RESUMO
We explored ancestry-related differences in the genetic architecture of whole-blood gene expression using whole-genome and RNA sequencing data from 2,733 African Americans, Puerto Ricans and Mexican Americans. We found that heritability of gene expression significantly increased with greater proportions of African genetic ancestry and decreased with higher proportions of Indigenous American ancestry, reflecting the relationship between heterozygosity and genetic variance. Among heritable protein-coding genes, the prevalence of ancestry-specific expression quantitative trait loci (anc-eQTLs) was 30% in African ancestry and 8% for Indigenous American ancestry segments. Most anc-eQTLs (89%) were driven by population differences in allele frequency. Transcriptome-wide association analyses of multi-ancestry summary statistics for 28 traits identified 79% more gene-trait associations using transcriptome prediction models trained in our admixed population than models trained using data from the Genotype-Tissue Expression project. Our study highlights the importance of measuring gene expression across large and ancestrally diverse populations for enabling new discoveries and reducing disparities.
Assuntos
Negro ou Afro-Americano , Hispânico ou Latino , Americanos Mexicanos , Humanos , Negro ou Afro-Americano/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/genética , Americanos Mexicanos/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , TranscriptomaRESUMO
BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician's diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV1/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10-8 in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10-6). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV1 (P = 3.3 × 10-3), postbronchodilator (PB) FEV1 (7.3 × 10-3), and PB FEV1/FVC ratio (P = 2.7 × 10-3). The identified baseline FEV1/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.
Assuntos
Asma/genética , Asma/fisiopatologia , Moléculas de Adesão Celular/genética , Volume Expiratório Forçado/genética , Fatores Reguladores de Interferon/genética , Capacidade Vital/genética , Sequenciamento Completo do Genoma , Adolescente , Adulto , Criança , Pré-Escolar , Costa Rica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenômenos Fisiológicos Respiratórios/genética , Adulto JovemRESUMO
INTRODUCCIÓN Para la disminución de las actuales tasas de segundo o tercer embarazo en la adolescencia, sabiendo que el 68% de dichas gestaciones fueron no intencionales, se implementa la estrategia de Anticoncepción Inmediata Postevento Obstétrico (AIPEO), con priorización de métodos anticonceptivos de larga duración (MALD), con niveles variables de implementación y éxito en distintos lugares del país. Esta investigación tiene como objetivo general analizar las estrategias de implementación de AIPEO en las maternidades de dos provincias argentinas, identificando barreras y facilitadores. METODOS Para el relevamiento de información en cada nivel se desarrollaron encuestas a trabajadores, entrevistas a informantes clave, y análisis estadístico de los indicadores de AIPEO en ambas provincias. RESULTADOS se incluyeron 5 instituciones de 2 provincias pertenecientes al NEA y NOA, con 131 encuestas y 21 entrevistas. En términos cuantitativos, la implementación en el 2020 ha sido más exitosa que en el 2019, con mayor uso de MALD en general. Se demostró también una diferencia entre años con significancia estadística en la implementación en adolescentes y en segundo embarazo. En cuanto a los modelos de gestión, lo relevado indica que en ambas provincias se basan en lineamientos del nivel central para el establecimiento de prioridades y en ambos casos, a nivel de las maternidades, las prioridades de gestión suelen verse afectadas por las demandas de urgencias cotidianas. Sin embargo, en la provincia 1 el nivel de institucionalización impresiona menor, con redes informales de articulación y comunicación. En la provincia 2, la red de regionalización establece un marco de institucionalidad, con instancias específicas de consenso, canales y formatos formales de difusión de decisiones. Aun así, en ninguna de las dos provincias han desarrollado protocolos de implementación ni registro o monitoreo específicos más allá de lo programático del nivel central. DISCUSIÓN Los principales mecanismos que actúan como obstáculos para esta implementación se concentran en aspectos centrales de la gestión; establecimiento de las prioridades, institucionalización de políticas priorizadas y desarrollo de protocolos de acción. Los ítems vinculados a cuestiones de perspectiva más macro son dependientes de esta institucionalización. Los factores facilitadores detectados fueron, por un lado, una fuerte gestión en las Direcciones de Maternidad e Infancia, y Salud Sexual y Reproductiva y, por otro lado, el conocimiento de la estrategia, así como el acuerdo con la misma por la mayor parte de los/las profesionales encuestados
Assuntos
Gravidez na AdolescênciaRESUMO
Dibenzyl trisulfide (DTS) is the major active ingredient expressed in Petiveria alliacea L., a shrub widely used for a range of conditions, such as, arthritis, asthma and cancer. Given its use alone and concomitantly with prescription medicines, we undertook to investigate its impact on the activities of important drug metabolizing enzymes, the cytochromes P450 (CYP), a key family of enzymes involved in many adverse drug reactions. DTS and seven standardized extracts from the plant were assessed for their impact on the activities of CYPs 1A2, 2C19, 2C9, 2D6 and 3A4 on a fluorometric assay. DTS revealed significant impact against the activities of CYPs 1A2, 2C19 and 3A4 with IC50 values of 1.9, 4.0 and 3.2µM, respectively, which are equivalent to known standard inhibitors of these enzymes (furafylline, and tranylcypromine), and the most potent interaction with CYP1A2 displayed irreversible enzyme kinetics. The root extract, drawn with 96% ethanol (containing 2.4% DTS), displayed IC50 values of 5.6, 3.9 and 4.2µg/mL respectively, against the same isoforms, CYPs 1A2, 2C19 and 3A4. These investigations identify DTS as a valuable CYP inhibitor and P. alliacea as a candidate plant worthy of clinical trials to confirm the conclusions that extracts yielding high DTS may lead to clinically relevant drug interactions, whilst extracts yielding low levels of DTS, such as aqueous extracts, are unlikely to cause adverse herb-drug interactions.
Assuntos
Compostos de Benzil/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Interações Ervas-Drogas , Phytolaccaceae/química , Extratos Vegetais/farmacologia , Sulfetos/farmacologia , HumanosRESUMO
RATIONALE: Adverse effects of exposures to ambient air pollution on lung function are well documented, but evidence in racial/ethnic minority children is lacking. OBJECTIVES: To assess the relationship between air pollution and lung function in minority children with asthma and possible modification by global genetic ancestry. METHODS: The study population consisted of 1,449 Latino and 519 African American children with asthma from five different geographical regions in the mainland United States and Puerto Rico. We examined five pollutants (particulate matter ≤10 µm and ≤2.5 µm in diameter, ozone, nitrogen dioxide, and sulfur dioxide), derived from participant residential history and ambient air monitoring data, and assessed over several time windows. We fit generalized additive models for associations between pollutant exposures and lung function parameters and tested for interaction terms between exposures and genetic ancestry. MEASUREMENTS AND MAIN RESULTS: A 5 µg/m(3) increase in average lifetime particulate matter less than or equal to 2.5 µm in diameter exposure was associated with a 7.7% decrease in FEV1 (95% confidence interval = -11.8 to -3.5%) in the overall study population. Global genetic ancestry did not appear to significantly modify these associations, but percent African ancestry was a significant predictor of lung function. CONCLUSIONS: Early-life particulate exposures were associated with reduced lung function in Latino and African American children with asthma. This is the first study to report an association between exposure to particulates and reduced lung function in minority children in which racial/ethnic status was measured by ancestry-informative markers.
Assuntos
Poluição do Ar/efeitos adversos , Asma/epidemiologia , Negro ou Afro-Americano/estatística & dados numéricos , Exposição Ambiental/estatística & dados numéricos , Hispânico ou Latino/estatística & dados numéricos , Pulmão/fisiopatologia , Grupos Minoritários/estatística & dados numéricos , Adolescente , Poluentes Atmosféricos/efeitos adversos , Asma/fisiopatologia , Criança , Feminino , Humanos , Masculino , Porto Rico/epidemiologia , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Nonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy. HYPOTHESIS/OBJECTIVES: The primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine. ANIMALS: Forty-seven client-owned dogs with measurable MCT. METHODS: Toceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m(2) . All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone. RESULTS: The MTD of lomustine was established at 50 mg/m(2) when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy. CONCLUSIONS AND CLINICAL IMPORTANCE: Combined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Doenças do Cão/tratamento farmacológico , Indóis/uso terapêutico , Lomustina/uso terapêutico , Mastocitose/veterinária , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/uso terapêutico , Animais , Antineoplásicos Alquilantes/administração & dosagem , Doenças do Cão/genética , Cães , Esquema de Medicação/veterinária , Quimioterapia Combinada , Feminino , Indóis/administração & dosagem , Lomustina/administração & dosagem , Masculino , Mastocitose/tratamento farmacológico , Mastocitose/genética , Reação em Cadeia da Polimerase/veterinária , Proteínas Proto-Oncogênicas c-kit/genética , Pirróis/administração & dosagemRESUMO
BACKGROUND: Atopy varies by ethnicity, even within Latino groups. This variation might be due to environmental, sociocultural, or genetic factors. OBJECTIVE: We sought to examine risk factors for atopy within a nationwide study of US Latino children with and without asthma. METHODS: Aeroallergen skin test responses were analyzed in 1830 US Latino subjects. Key determinants of atopy included country/region of origin, generation in the United States, acculturation, genetic ancestry, and site to which subjects migrated. Serial multivariate zero-inflated negative binomial regressions stratified by asthma status examined the association of each key determinant variable with the number of positive skin test responses. In addition, the independent effect of each key variable was determined by including all key variables in the final models. RESULTS: In baseline analyses African ancestry was associated with 3 times (95% CI, 1.62-5.57) as many positive skin test responses in asthmatic participants and 3.26 times (95% CI, 1.02-10.39) as many positive skin test responses in control participants. Generation and recruitment site were also associated with atopy in crude models. In final models adjusted for key variables, asthmatic patients of Puerto Rican (exp[ß] [95% CI], 1.31 [1.02-1.69]) and mixed (exp[ß] [95% CI], 1.27 [1.03-1.56]) ethnicity had a greater probability of positive skin test responses compared with Mexican asthmatic patients. Ancestry associations were abrogated by recruitment site but not region of origin. CONCLUSIONS: Puerto Rican ethnicity and mixed origin were associated with degree of atopy within US Latino children with asthma. African ancestry was not associated with degree of atopy after adjusting for recruitment site. Local environment variation, represented by site, was associated with degree of sensitization.
Assuntos
Asma/complicações , Asma/etnologia , Emigração e Imigração , Interação Gene-Ambiente , Hispânico ou Latino/estatística & dados numéricos , Hipersensibilidade Imediata/etnologia , Hipersensibilidade Imediata/genética , Adolescente , Alérgenos/imunologia , Asma/genética , Asma/imunologia , População Negra , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Hipersensibilidade Imediata/diagnóstico , Hipersensibilidade Imediata/imunologia , Masculino , Prevalência , Porto Rico , Fatores de Risco , Testes Cutâneos , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: The effects of in utero tobacco smoke exposure on childhood respiratory health have been investigated, and outcomes have been inconsistent. OBJECTIVE: To determine if in utero tobacco smoke exposure is associated with childhood persistent asthma in Mexican, Puerto Rican, and black children. PATIENTS AND METHODS: There were 295 Mexican, Puerto Rican, and black asthmatic children, aged 8 to 16 years, who underwent spirometry, and clinical data were collected from the parents during a standardized interview. The effect of in utero tobacco smoke exposure on the development of persistent asthma and related clinical outcomes was evaluated by logistic regression. RESULTS: Children with persistent asthma had a higher odds of exposure to in utero tobacco smoke, but not current tobacco smoke, than did children with intermittent asthma (odds ratio [OR]: 3.57; P = .029). Tobacco smoke exposure from parents in the first 2 years of life did not alter this association. Furthermore, there were higher odds of in utero tobacco smoke exposure in children experiencing nocturnal symptoms (OR: 2.77; P = .048), daily asthma symptoms (OR: 2.73; P = .046), and emergency department visits (OR: 3.85; P = .015) within the year. CONCLUSIONS: Exposure to tobacco smoke in utero was significantly associated with persistent asthma among Mexican, Puerto Rican, and black children compared with those with intermittent asthma. These results suggest that smoking cessation during pregnancy may lead to a decrease in the incidence of persistent asthma in these populations.
Assuntos
Asma/etnologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Fumar/epidemiologia , Poluição por Fumaça de Tabaco/estatística & dados numéricos , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Asma/epidemiologia , Criança , Feminino , Hispânico ou Latino/estatística & dados numéricos , Humanos , Modelos Logísticos , Bem-Estar Materno , Americanos Mexicanos/estatística & dados numéricos , Gravidez , Porto Rico/etnologiaRESUMO
We investigated the in vitro effect of dibenzyl trisulfide (DTS), a secondary metabolite of Petiveria alliacea, on erythrocyte elasticity, relaxation time and membrane morphology. Blood samples from 8 volunteers with hemoglobin AA were exposed to 100, 200, 400, 800 and 1000 ng/ml of DTS respectively and the elasticity and relaxation time measured. There were statistically significant, dose-dependent increases in elasticity and relaxation times. The changes in membrane morphology observed also increased with increased concentration of DTS. This suggests that DTS interaction with membrane protein resulted in increased elasticity, relaxation time and deformation of the erythrocyte membrane.
Assuntos
Compostos de Benzil/química , Compostos de Benzil/farmacologia , Membrana Eritrocítica/efeitos dos fármacos , Phytolaccaceae/química , Phytolaccaceae/metabolismo , Sulfetos/química , Sulfetos/farmacologia , Feminino , Humanos , Masculino , Estrutura MolecularRESUMO
BACKGROUND: Ethnic-specific interactions between different asthma medications are not well described. OBJECTIVE: To determine whether the use of leukotriene modifiers is associated with the magnitude of bronchodilator responsiveness among Mexican American and Puerto Rican children with persistent asthma. METHODS: A cross-sectional study of 84 Mexican American and 192 Puerto Rican children, with persistent asthma who were aged 8 to 16 years. Within each group, bronchodilator responsiveness to albuterol, objectively assessed via spirometry, was compared between participants using leukotriene modifiers and those not using leukotriene modifiers. RESULTS: Leukotriene modifier use was associated with a clinically significant increase in percentage change in forced expiratory volume in 1 second of 11.8 (P < .001) in Puerto Rican children, but there was no significant change in percentage change in forced expiratory volume in 1 second (-3.2, P=.57) in Mexican American children. This finding persisted after controlling for the use of inhaled corticosteroids. In addition, among the Puerto Rican children, the association between leukotriene modifier use and augmented bronchodilator responsiveness was greatest in those younger than 12 years. CONCLUSIONS: Among children with persistent asthma, use of leukotriene modifiers is associated with augmented bronchodilator responsiveness to albuterol in Puerto Ricans, but not Mexican Americans. This ethnic-specific, drug-drug interaction highlights the need for the further understanding of asthma pharmacogenetics among children from different ethnic groups to improve asthma outcomes.
Assuntos
Asma/tratamento farmacológico , Asma/fisiopatologia , Broncodilatadores/administração & dosagem , Interações Medicamentosas , Antagonistas de Leucotrienos/administração & dosagem , Adolescente , Albuterol/administração & dosagem , Asma/etnologia , Criança , Estudos Transversais , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Hispânico ou Latino , Humanos , Masculino , Americanos Mexicanos , Resultado do TratamentoRESUMO
Studies conducted on the secondary metabolite (natural product), dibenzyl trisulphide (DTS), which was isolated from the sub-tropical shrub Petiveria alliacea (guinea hen weed, anamu) [Phytolaccaceae] have shown tremendous pharmaceutical promise as a drug prototype. This is now reflected in the development of the broad spectrum anti-cancer molecule, fluorapacin (bis(4-fluorobenzyl) trisulphide) which has an excellent safety profile. The mode of action elucidated for DTS is the mitogen activated protein extracellular regulated kinases 1 and 2 (MAPKinases ERK 1 and ERK 2). The MAPKinase signal transduction biochemical pathways are important in the regulation of a wide range of cellular processes which are important in disease establishment. These processes include: cancer cell proliferation, nerve repair, memory enhancement, autoimmune diseases, which are linked to thymic cell involution and bone marrow functions, cerebrovascular and cardiovascular diseases. In addition to the MAPkinase signal transduction mode of action, DTS also prevents the denaturation of serum albumin which is a feature of nonsteroidal anti-inflammatory drugs, thus supporting the molecule's possible role in the treatment of inflammatory ageing diseases.
Assuntos
Compostos de Benzil/farmacologia , Desenho de Fármacos , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Fluorbenzenos/farmacologia , Phytolaccaceae , Transdução de Sinais/efeitos dos fármacos , Sulfetos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Degeneração Neural/tratamento farmacológico , Extratos Vegetais/farmacologiaRESUMO
The present article reports on the comparative cost of using the Bovine Serum Albumin as an assay for detecting natural products with anti-inflammatory activities relative to the use of animals. This is an addendum to the West Indian Medical Journal article; 2008; 57(4); 327-31.
Assuntos
Bioensaio , Soroalbumina Bovina/análise , Alternativas aos Testes com Animais/economia , Animais , Bioensaio/economia , Ratos , Ratos Sprague-DawleyRESUMO
AIMS: Thirty Campylobacter jejuni strains isolated from fecal samples (n = 94; 32%) from 13 positive farms (n = 17; 76%) from commercial broiler chickens in Puerto Rico were analysed by molecular methods. METHODS AND RESULTS: Isolates were identified with multiplex polymerase chain reaction assays, tested for their antimicrobial susceptibility and characterized with pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), serotyping and bacterial cytotoxicity in mammalian cells. Isolates exhibited high resistance to vancomycin (minimum inhibitory concentration, MIC of >256 microg ml(-1)) and trimethoprim (MIC of >32 microg ml(-1)); few were resistant to clindamycin (MIC(90) 4 microg ml(-1)), erythromycin (MIC(90) 8 microg ml(-1)) and tetracycline (MIC(90) 8 microg ml(-1)); but none was resistant to azithromycin (MIC(90) 4 microg ml(-1)), ciprofloxacin (MIC(90) 1 microg ml(-1)) or gentamycin (MIC(90) 4 microg ml(-1)). Most strains restricted with SmaI, but a combination of SmaI-KpnI digestion was more discriminatory. MLST analysis yielded four sequence types (ST), and ST-2624 was the predominant one. Phylogenetic analysis revealed a high degree of recombination for glnA and pgm genes. The predominant serotypes were O:3 and O:5. Most strains had lowest cytotoxicity potential with Caco-2 cells, medium cytotoxicity with INT-407 and Hep-2 cells and high cytotoxicity with CHO cells. CONCLUSION: A low degree of antimicrobial resistance, 13 PFGE profiles, 4 ST and a large variability in cytotoxicity assays were found for these strains. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first characterization of C. jejuni strains isolated from broilers in Puerto Rico. The genetic diversity of these strains suggests that several techniques are needed for strain characterization.
Assuntos
Infecções por Campylobacter/microbiologia , Infecções por Campylobacter/veterinária , Campylobacter jejuni/classificação , Galinhas/microbiologia , Microbiologia de Alimentos , Doenças das Aves Domésticas/microbiologia , Animais , Células CACO-2 , Campylobacter jejuni/efeitos dos fármacos , Campylobacter jejuni/genética , Testes Imunológicos de Citotoxicidade , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Genótipo , Humanos , Testes de Sensibilidade Microbiana , Porto Rico , Sorotipagem , Resistência a VancomicinaRESUMO
There are emerging ethical issues with regards to the use of animals in the early stages of drug discovery for anti-inflammatory and degenerative diseases from natural products using the activity-directed isolation pathways when many compounds (eg > 100) are present in the crude extract or fraction and are to be tested The above-mentioned is the main reason for proposing the use of the in vitro anti-denaturation (stabilization) effects of heat treated (immunogenic) bovine serum albumin (BSA) as an assay. Current methods used for detecting and isolating a wide range of anti-inflammatory compounds in the early stages of the drug discovery process utilize a large number of animals. When BSA is heated and is undergoing denaturation, it expresses antigens associated to Type III hypersensitive reaction and which are related to diseases such as serum sickness, glomerulonephritis, rheumatoid arthritis and systemic lupus erythematosus. Thus, the assay that is being proposed should be applicable to the discovery of drugs for treating the above mentioned diseases and others, once the compounds stabilize the denaturation process.
Assuntos
Anti-Inflamatórios/sangue , Preparações de Plantas/farmacologia , Desnaturação Proteica/efeitos dos fármacos , Soroalbumina Bovina/análise , Animais , Bioensaio , Bovinos , Descoberta de Drogas , Temperatura Alta/efeitos adversos , Doenças do Sistema Imunitário/tratamento farmacológico , Técnicas In Vitro , Programas de RastreamentoRESUMO
Mixed lymphocyte responses assays were conducted at 25.0 and 250.0 microg/mL of the crude ethanolic extract of Boehmeria jamaicensis Urb (coded as BJE) using peripheral lymphocytes obtained from individuals suffering from the common cold after four days of infection and from healthy individuals (without the common cold infection). At a concentration of 25 ug/mL, gamma interferon (IFN-gamma) was increased by 24.03 fold and interleukin 4 (IL-4) by 1.71 fold for the cells obtained from individuals with the common cold (Group A). The extract suppressed IFN-gamma by 8.3% while IL-4 was stimulated by 9.90 fold from peripheral lymphocytes obtained from healthy individuals (Group B). Gamma interferon was suppressed at 250 microg/mL while IL-4 was elevated by 1.86 fold for cells obtained from individuals suffering from the common cold (Group A). In conclusion, BJE could have implications for the treatment of the common cold.
Ensayos de reacci¨®n linfocitaria mixta fueron realizados a 25.0 y 250.0 ¦Ìg/mL de extracto etan¨®lico crudo de Boehmeria jamaicensis Urb (codificado como BJE), usando linfocitos perif¨¦ricos obtenidos de individuos con catarro com¨²n luego de cuatro d¨ªas de infecci¨®n, y de individuos sanos (sin la infecci¨®n del catarro com¨²n). Se hall¨® que el interfer¨®n-gamma (IFN-¦Ã) aument¨® en 24.03 veces, y la interleucina 4 (IL-4) en 1.71 veces para las c¨¦lulas obtenidas de individuos con catarro com¨²n, a 25¦Ìg/mL. El extracto inhibi¨® IFN-¦Ã en un 8.3 % en tanto que el IL-4 fue estimulado en 9.90 veces a partirde los linfocitos perif¨¦ricos obtenidos de individuos sanos. El gamma-interfer¨®n fue inhibido a 250 ¦Ìg/mL, mientras que la IL-4 se elev¨® en 1.86 veces para las c¨¦lulas obtenidas de individuos que sufren de catarro com¨²n.
Assuntos
Humanos , Boehmeria , Fitoterapia/métodos , Interferon gama/imunologia , /imunologia , Resfriado Comum/imunologia , Resfriado Comum/terapia , Sinusite/imunologia , Sinusite/terapia , Sinusite/microbiologiaRESUMO
Epingaione (4-Methyl-1-(5-methyl-2, 3,4,5-tetrahydro-[2,3']bifuranyl-5-yl)-pentan-2-one) was isolated as one of the major lipophilic secondary metabolites from the leaves and stems of Bontia daphnoides L. The compound gave 79.24% and 50.83% anti-proliferation/cytotoxic activity on the human SH-SY5Y neuroblastoma and TE-671 sarcoma cells in vitro at 50 pg/mL, respectively. Epingaione was transformed into eleven derivatives under laboratory conditions using ethanol, some gave greater anti-proliferation/cytotoxic activity on the cancer cell lines tested. One of the derivatives (compound 2) with enhanced cytotoxic activity was elucidated as 5'-Ethoxy-5-methyl-5-(4-methyl-2-oxo-pentyl)-2,3,4,5-tetrahydro-5'H-[2,3']bifuranyl-2'-one. Both epingaione and compound 2 caused an accumulation of arrested or dead SH-SY5Y neuroblastoma in the m-phase of the cell cycle as revealed by the m-phase specific marker KE 67.
Assuntos
Furanos/farmacologia , Myoporaceae , Neuroblastoma/tratamento farmacológico , Pentanonas/farmacologia , Fitoterapia , Sarcoma/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/química , Humanos , Pentanonas/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta , Caules de PlantaRESUMO
The data compiled in the present review on dibenzyl trisulphide (DTS) isolated from Petiveria alliacea L (the guinea hen weed or anamu) revealed that the compound and its derivatives could be of tremendous pharmaceutical interest. The mode of action elucidated for DTS revealed that it is a mitogen activated protein extracellular regulated kinases 1 and 2 (MAPKinases erk1 and erk 2) signal transduction molecule. Dibenzyl trisulphide caused hyper-phosphorylation of growth factor induced MAPKinases (erk 1 and erk 2) phosphorylation, a process critical for the improvement of long term memory, and is implicated in neuronal growth. Dibenzyl trisulphide and its derivatives exhibited potent anti-proliferation/cytotoxic activity on a wide range of cancer cell lines. The cytotoxic activity of DTS was increased by 70-1000 fold when bound to albumin in vitro. Dibenzyl trisulphide seems to have a cytokine switching mechanism in which it down regulates cytokines from the Type I helper cells (Th -1 cell) pathway which contained several pro-inflammatory cytokines and up-regulates those on the Type 2 helper cells (Th-2) pathway. The trisulphide up-regulates some reticuloendothelial system parameters eg granulocyte counts and increased thymic and Peyer's patches masses via cell proliferation processes which are known to be regulated via the MAPKinase signal transduction pathway. When the zygotes ofAsternia pectinifera (Starfish) were exposed to DTS at concentration of 10 mM, a dose lethal to all cancer cells tested, it was observed that the sensitive process of protein biosynthesis was not affected Similarly, the proliferation of the HOFA human fibroblast, a noncancerous cell line, was not severely affected by DTS at 8.9 microM over seven days, a concentration also lethal to most cancer cell lines tested The implications of the findings will be highlighted in the present review.
Assuntos
Compostos de Benzil/uso terapêutico , Fitoterapia , Extratos Vegetais , Sulfetos/uso terapêutico , Antígenos CD/fisiologia , Compostos de Benzil/farmacologia , Caderinas/fisiologia , Humanos , Transdução de Sinais/efeitos dos fármacos , Sulfetos/farmacologia , Regulação para Cima/fisiologiaRESUMO
The data compiled in the present review on dibenzyl trisulphide (DTS) isolated from Petiveria alliacea L (the guinea hen weed or anamu) revealed that the compound and its derivatives could be of tremendous pharmaceutical interest. The mode of action elucidated for DTS revealed that it is a mitogen activated protein extracellular regulated kinases 1 and 2 (MAPKinases erk1 and erk 2) signal transduction molecule. Dibenzyl trisulphide caused hyper-phosphorylation of growth factor induced MAPKinases (erk 1 and erk 2) phosphorylation, a process critical for the improvement of long term memory, and is implicated in neuronal growth. Dibenzyl trisulphide and its derivatives exhibited potent anti-proliferation/cytotoxic activity on a wide range of cancer cell lines. The cytotoxic activity of DTS was increased by 70-1000 fold when bound to albumin in vitro. Dibenzyl trisulphide seems to have a cytokine switching mechanism in which it down regulates cytokines from the Type I helper cells (Th -1 cell) pathway which contained several pro-inflammatory cytokines and up-regulates those on the Type 2 helper cells (Th-2) pathway. The trisulphide up-regulates some reticuloendothelial system parameters eg granulocyte counts and increased thymic and Peyer's patches masses via cell proliferation processes which are known to be regulated via the MAPKinase signal transduction pathway. When the zygotes ofAsternia pectinifera (Starfish) were exposed to DTS at concentration of 10 mM, a dose lethal to all cancer cells tested, it was observed that the sensitive process of protein biosynthesis was not affected Similarly, the proliferation of the HOFA human fibroblast, a noncancerous cell line, was not severely affected by DTS at 8.9 microM over seven days, a concentration also lethal to most cancer cell lines tested The implications of the findings will be highlighted in the present review.
Los datos compilados en el presente estudio sobre el trisulfuro de dibencilo (TSD) aislado a partir de Petiveria alliacea L (yerba de Guinea, ó anamú) revelaron que el compuesto y sus derivados podrían tener extraordinario interés farmacéutico. El modo de acción esclarecido en el TSD, reveló que se trata de una molécula de transducción de señales de proteínas kinasas 1 y 2 (MAP quinasas ERk 1 y 2) reguladas extracelularmente y activadas por mitógenos. El trisulfuro de dibencilo causó hiperfosforilación de la fosforilación de las quinasas MAP (Erk 1 y 2) inducidas mediante factor de crecimiento, un proceso crítico para el mejoramiento de la memoria a largo plazo, y que está implicado en el crecimiento neuronal. El trisulfuro de dibencilo y sus derivados mostraron una poderosa actividad citotóxica y antiproliferativa en una amplia gama de líneas celulares de cáncer. La actividad citotóxica del TSD se incrementaba de 70 á 1000 veces, cuando se vinculaba a la albúmin in vitro. El trisulfuro de dibencilo parece poseer un mecanismo conmutador citoquínico que regula por decremento las citoquinas provenientes de la vía de las células auxiliares de tipo 1 (células Th-1), que contiene varias citoquinas pro-inflamatorias y regula por incremento las de la vía de las células auxiliares de tipo 2 (Th-2). El trisulfuro regula por incremento los parámetros del sistema reticuloendotelial, p.ej. los conteos de granulocitos y el aumento tanto de las masas tímicas como de las masas de placas de Peyer, a través de los procesos de proliferación celular, de los cuales se sabe que son regulados mediante la vía de la transducción de señales de la quinasa MAP. Cuando los cigotos de Asternia pectinifera (estrella de mar) fueron expuestos al TSD a una concentración de 10 mM una dosis letal para todas las células cancerosas sometidas a prueba se observó que el proceso sensible de biosíntesis de la proteína no era afectado. De modo similar, la proliferación del fibroblasto humano HOFA una línea celular no cancerosa no fue afectada severamente por el TSD a 8.9 µM en siete días una concentración letal para la mayoría de las líneas celulares cancerosas sometidas a prueba. Las implicaciones de los hallazgos se pondrán de relieve en el presente estudio
Assuntos
Humanos , Compostos de Benzil/uso terapêutico , Extratos Vegetais , Fitoterapia , Sulfetos/uso terapêutico , Antígenos CD/fisiologia , Caderinas/fisiologia , Compostos de Benzil/farmacologia , Regulação para Cima/fisiologia , Sulfetos/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Epingaione (4-Methyl-1-(5-methyl-2, 3,4,5-tetrahydro-[2,3']bifuranyl-5-yl)-pentan-2-one) was isolated as one of the major lipophilic secondary metabolites from the leaves and stems of Bontia daphnoides L. The compound gave 79.24and 50.83anti-proliferation/cytotoxic activity on the human SH-SY5Y neuroblastoma and TE-671 sarcoma cells in vitro at 50 pg/mL, respectively. Epingaione was transformed into eleven derivatives under laboratory conditions using ethanol, some gave greater anti-proliferation/cytotoxic activity on the cancer cell lines tested. One of the derivatives (compound 2) with enhanced cytotoxic activity was elucidated as 5'-Ethoxy-5-methyl-5-(4-methyl-2-oxo-pentyl)-2,3,4,5-tetrahydro-5'H-[2,3']bifuranyl-2'-one. Both epingaione and compound 2 caused an accumulation of arrested or dead SH-SY5Y neuroblastoma in the m-phase of the cell cycle as revealed by the m-phase specific marker KE 67.
La epingaiona (4-Metil-1-(5-metil-2,3,4,5-tetrahidro-[2,3']bifuranil-5-il)-pentan-2-uno) fue aislada como uno de los principales metabolitos lipofilicos secundarios de las hojas y tallos de Bontia daphnoides L. El compuesto produjo 79.24 % y 50.83 % de actividad citotóxica/anti-proliferación sobre el neuroblastoma humano SH-SY5Y y las células del sarcoma TE-671 in vitro a 50 µg/mL, respectivamente. La epingaiona fue transformada en once derivados en condiciones de laboratorio, utilizando etanol. Algunos produjeron mayor actividad citotóxica y antiproliferativa sobre las líneas celulares cancerosas sometidas a ensayo. Uno de los derivados (compuesto 2) de elevada actividad citotóxica fue identificado como 5'-Etoxi-5-metil-5-(4-metil-2-oxo-pentil)-2,3,4,5-tetrahidro-5'H- [2,3']bifuranil-2'-uno. Tanto la epingaiona como el compuesto 22 causaron una acumulación de neuroblastomas SH-SY5Y muertos o detenidos en la fase m del ciclo celular, según lo revela el marcador KE 67 específico de la fase m.