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1.
Sci Rep ; 11(1): 10654, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34017038

RESUMO

The purpose of this study was to determine if a methanolic extract of the Pulsatilla patens (L.) Mill. can inhibit the progression of cancer through the modulation of cancer-related metabolic signaling pathways. We analyzed a panel of 13 inducible luciferase reporter gene vectors which expression is driven by enhancer elements that bind to specific transcription factors for the evaluation of the activity of cancer signaling pathways. The root extract of P. patens exhibited strong inhibition of several signaling pathways in HeLa cells, a cervical cancer cell line, and was found to be the most potent in inhibiting the activation of Stat3, Smad, AP-1, NF-κB, MYC, Ets, Wnt and Hdghog, at a concentration of 40 µg/mL. The methanolic extracts of P. patens enhanced apoptotic death, deregulated cellular proliferation, differentiation, and progression towards the neoplastic phenotype by altering key signaling molecules required for cell cycle progression. This is the first study to report the influence of Pulsatilla species on cancer signaling pathways. Further, our detailed phytochemical analysis of the methanolic extracts of the P. patens allowed to deduce that compounds, which strongly suppressed the growth and proliferation of HeLa cancer cells were mainly triterpenoid saponins accompanied by phenolic acids.


Assuntos
Neoplasias/metabolismo , Extratos Vegetais/farmacologia , Pulsatilla/química , Transdução de Sinais , Morte Celular/efeitos dos fármacos , Ácidos Cumáricos/farmacologia , Genes Reporter , Células HeLa , Humanos , Limite de Detecção , Luciferases/metabolismo , Metanol , Proteínas de Neoplasias/metabolismo , Neoplasias/patologia , Raízes de Plantas/química , Reprodutibilidade dos Testes , Saponinas/química , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/química , Triterpenos/farmacologia
2.
Molecules ; 26(3)2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33572569

RESUMO

The anticancer activities of Rubia cordifolia and its constituents have been reported earlier, but their influence on the crosstalk of complex cancer-related signaling metabolic pathways (i.e., transcription factors; TF) has not yet been fully investigated. In this study, R. cordifolia root extract was subjected to the cancer signaling assay based bioactivity-guided fractionation, which yielded the following compounds viz., three anthraquinones, namely alizarin (1), purpurin (2), and emodin (3); two lignans, namely eudesmin (4) and compound 5; and two cyclic hexapeptides, namely deoxybouvardin RA-V (6), and a mixture of 6+9 (RA-XXI). The structures of the isolated compounds were determined by NMR spectroscopy and HRESIMS. The isolated compounds 1, 2, 3, 6, and a mixture of 6+9 were tested against a panel of luciferase reporter genes that assesses the activity of a wide-range of cancer-related signaling pathways. In addition, reference anthraquinones viz., chrysophanol (11), danthron (12), quinizarin (13), aloe-emodin (14), and α-lapachone (15) were also tested. Among the tested compounds, the cyclic hexapeptide 6 was found to be very active against several signaling pathways, notably Wnt, Myc, and Notch with IC50 values of 50, 75, and 93 ng/mL, respectively. Whereas, the anthraquinones exhibited very mild or no inhibition against these signaling pathways. Compound 6 being the most active, we tested it for stability in simulated intestinal (SIF) and gastric fluids (SGF), since the stability in biological fluid is a key short-coming of cyclic hexapeptides. The anticancer activity of 6 was found to remain unchanged before and after the treatment of simulated gastric/intestinal fluids, indicating that RA-V was stable. As a result, it could be bioavailable when orally used in therapeutics and possibly a drug candidate for cancer treatment. The mechanism for the preferential inhibition of these pathways and the possible crosstalk effect with other previously reported signaling pathways has been discussed.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Peptídeos Cíclicos/farmacologia , Rubia/química , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos
3.
Food Funct ; 10(12): 8208-8217, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31701990

RESUMO

Research supports the theory that the microbiome of plants and mushrooms produce potent activators of pathogen recognition receptors which are principal contributors to the stimulation of macrophages. We have previously reported that the in vitro macrophage stimulatory activity of water-soluble extracts from 13 different types of edible mushrooms is predominantly due to bacterial components originating from the naturally occurring bacterial communities within these materials. The purpose of the current study was to further investigate the bacterial-dependent activity of the water-soluble extracts and assess whether these 13 types of mushrooms contain water-insoluble beta glucans that activate the dectin-1b signaling pathway. Activity of the water-soluble extracts was predominantly due to Toll-like receptor 2 (TLR2) and TLR4 agonists. For dectin-1b-dependent activity (indicative of water-insoluble beta glucans), culinary mushrooms (Agaricus bisporus varieties) were essentially inactive, whereas most of the medicinal mushrooms (Lentinula edodes, Grifola frondosa, Hypsizygus marmoreus varieties, Flammulina velutipes) exhibited potent activation. A. bisporus samples with no detectable dectin-1b-dependent activity had yeast colony forming units that were 687 times lower than L. edodes exhibiting high activity, indicating that the active insoluble beta glucans are derived from colonizing yeast. In addition, co-stimulation of macrophages with the TLR agonists and insoluble beta glucan was found to result in a synergistic enhancement of in vitro cytokine production. Taken together, these findings indicate that the in vitro macrophage activating potential of edible mushrooms is due to the collaborative interaction of water-soluble TLR agonists (derived from colonizing bacteria) and water-insoluble beta glucans (derived from colonizing yeast).


Assuntos
Agaricales/química , Bactérias/química , Lectinas Tipo C/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Extratos Vegetais/farmacologia , Receptores Toll-Like/imunologia , Verduras/microbiologia , Leveduras/química , beta-Glucanas/farmacologia , Agaricales/classificação , Animais , Bactérias/crescimento & desenvolvimento , Bactérias/metabolismo , Lectinas Tipo C/genética , Macrófagos/efeitos dos fármacos , Camundongos , Extratos Vegetais/química , Células RAW 264.7 , Receptores Toll-Like/agonistas , Receptores Toll-Like/genética , Verduras/química , Verduras/classificação , Leveduras/crescimento & desenvolvimento , Leveduras/metabolismo , beta-Glucanas/metabolismo
4.
Sci Rep ; 9(1): 136, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30644442

RESUMO

We previously demonstrated that extracts from Echinacea purpurea material varied substantially in their ability to activate macrophages in vitro and that this variation was due to differences in their content of bacterial components. The purpose of the current study was to identify soil conditions (organic matter, nitrogen, and moisture content) that alter the macrophage activation potential of E. purpurea and determine whether these changes in activity correspond to shifts in the plant-associated microbiome. Increased levels of soil organic matter significantly enhanced macrophage activation exhibited by the root extracts of E. purpurea (p < 0.0001). A change in soil organic matter content from 5.6% to 67.4% led to a 4.2-fold increase in the macrophage activation potential of extracts from E. purpurea. Bacterial communities also differed significantly between root materials cultivated in soils with different levels of organic matter (p < 0.001). These results indicate that the level of soil organic matter is an agricultural factor that can alter the bacterial microbiome, and thereby the activity, of E. purpurea roots. Since ingestion of bacterial preparation (e.g., probiotics) is reported to impact human health, it is likely that the medicinal value of Echinacea is influenced by cultivation conditions that alter its associated bacterial community.


Assuntos
Echinacea/microbiologia , Ativação de Macrófagos/imunologia , Microbiota/imunologia , Solo/química , Extratos Vegetais/imunologia , Extratos Vegetais/uso terapêutico , Raízes de Plantas/imunologia , Raízes de Plantas/microbiologia , Microbiologia do Solo
5.
Molecules ; 23(11)2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30366372

RESUMO

Enteric septicemia of catfish, columnaris disease and streptococcosis, caused by Edwardsiella ictaluri, Flavobacterium columnare and Streptococcus iniae, respectively, are the most common bacterial diseases of economic significance to the pond-raised channel catfish Ictalurus punctatus industry. Certain management practices are used by catfish farmers to prevent large financial losses from these diseases such as the use of commercial antibiotics. In order to discover environmentally benign alternatives, using a rapid bioassay, we evaluated a crude extract from the roots of muscadine Vitis rotundifolia against these fish pathogenic bacteria and determined that the extract was most active against F. columnare. Subsequently, several isolated compounds from the root extract were isolated. Among these isolated compounds, (+)-hopeaphenol (2) and (+)-vitisin A (3) were found to be the most active (bacteriostatic activity only) against F. columnare, with 24-h 50% inhibition concentrations of 4.0 ± 0.7 and 7.7 ± 0.6 mg/L, respectively, and minimum inhibitory concentrations of 9.1 ± 0 mg/L for each compound which were approximately 25X less active than the drug control florfenicol. Efficacy testing of 2 and 3 is necessary to further evaluate the potential for these compounds to be used as antibacterial agents for managing columnaris disease.


Assuntos
Antibacterianos/uso terapêutico , Extratos Vegetais/uso terapêutico , Raízes de Plantas/química , Vitis/química , Animais , Antibacterianos/química , Bioensaio , Peixes-Gato , Edwardsiella ictaluri/efeitos dos fármacos , Edwardsiella ictaluri/patogenicidade , Doenças dos Peixes/tratamento farmacológico , Doenças dos Peixes/microbiologia , Flavobacterium/efeitos dos fármacos , Flavobacterium/patogenicidade , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Streptococcus iniae/efeitos dos fármacos , Streptococcus iniae/patogenicidade
6.
Curr Top Med Chem ; 18(3): 182-191, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29332583

RESUMO

Enthusiasm for the use of dietary bioactive compounds as chemopreventive agents and adjuvants for current therapies has increased laboratory research conducted on several types of cancers including Head and Neck Squamous Cell Carcinoma (HNSCC). The green chemoprevention movement is a modern approach to highlight healthy lifestyle changes that aim to decrease the incidence of HNSCC. A healthy diet can be an effective way to prevent the development of oral cancers. Discovery of the naturally occurring plant based compounds called phytochemicals has facilitated the development of new treatment strategies for patients that are at risk for, or have developed HNSCC. Many of these compounds have been shown to elicit very potent anti-carcinogenic properties. While there are many compounds that have been studied, the compounds from two specific categories of phytochemicals, phenolics (resveratrol, EGCG, curcumin, quercetin, and honokiol) and glucosinolates (sulforaphane, PEITC and BITC), are emerging as potent and effective inhibitors of oral carcinogenesis. These compounds have been shown to inhibit HNSCC growth through a variety of mechanisms. Research has demonstrated that these compounds can regulate cancer cell proliferation through the regulation of multiple cell signaling pathways. They can impede cell cycle progression, induce differentiation and apoptosis, prevent angiogenesis, and inhibit cancer cell invasive and metastatic properties. They can protect normal cells during treatment and reduce the damage caused by chemotherapy and radiotherapy. This review aims to provide an overview of some of the most effective phytochemicals that have the potential to successfully prevent and treat head and neck squamous cell carcinoma.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/prevenção & controle , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/prevenção & controle , Compostos Fitoquímicos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/patologia , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Compostos Fitoquímicos/química , Relação Estrutura-Atividade
7.
Food Funct ; 7(10): 4213-4221, 2016 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-27711863

RESUMO

Recent studies have indicated that a major contributor to the innate immune enhancing properties of some medicinal plants is derived from the cell wall components of bacteria colonizing these plants. The purpose of the current study was to assess if the bacteria present within edible and medicinal mushrooms substantially contribute to the innate immune stimulating potential of these mushrooms. Whole mushrooms from thirteen types of edible fungi and individual parts from Agaricus bisporus were analyzed for in vitro macrophage activation as well as bacterial lipopolysaccharides (LPS) content, cell load, and community composition. Substantial variation between samples was observed in macrophage activation (over 500-fold), total bacterial load (over 200-fold), and LPS content (over 10 million-fold). Both LPS content (ρ = 0.832, p < 0.0001) and total bacterial load (ρ = 0.701, p < 0.0001) correlated significantly with macrophage activation in the whole mushroom extracts. Extract activity was negated by treatment with NaOH, conditions that inactivate LPS and other bacterial components. Significant correlations between macrophage activation and total bacterial load (ρ = 0.723, p = 0.0001) and LPS content (ρ = 0.951, p < 0.0001) were also observed between different tissues of Agaricus bisporus. Pseudomonas and Flavobacterium were the most prevalent genera identified in the different tissue parts and these taxa were significantly correlated with in vitro macrophage activation (ρ = 0.697, p < 0.0001 and ρ = 0.659, p = 0.0001, respectively). These results indicate that components derived from mushroom associated bacteria contribute substantially to the innate immune enhancing activity exhibited by mushrooms and may result in similar therapeutic actions as reported for ingestion of bacterial preparations such as probiotics.


Assuntos
Agaricales/química , Bactérias/química , Misturas Complexas/química , Macrófagos/efeitos dos fármacos , Animais , Bactérias/genética , Camundongos , Células RAW 264.7 , RNA Ribossômico 16S/genética
8.
Planta Med ; 82(14): 1258-65, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27286330

RESUMO

Evidence supports the theory that bacterial communities colonizing Echinacea purpurea contribute to the innate immune enhancing activity of this botanical. Previously, we reported that only about half of the variation in in vitro monocyte stimulating activity exhibited by E. purpurea extracts could be accounted for by total bacterial load within the plant material. In the current study, we test the hypothesis that the type of bacteria, in addition to bacterial load, is necessary to fully account for extract activity. Bacterial community composition within commercial and freshly harvested (wild and cultivated) E. purpurea aerial samples was determined using high-throughput 16S rRNA gene pyrosequencing. Bacterial isolates representing 38 different taxa identified to be present within E. purpurea were acquired, and the activity exhibited by the extracts of these isolates varied by over 8000-fold. Members of the Proteobacteria exhibited the highest potency for in vitro macrophage activation and were the most predominant taxa. Furthermore, the mean activity exhibited by the Echinacea extracts could be solely accounted for by the activities and prevalence of Proteobacteria members comprising the plant-associated bacterial community. The efficacy of E. purpurea material for use against respiratory infections may be determined by the Proteobacterial community composition of this plant, since ingestion of bacteria (probiotics) is reported to have a protective effect against this health condition.


Assuntos
Echinacea/microbiologia , Ativação de Macrófagos , Extratos Vegetais/imunologia , Proteobactérias/imunologia , Animais , Echinacea/imunologia , Camundongos , Células RAW 264.7
9.
Phytomedicine ; 22(2): 271-6, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25765832

RESUMO

A growing body of research indicates that oral administration of bacteria (such as probiotics) can exhibit a protective effect against influenza A (H1N1) viral infection in mice. In the present study, we used a mouse model to examine whether oral administration of Immulina(®), a commercial extract from the cyanobacteria Arthrospira (Spirulina) platensis, can reduce the severity of illness resulting from influenza A (H1N1) viral infection. The main active compounds within Immulina(®) are bacterial Braun-type lipoproteins that activate innate immune cells through a toll-like receptor (TLR) 2-dependent pathway. Mice that were fed Immulina(®) for 30 days before and 21 days after infection with influenza A (H1N1) virus exhibited a statistically significant reduction in the severity of infection. Compared to the control group, Immulina(®)-fed mice exhibited less weight loss, increased appetite, decreased clinical signs of disease, and lower lung histopathology scores. The results from the present study adds to the increasing evidence that oral administration of bacterial components that activate innate immune cells, whether derived from a bacterial preparation (probiotics or cyanobacteria) or from plant material containing endophytic bacteria, can exhibit a protective effect against influenza A (H1N1) viral infection.


Assuntos
Suplementos Nutricionais , Infecções por Orthomyxoviridae/tratamento farmacológico , Polissacarídeos Bacterianos/farmacologia , Spirulina/química , Administração Oral , Animais , Linhagem Celular , Modelos Animais de Doenças , Feminino , Vírus da Influenza A Subtipo H1N1 , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos BALB C
10.
Innate Immun ; 20(8): 857-66, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24323452

RESUMO

Inflammasome activation has been shown to regulate both innate and adaptive immune responses. It is important to investigate whether immune-enhancing natural products can also activate inflammasome. The current study examined the potential of protein-bound polysaccharide-K (PSK), a hot water extract from Trametes versicolor, to activate inflammasome. Using THP-1 cells, we have demonstrated that PSK induces both pro-IL-1ß and mature IL-1ß in THP-1 cells in a caspase 1- and NLRP3-dependent manner. PSK also induces IL-1ß and IL-18 in human PBMC. Cathepsin B is required for PSK-induced inflammasome activation as CA-074-Me, a cathepsin B inhibitor, significantly decreased PSK-induced IL-1ß. PSK induces NLRP3 at both mRNA and protein level. Comparison of PSK-induced IL-1ß in bone marrow-derived macrophages from wild type C57BL/6 mice, TLR2(-/-), P2X7R(-/-) and NLRP3(-/-) mice demonstrated that PSK-induced IL-1ß is dependent on both TLR2 and NLRP3. P2X7R is not required for PSK-induced inflammasome activation, but enhances PSK-induced caspase-1 activation and IL-1ß induction. Altogether, these results demonstrated that PSK induces inflammasome activation and production of IL-1ß in a TLR2- and NLRP3-dependent mechanism. These results provide novel insights into the mechanisms of the immune modulatory effects of PSK.


Assuntos
Proteínas de Transporte/efeitos dos fármacos , Inflamassomos/efeitos dos fármacos , Interleucina-1beta/biossíntese , Proteoglicanas/farmacologia , Receptor 2 Toll-Like/efeitos dos fármacos , Animais , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Caspases/biossíntese , Catepsina B/fisiologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Potássio/metabolismo , Receptor 2 Toll-Like/biossíntese , Receptor 2 Toll-Like/genética
11.
J Nat Prod ; 76(4): 679-84, 2013 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-23547843

RESUMO

Bioassay-guided fractionation of the leaves of Eugenia rigida yielded three stilbenes, (Z)-3,4,3',5'-tetramethoxystilbene (1), (E)-3,4,3',5'-tetramethoxystilbene (2), and (E)-3,5,4'-trimethoxystilbene (3). Their structures were determined using 1D- and 2D-NMR spectroscopy and HRESIMS. The sterically hindered Z-stereoisomer 1, a new natural product, was prepared by time-dependent photoisomerization of the E-isomer (2) under UV irradiation at λ254 nm, while 2,3,5,7-tetramethoxyphenanthrene (5) was identified at λ365 nm by UHPLC/APCI-MS and NMR spectroscopy. Compounds 1-3 were tested against a panel of luciferase reporter gene assays that assess the activity of many cancer-related signaling pathways, and the Z-isomer (1) was found to be more potent than the E-isomer (2) in inhibiting the activation of Stat3, Smad3/4, myc, Ets, Notch, and Wnt signaling, with IC50 values between 40 and 80 µM. However, both compounds showed similar inhibition against Ap-1 and NF-κB signaling. In addition, 1 demonstrated cytotoxic activity toward human leukemia cells, solid tumor cells of epidermal, breast, and cervical carcinomas, and skin melanoma, with IC50 values between 3.6 and 4.3 µM, while 2 was weakly active against leukemia, cervical carcinoma, and skin melanoma cells. Interestingly, 2 showed antioxidant activity by inhibition of ROS generation to 50% at 33.3 µM in PMA-induced HL-60 cells, while 1 was inactive at 100 µM (vs Trolox 1.4 µM).


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/isolamento & purificação , Estilbenos/isolamento & purificação , Estilbenos/farmacologia , Syzygium/química , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Antioxidantes/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HL-60 , Humanos , Concentração Inibidora 50 , Estrutura Molecular , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Porto Rico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Estereoisomerismo , Estilbenos/química
12.
Planta Med ; 79(1): 9-14, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23212786

RESUMO

Our previous studies indicate that the majority of in vitro monocyte/macrophage activation exhibited by extracts of Echinacea depends on bacterial components. In the present study, total bacterial load was determined within E. purpurea samples and ranged from 6.4 × 10(6) to 3.3 × 10(8) bacteria/g of dry plant material. To estimate total bacterial load, we developed a PCR-based quantification method that circumvents the problems associated with nonviable/nonculturable cells (which precludes using plate counts) or the coamplification of mitochondrial or chloroplast DNA with the use of universal bacterial primers (which precludes the use of qPCR). Differences in total bacterial load within Echinacea samples were strongly correlated with the activity (NF-κB activation in THP-1 cells) and content of bacterial lipopolysaccharides within extracts of this plant material. These results add to the growing body of evidence that bacteria within Echinacea are the main source of components responsible for enhancing innate immune function.


Assuntos
Bactérias/isolamento & purificação , Carga Bacteriana , Echinacea/microbiologia , Lipopolissacarídeos/análise , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Extratos Vegetais/química , Linhagem Celular , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , NF-kappa B/metabolismo , Componentes Aéreos da Planta/microbiologia , Raízes de Plantas/microbiologia , Reação em Cadeia da Polimerase
13.
Planta Med ; 76(16): 1802-8, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20560112

RESUMO

Immulina®, a commercial extract of Arthrospira (Spirulina) platensis is a potent activator of THP-1 monocytes and CD4+ T cells IN VITRO and enhances several immunological functions in mice. We further characterized Immulina® by determining that Braun-type lipoproteins are responsible for a major portion of the IN VITRO monocyte activation exhibited by this material. In order to understand the effect of Immulina® on NK cell activity, a pilot study was conducted on ten healthy North American individuals who supplemented their diet with Immulina® (400 mg/day) for seven days. We observed a 40% average increase in the killing of K562 tumor cells by NK cells (p < 0.01) after Immulina® supplementation. In a separate placebo-controlled, crossover study involving 11 healthy Danish subjects, we observed increased mRNA expression of the NK cell marker NKG2D by 37% (p = 0.02) and by 55% (p = 0.0003) after administration of Immulina® (200 mg and 400 mg per day, respectively) for seven days. The mRNA expression of the NK- and T-cell marker perforin increased by 75% (p = 0.008) after administration of 400 mg Immulina® per day. Both markers displayed significant dose-dependent effects (p = 0.0003 and p = 0.02, respectively). The ratio between CD56 (bright) and CD56 (dim) NK cells was not affected by Immulina® administration. In summary, two independent studies showed enhancement of NK cell activity following administration of Immulina® for seven days.


Assuntos
Adjuvantes Imunológicos/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Leucemia Eritroblástica Aguda/tratamento farmacológico , Lipoproteínas/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Extratos Vegetais/farmacologia , Spirulina/química , Adjuvantes Imunológicos/uso terapêutico , Adulto , Idoso , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Estudos Cross-Over , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Lipoproteínas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Perforina/genética , Perforina/metabolismo , Fitoterapia , Projetos Piloto , Extratos Vegetais/uso terapêutico , RNA Mensageiro/metabolismo , Valores de Referência , Linfócitos T , Adulto Jovem
14.
Cancer Chemother Pharmacol ; 63(4): 673-80, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18597088

RESUMO

PURPOSE: Breast cancer is one of the most prevalent woman cancers. Genomic instability, accumulative mutations, and subsequent changes in intracellular signaling cascades play key roles in the development of human breast cancers. Activation of nuclear factor-kappaB (NF-kappaB) has been implicated in oncogenesis of breast cancers and is known to be associated with resistance to anticancer agents and apoptosis. Blocking NF-kappaB signaling may represent a therapeutic strategy in breast cancer therapy. The objective of this study is to investigate the in vitro effects of epoxypseudoisoeugenol-2-methyl butyrate (EPB), a phenylpropranoid isolated from Pimpinella corymbosa, on the activation of NF-kappaB, cell growth, cell cycle progression and apoptosis in MCF-7 (estrogen-dependent) and BT-549 (estrogen-independent) breast cancer cells. METHODS: Transcriptional activity of NF-kappaB was measured by cell based reporter gene assay. Cell proliferation was determined by MTT assay. Cell cycle analysis was carried out by flow cytometry and apoptosis was observed by DAPI staining assy. RESULTS: EPB inhibited the NF-kappaB-mediated transcription activity induced by tumor necrosis factor-alpha (TNF-alpha) and phorbol myristate acetate (PMA) in MCF-7 cells. EPB also inhibited constitutive NF-kappaB transcriptional activity in BT-549 cells. EPB inhibited the proliferation of both MCF-7 and BT-549 cells in a concentration- and time-dependent manner. EPB induced cell cycle arrest in G(1)/G(0) phase and apoptosis in both MCF-7 and BT 549 cells. CONCLUSIONS: These in vitro results indicated that EPB has a potential for use against both hormone-dependent and hormone-independent breast cancers and its effects seem to be mediated by inhibiting the NF-kappaB activity.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Butiratos/farmacologia , NF-kappa B/genética , Transcrição Genética/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , NF-kappa B/metabolismo , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Pimpinella/química , Transdução de Sinais
15.
J Agric Food Chem ; 56(22): 10552-6, 2008 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-18942831

RESUMO

We previously reported that the majority of in vitro monocyte/macrophage activation exhibited by extracts of Echinacea and other botanicals depends upon bacterial lipopolysaccharides and Braun-type bacterial lipoproteins. We determined the contribution made by these bacterial components to the overall immune-enhancing activity detected in E. purpurea and E. angustifolia bulk root and aerial material obtained from six major growers/suppliers in North America. Substantial variation in activity (up to 200-fold) was observed in extracts of these materials when tested in two monocyte/macrophage cell lines. The majority of activity was negated by treatment with agents that target bacterial lipoproteins (lipoprotein lipase) and lipopolysaccharides (polymyxin B). Experiments comparing the activity of freeze-dried, freshly harvested Echinacea plants to those harvested and dried using various commercially relevant conditions suggest that postharvesting procedures do not substantially contribute to the variation observed in the commercial material.


Assuntos
Bactérias/química , Echinacea/química , Lipopolissacarídeos/farmacologia , Lipoproteínas/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Dessecação/métodos , Escherichia coli/química , Folhas de Planta/química , Raízes de Plantas/química
16.
Int Immunopharmacol ; 8(7): 1023-32, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18486914

RESUMO

We have identified potent monocyte/macrophage activating bacterial lipoproteins within commonly used immune enhancing botanicals such as Echinacea, American ginseng and alfalfa sprouts. These bacterial lipoproteins, along with lipopolysaccharides, were substantially more potent than other bacterially derived components when tested in in vitro monocyte/macrophage activation systems. In experiments using RAW 264.7 and mouse peritoneal macrophages the majority (85-98%) of the activity within extracts from eight immune enhancing botanicals was eradicated by treatment with agents (lipoprotein lipase and polymyxin B) known to target these two bacterial components. Alfalfa sprouts exhibited the highest activity of those botanicals tested but the appearance of this activity during the germination of surface sterilized seeds was abolished by the presence of antibiotics. These studies indicate that the majority of the in vitro macrophage activating properties in extracts from these botanicals can be attributed to the presence of lipoproteins and lipopolysaccharides derived from bacteria and that bacterial endophytes may be a significant source of these components.


Assuntos
Adjuvantes Imunológicos/farmacologia , Proteínas de Bactérias/farmacologia , Lipopolissacarídeos/farmacologia , Lipoproteínas/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Antibacterianos/farmacologia , Echinacea , Masculino , Medicago sativa , Melaninas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Panax , Receptor 2 Toll-Like/fisiologia
17.
Phytother Res ; 21(8): 741-5, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17450505

RESUMO

Pimpinella essential oils and isolated compounds were screened for their inhibitory activity against NF-kappaB mediated transcription in SW1353 cells. Twelve oils were effective in inhibiting NF-kappaB mediated transcription. Especially the roots of P. corymbosa, P. tragium and P. rhodanta showed potent activities with IC(50) values of 2, 3 and 6 microg/mL, respectively. Five pure compounds, 7 (4-(2-propenyl)phenylangelate), 12 (4-(3-methyloxiranyl)phenyltiglate), 17 (4-methoxy-2-(3-methyloxiranyl)phenyl isobutyrate), 18 (4-methoxy-2-(3-methyloxiranyl)phenylangelate) and 21 (epoxy pseudoisoeugenol-2-methylbutyrate) inhibited NF-kappaB mediated transcription with IC(50) values of 5.5, 1.2, 0.01, 3.6 and 11 microg/mL, respectively. None of the compounds were cytotoxic to mammalian cells. These findings add significant information to the pharmacological activity of Pimpinella species and their beneficial effects and use in disease prevention especially those related to inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , NF-kappa B/antagonistas & inibidores , Óleos Voláteis/farmacologia , Pimpinella/química , Óleos Vegetais/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Linhagem Celular , Chlorocebus aethiops , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Estrutura Molecular , Óleos Voláteis/química , Fitoterapia , Componentes Aéreos da Planta/química , Óleos Vegetais/química , Raízes de Plantas/química , Especificidade da Espécie
18.
Cancer Chemother Pharmacol ; 60(1): 35-43, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17149609

RESUMO

PURPOSE: Nuclear factor-kappaB (NF-kappaB) plays a crucial role in the regulation of inflammatory processes, cell proliferation, and apoptosis. Blocking NF-kappaB signaling may represent a therapeutic strategy in cancer and inflammation therapy. The aim of this study was to investigate the effects of sesquiterpenes isolated from Asteraceae, namely melampolides (enhydrin, tetraludin A) and repandolides (repandins A, B, D and E) on the activation of NF-kappaB, cell growth of cancer cells, cell cycle progression and apoptosis. In addition, their effects on the activity of cyclooxygenase-2 (COX-2) enzyme were also evaluated. METHODS: Cell-based reporter gene assay was conducted in SW1353 cells. COX-2 enzyme activity and cell growth inhibition was determined by enzyme immunoassay and MTT assay respectively. Cell cycle analysis was carried out by flow cytometry and apoptosis was observed by DAPI staining assay. RESULTS: In SW1353 cells, transcription mediated by NF-kappaB was inhibited by enhydrin, tetraludin A and repandins A, B, D and E, while Sp-1 mediated transcription was not affected. COX-2 enzyme activity was inhibited by enhydrin, repandin A and E, but not by tetraludin A, repandin B and D. These compounds were effective in inhibiting the growth of a panel of human tumor cell lines in a concentration-dependent manner. Cell cycle analysis and DAPI staining indicated cell cycle arrest in G(2)/M phase and induction of apoptosis. CONCLUSIONS: Enhydrin, tetraludin A and repandins A, B, D and E inhibited tumor cell growth and induced cell cycle arrest and apoptosis. These effects may be related to inhibition of NF-B activation.


Assuntos
Apoptose/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Sesquiterpenos/farmacologia , Transcrição Genética/efeitos dos fármacos , Asteraceae/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Inibidores de Ciclo-Oxigenase 2/farmacologia , Relação Dose-Resposta a Droga , Fase G2/efeitos dos fármacos , Células HL-60 , Humanos , Concentração Inibidora 50 , Lactonas/química , Lactonas/isolamento & purificação , Lactonas/farmacologia , Luciferases/genética , Luciferases/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Microscopia de Fluorescência , Estrutura Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Fator de Transcrição Sp1/metabolismo , Acetato de Tetradecanoilforbol/farmacologia
19.
Int Immunopharmacol ; 6(12): 1808-14, 2006 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-17052671

RESUMO

We reported previously that a high molecular weight polysaccharide fraction (Immulina) from Spirulina was a potent activator of NF-kappa B and induced both IL-1 beta and TNF-alpha mRNAs in THP-1 human monocytes. In the present study, we show that NF-kappa B activation by Immulina is suppressed by antibodies to CD14 and TLR2 but not by antibodies to TLR4. Similarly, NF-kappa B directed luciferase expression was enhanced by Immulina treatment when cells were co-transfected with vectors expressing proteins supporting TLR2- (CD14 and TLR2) but not TLR4-(CD14, TLR4, and MD-2) dependent activation. Mice that consumed a chemically defined chow mixed with an extract containing Immulina exhibited changes in several immune parameters. The ex vivo production of IgA and IL-6 from Peyer's patch cells was enhanced 2-fold and interferon-gamma production from spleen cells was increased 4-fold in Immulina-treated mice. The enhanced production of these factors was most notable with mice that had consumed this extract for 4 or 5 days. These studies shed light on how Immulina activates cells of the innate immune system and suggests that oral consumption of this polysaccharide can enhance components within both the mucosal and systemic immune systems.


Assuntos
Monócitos/efeitos dos fármacos , Polissacarídeos/farmacologia , Spirulina/química , Receptor 2 Toll-Like/imunologia , Animais , Linhagem Celular , Humanos , Imunoglobulina A/imunologia , Interferon gama/imunologia , Interleucina-6/imunologia , Receptores de Lipopolissacarídeos/imunologia , Camundongos , Monócitos/imunologia , NF-kappa B/imunologia , Nódulos Linfáticos Agregados/citologia , Nódulos Linfáticos Agregados/imunologia , Extratos Vegetais/química , Polissacarídeos/isolamento & purificação , Polissacarídeos Bacterianos , Baço/citologia , Baço/imunologia
20.
Kidney Int ; 67(5): 1797-805, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15840026

RESUMO

BACKGROUND: Aristolochia species are nephrotoxic and carcinogenic. Recent studies showed that aristolochic acid (AA) could induce acute renal failure and tubular lesions in several species and available evidences demonstrate the unequivocal role of AA in so called Chinese herbs nephropathy. METHODS: A series of AA derivatives isolated from Aristolochia spp. were analyzed for their nephrotoxic potential using the neutral red dye exclusion assay in cultures of LLC-PK(1) cells. The structural relationships between AA I and its analogues were compared with their cytotoxic effects to predict structural determinants for AA toxicity. Further, caspase-3 assay was performed on toxic compounds to determine if caspases, the enzymes that play a critical role in apoptosis are involved in AA-induced cytotoxicity. RESULTS: AA I was found to be most toxic followed by AA II, AA VIIIa, and AA Ia in decreasing levels of toxicity. The other compounds, nitrophenanthrene carboxylic acid analogues of AA I, aristolactams, and other derivatives did not exhibit considerable toxicity. The results showed significant relationships between cytotoxicity of AA compounds and the localization of functional groups in their structure. Analogues containing hydroxyl groups diminished cytotoxicity. The demethylated analogues of AA I are markedly less active. The negative impact on cytotoxicity was found on nitroreduction of AA I. AA induced caspase activation was also observed. CONCLUSION: These cytotoxic data suggest that the nitro and methoxy groups are critical determinants of nephrotoxicologic potency of AA.


Assuntos
Ácidos Aristolóquicos/química , Ácidos Aristolóquicos/toxicidade , Rim/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspase 3 , Caspase 7 , Caspases/metabolismo , Linhagem Celular , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/toxicidade , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Rim/enzimologia , Rim/patologia , Células LLC-PK1 , Nefrite Intersticial/induzido quimicamente , Nefrite Intersticial/enzimologia , Nefrite Intersticial/patologia , Relação Estrutura-Atividade , Suínos
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