenazinedicarboxylic acid (5) were identified. The structures of the isolated compounds (1-5) were characterized by spectroscopic methods including NMR and mass spectrometry data. Compound 1 showed the ability to overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance at concentration of 12.5 µM. Aotaphenazine (1) enhanced the levels of apoptosis inducing proteins DR4, DR5, p53 and also decreased the levels of cell survival protein Bcl-2 in TRAIL-resistant human gastric adenocarcinoma (AGS) cells in a dose-dependent manner.
Assuntos
Adenocarcinoma/tratamento farmacológico , Fenazinas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Streptomyces/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Adenocarcinoma/patologia , Antineoplásicos/administração & dosagem , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Humanos , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Fenazinas/administração & dosagem , Fenazinas/isolamento & purificação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias Gástricas/patologiaRESUMO
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has emerged as a promising anticancer agent because of its ability to selectively kill tumor cells. But TRAIL-resistance is a major problem of its therapy. A search for compounds for abrogating TRAIL-resistance has, thus, become an important strategy for anticancer drug discovery. In search of bioactive natural products for overcoming TRAIL-resistance, we previously reported some compounds with TRAIL-resistance overcoming activity. Bioassay guided fractionation of Entada scandens led to the isolation of four compounds (1-4). Of the isolates, compounds 1 and 3 showed moderate TRAIL-resistance overcoming activity in TRAIL-resistant human gastric adenocarcinoma (AGS) cells.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fabaceae/química , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Antineoplásicos Fitogênicos/química , Produtos Biológicos , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Estrutura MolecularRESUMO
TRAIL is a potent inducer of apoptosis in most cancer cells, but not in normal cells, and therefore has deserved intense interest as a promising agent for cancer therapy. In the search for bioactive natural products for overcoming TRAIL-resistance, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionation of the MeOH extract of Datura stramonium leaves led to the isolation of three alkaloids--scopolamine (1), trigonelline (2), and tyramine (3). Compounds 1, 2, and 3 exhibited TRAIL-resistance overcoming activity at 50, 150, and 100 µM, respectively in TRAIL-resistant AGS cells.
Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Bioensaio/métodos , Datura stramonium/química , Regulação da Expressão Gênica/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Alcaloides/química , Antineoplásicos Fitogênicos/química , Linhagem Celular , Sobrevivência Celular , Resistencia a Medicamentos Antineoplásicos , Humanos , Extratos Vegetais/químicaRESUMO
The Hes1 dimer inhibitor, agalloside (2), which can accelerate the differentiation of neural stem cells is described. Six natural products, including one new natural product, which bind to Hes1 were rapidly isolated by a developed "target protein oriented natural products isolation" (TPO-NAPI) method using Hes1-immobilized beads. Of the six compounds, 2 inhibited Hes1 dimer formation at both the protein- and cellular level. Neural stem cells treated with 2 differentiated to neurons with longer neurites than cells treated with varproic acid or retinoic acid. Moreover, 2 exhibited specificity for neurons. This promotion of differentiation was supported by an increase in the mRNA expression of the proneural genes, Mash1 and Ngn2, which were inhibited by Hes1.