68 research outputs found
In vitro modulation of ABCB1/P-glycoprotein expression by polyphenols from Mangifera indica
No full textMany plant compounds are able to modulate the activity and/or the expression of the major multidrug transporter ABCB1/P-glycoprotein (P-gp). In this study, mango (Mangifera indica L.) stem bark extract (MSBE), its main polyphenol mangiferin and the mangiferin aglycone derivative norathyriol, as well as catechin, gallic acid and quercetin, were investigated for their potential ability to influence ABCB1 gene and P-gp expression in HK-2 cells, a proximal tubule line constitutively expressing this transporter. Western blot analysis demonstrated a concentration-dependent decrease in P-gp in cells cultured in the presence of MSBE for 72 h. Gallic acid and quercetin also decreased the levels of P-gp at all studied concentrations, whereas catechin was almost ineffective. However, in cells exposed to mangiferin (10-200 microM), the P-gp amount showed a concentration- and time-dependent increase, being 2-fold higher than the controls after 72 h. Norathyriol (5 microM) induced P-gp, but the effect decreased at higher concentrations. The changes in the P-gp protein amount were correlated with relative changes in the ABCB1 mRNA content and with the efflux activity of the transporter. The transcriptional inhibitor 1-d-ribofuranosylbenzimidazole (DRB) contrasted the increased expression of ABCB1 by mangiferin, suggesting that the increase could be due to transcriptional up-regulation of ABCB1 mRNA. Mangiferin-treated cells overexpressing the transporter were protected against the cytotoxicity of the known P-gp substrate cyclosporine A. However, the opposite effect was not observed in cells pretreated with MSBE. These results demonstrate that MSBE and mango polyphenols, already shown in our previous studies to influence P-gp activity, may also interact with ABCB1/P-gp at the expression level. In particular, we show for the first time that the main mango polyphenol mangiferin up-regulates this multidrug transporter. The molecular mechanisms and the consequences of these effects, including the possibility of interactions with conventional drugs or other herbal constituents, remain to be elucidated.
Many plant compounds are able to modulate the activity and/or the expression of the major multidrug transporter ABCB1/P-glycoprotein (P-gp). In this study, mango (Mangifera indica L.) stem bark extract (MSBE), its main polyphenol mangiferin and the mangiferin aglycone derivative norathyriol, as well as catechin, gallic acid and quercetin, were investigated for their potential ability to influence ABCB1 gene and P-gp expression in HK-2 cells, a proximal tubule line constitutively expressing this transporter. Western blot analysis demonstrated a concentration-dependent decrease in P-gp in cells cultured in the presence of MSBE for 72 h. Gallic acid and quercetin also decreased the levels of P-gp at all studied concentrations, whereas catechin was almost ineffective. However, in cells exposed to mangiferin (10-200 microM), the P-gp amount showed a concentration- and time-dependent increase, being 2-fold higher than the controls after 72 h. Norathyriol (5 microM) induced P-gp, but the effect decreased at higher concentrations. The changes in the P-gp protein amount were correlated with relative changes in the ABCB1 mRNA content and with the efflux activity of the transporter. The transcriptional inhibitor 1-d-ribofuranosylbenzimidazole (DRB) contrasted the increased expression of ABCB1 by mangiferin, suggesting that the increase could be due to transcriptional up-regulation of ABCB1 mRNA. Mangiferin-treated cells overexpressing the transporter were protected against the cytotoxicity of the known P-gp substrate cyclosporine A. However, the opposite effect was not observed in cells pretreated with MSBE. These results demonstrate that MSBE and mango polyphenols, already shown in our previous studies to influence P-gp activity, may also interact with ABCB1/P-gp at the expression level. In particular, we show for the first time that the main mango polyphenol mangiferin up-regulates this multidrug transporter. The molecular mechanisms and the consequences of these effects, including the possibility of interactions with conventional drugs or other herbal constituents, remain to be elucidated.
Copyright 2010 Elsevier Ireland Ltd. All rights reserved
Prevalence of single-nucleotide variants in twenty-five pharmacogenes from a Cuban sample cohort
No full textIntroduction The Cuban population is genetically diverse, and information on the prevalence of genetic variants is still limited. As complex admixture processes have occurred, we hypothesized that the frequency of pharmacogenetic variants and drug responses may vary within the country. The aims of the study were to describe the frequency distribution of 43 single-nucleotide variants (SNVs) from 25 genes of pharmacogenetic interest within the Cuba population and in relation to other populations, while taking into consideration some descriptive variables such as place of birth and skin color.Materials and Methods SNVs were analyzed in 357 unrelated healthy Cuban volunteers. Genotype, allele frequencies, and ancestry proportions were determined, and the pairwise fixation index (FST ) was evaluated.Results Hardy-Weinberg equilibrium (HWE) deviations in six loci (rs11572103, rs2740574, rs776746, rs3025039, rs861539, and rs1762429) were identified. Minor allele frequencies (MAFs) ranged from 0.00 to 0.15 for variants in genes encoding xenobiotic metabolizing enzymes. They also ranged from 0.01 to 0.21 for variants in DNA repair, growth factors, methyltransferase, and methyl-binding proteins, while they ranged from 0.04 to 0.27 for variants in the O-6-methylguanine-DNA methyltransferase enzyme. Moderate genetic divergence was observed upon comparison to Africans (FST = 0.071 and SD 0.079), with 19 markers exhibiting moderate-to-large genetic differentiation. The average European, African, and Amerindian ancestry proportions were 67.8%, 27.2%, and 5.3%, respectively. Ancestry proportions differed by skin color and birthplace for both African and European components, with the exception of the European component, which showed no significant difference between individuals from Western and Eastern regions. Meanwhile, the statistical significance varied in comparisons by skin color and birthplace within the Amerindian component. Low genetic divergence was observed across geographical regions. We identified 12 variants showing moderate-to-large differentiation between White/Black individuals.Conclusion Altogether, our results may support national strategies for the introduction of pharmacogenetic tools in clinical practice, contributing to the development of precision medicine in Cuba.Funding
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was funded by Project: VLIR TEAM CU2022TEA501A102 “Building in vitro plant biotechnology capacities for ecological sustainable production of marine phytochemical formulations against skin-cancer in Cuba” and the Project UNPD/GEF 11037 “Developing the potential of Thalassia testudinum in the health sector in Cuba in accordance with the Nagoya Protocol and Biodiversity Conservation.” VLIR TEAM ZEIN2016PR420–75155 Implementation of personalized medicine and pharmaco(epi) genetic biomarkers for cost effective improvement of the therapeutic outcome of lung cancer treatment in Cuba.
Acknowledgments
The authors thank the volunteers, administrators, and staff members from the recruitment sites for contributing with their time and expertise to our research and sharing their experiences with us
Sacha Inchi (Plukenetia volubilis L.) powder: acute toxicity, 90 days oral toxicity study and micronucleus assay in rodents
No full textContext: Sacha Inchi has been consumed for years by indigenous peoples. Meanwhile, its toxicological potential has not been sufficiently studied.
Aims: To assess the acute, sub-chronic toxicity and genotoxicity evaluation of Sacha Inchi powder obtained from Plukenetia volubilis L.
Methods: A dose of 2000 mg/kg was orally administered to rats and mice and toxicity symptoms for 14 days were observed. In repeated dose study, the product was orally administered to Sprague Dawley rats of both sexes. Animals received 50, 250 and 500 mg/kg/day of the product for 90 days. At the end, animals were sacrificed and samples were done for hematological and biochemical analysis, organ weighs and histopathological examination. Genotoxicity potential of Sacha Inchi powder was evaluated through micronucleus test in mice. Negative controls received the vehicle (carboxymethyl cellulose, 0.5%) used.
Results: No morbidity or mortality at 2000 mg/kg of the product were found. Sacha Inchi powder oral administration during 90 days to rats did not lead to death, body weight gain, food consumption, or adverse events. No significant changes on hematological or biochemical parameters, organ weights or histopathological findings were observed. Induction of micronucleus formation attributable to the product was not found in mice.
Conclusions: No toxicity effects after oral acute exposure of Sacha Inchi power to rats and mice were observed. Neither toxicity attributable to oral doses of the product up to 500 mg/kg during 90 days to rats were found. Results suggested Sacha Inchi powder does not have genotoxicity potential under our experimental conditions
Anti-inflammatory and Analgesic Effects of Friedelane Triterpenoid, 29-Hydroxyfriedelan-3-one, Extracted from Maytenus gonoclada Mart. (Maytenus robusta Reissek) in LPS-Induced Acute Lung Injury and Mechanical Hyperalgesia
No full textThe present work focuses on exploring the pharmacological potential of the compound 29-hydroxyfriedelan-3-one (29-HF), isolated from the branches of Maytenus gonoclada Mart., in relation to experimentally induced innate immune response and mechanical hyperalgesia by LPS administration in the lungs and paws of mice, respectively. To investigate the effects of pre-treatment with 29-HF, administered subcutaneously, on the LPS response, we collected bronchoalveolar lavage and assessed the recruitment of white blood cells in this space, along with the release of cytokines IL-6, IL-1β, and TNF-α, along with myeloperoxidase activity. Furthermore, to evaluate the analgesic potential of 29-HF in relation to inflammation-induced mechanical hyperalgesia in response to intraplantar LPS injection, we conducted the modified Randall-Selitto test in mice. The results demonstrated that pre-treatment with 29-HF exhibited significant anti-inflammatory effects in a model of acute pulmonary inflammation induced by intranasal LPS instillation. This was manifested by a significant reduction in neutrophil recruitment into the bronchoalveolar space, as well as a reduction in the release of IL-1β and IL-6 in this model. Additionally, 29-HF also showed efficacy in reducing myeloperoxidase activity in the bronchoalveolar lavage. In the model of mechanical hyperalgesia induced by intraplantar LPS injection, treatment with 29-HF, administered intraperitoneally and intraplantar, resulted in a significant increase in the nociceptive response threshold in animals challenged with intraplantar LPS injection. This analgesic effect of 29-HF was further confirmed in tests to assess potential neuromotor alterations on a Rotarod, where animals treated with 29-HF did not exhibit significant differences in motor performance compared to the PBS-treated group. In summary, our findings suggest that 29-HF possesses pharmacological anti-inflammatory and analgesic effects in models of acute pulmonary inflammation and LPS-induced mechanical hyperalgesia.O presente trabalho aborda o estudo do potencial farmacológico do composto 29-
hidroxifriedelan-3-ona (29-HF), isolado do galho da espécie Maytenus gonoclada Mart.
na resposta imune inata e hiperalgesia mecânica induzidas experimentalmente por
LPS administrado, respectivamente, nos pulmões e patas de camundongos. Foram
avaliados, através da coleta de lavado broncoalveolar, os efeitos do pré-tratamento
com 29-HF, administrado pela via subcutânea, sobre o recrutamento leucocitário ao
espaço broncoalveolar de camundongos desafiados com instilação intranasal de LPS.
Além disso, avaliamos a liberação das citocinas IL-6, IL-1β e TNF-α e da atividade da
mieloperoxidase no lavado broncoalveolar. Para investigar o potencial analgésico a
nível sistêmico e local do 29-HF contra a hiperalgesia mecânica induzida por
inflamação em resposta à injeção intraplantar de LPS, foi realizado o teste de Randall Selitto modificado para camundongos. O pré-tratamento com 29-HF apresentou efeito
anti-inflamatório em modelo de inflamação pulmonar aguda induzida pela instilação
intranasal de LPS, que foi caracterizado pela redução significativa do recrutamento
neutrofílico ao espaço broncoalveolar, além de ter proporcionado redução significativa
da liberação de IL-1β e IL-6 nesse mesmo modelo. O 29-HF também mostrou eficácia
na redução da atividade da mieloperoxidase obtido em lavado broncoalveolar. No
modelo de hiperalgesia mecânica induzida por injeção intraplantar de LPS, o
tratamento com 29-HF, injetado pela via intraperitoneal e intraplantar, demonstrou
aumento significativo do limiar nociceptivo de animais desafiados com injeção
intraplantar de LPS. O efeito analgésico do 29-HF foi revalidado em teste para avaliar
possíveis alterações neuromotoras em Rotarod, onde os animais tratados com 29-HF
não apresentaram diferença no desempenho motor comparado ao grupo tratado com
PBS. Em suma, nossos resultados sugerem que o 29-HF apresenta efeito
farmacológico anti-inflamatório e analgésico em modelos de inflamação pulmonar
aguda e hiperalgesia mecânica induzidos por LPS.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superio
Heme-oxygenase-1: a promissory therapeutic target
No full textLa enzima hemo-oxigenasa es la principal enzima implicada en el catabolismo del grupo hemo y da lugar a tres productos fundamentales: biliverdina, el hierro libre y el monóxido de carbono. Fue descubierta a principios de la década del 60, pero no fue hasta mediado de los años ´80 donde empezó a estudiarse con detenimiento y se determinó que existía una isoforma inducible, denominada hemo oxigenasa-1. Esta proteína juega un papel muy importante en la modulación de procesos inflamatorios y eso ha sido demostrado en diferentes modelos experimentales tanto en animales como humanos, en los mecanismos de defensa antioxidantes que posee el organismo ante la presencia de algún daño y en el bloqueo de los procesos apoptóticos donde han sido involucradas distintas rutas de señalización celular. El estudio de esta enzima y de su mecanismo de acción ha sido objeto de estudio por parte de muchos científicos y su esclarecimiento será un paso importante para su posterior inclusión en la clínica.Heme oxygenase is the rate-limiting enzyme in the catabolism of heme, followed by production of biliverdin, free iron and carbon monoxide. It was discovered at the beginning of the 60´s decade, but didn't go until half-filled of eighties when an inducible form of heme oxygenase was discovered, named heme oxygenase-1. This protein plays a very important role in the modulation of inflammatory processes and that has been demonstrated in different experimental models so much in
animals as human, in the mechanisms of antioxidant defense that it possesses the organism before the presence of
different damage and in the blockade of the apoptotic process where different routes of cellular signaling have been involved. The study of this enzyme and of their action mechanism has been matter of study by many scientists and their clarification will be an important step for its later inclusion in the clinic.Colegio de Farmacéuticos de la Provincia de Buenos Aire
Medicinal plant reported with adverse reactions in Cuba: potential interactions with conventional drugs
No full textContext: Herbal drugs are a mixture of active compounds and the chemical complexity of each formulation increase with the possibility of interactions between them and conventional drugs. Many mechanisms are implicated in the interactions; scientific community has dedicated the attentions to enzymes as P-gp and CYP450.
Aims: To investigate in the literature the principal plants with suspicions of adverse reactions in Cuba and their potential interactions with conventional drugs.
Methods: PubMed was the database used as source of information until February 2014. Key words: Herb-Drug, Drug-Plant, Herbal–Drug, Interactions with scientific names of plants was used. Information was structured and analysed with EndNote X4.
Analysis and integration of the information: Allium sativum L. (garlic) was the plant with the high number of studies related with CYP450 and P-gp. Plants with great demand as Morinda citrifolia L. (noni), Psidium guajava L. (guayaba), Zingiber officinale Roscoe (ginger) and Eucalyptus spp. (eucalyptus) have a very small number of studies. The professionals of the health should keep in mind the possibility of interactions between herbal products and conventional drugs to increase the effectiveness of phytotherapy.
Conclusions: It is necessary enhance reports and investigations and to put to disposition of the system of health information on the interactions of plants and to stimulate the investigation that offers information for the rational use of our medicinal plants
Heme-oxygenase-1: a promissory therapeutic target
No full textLa enzima hemo-oxigenasa es la principal enzima implicada en el catabolismo del grupo hemo y da lugar a tres productos fundamentales: biliverdina, el hierro libre y el monóxido de carbono. Fue descubierta a principios de la década del 60, pero no fue hasta mediado de los años ´80 donde empezó a estudiarse con detenimiento y se determinó que existía una isoforma inducible, denominada hemo oxigenasa-1. Esta proteína juega un papel muy importante en la modulación de procesos inflamatorios y eso ha sido demostrado en diferentes modelos experimentales tanto en animales como humanos, en los mecanismos de defensa antioxidantes que posee el organismo ante la presencia de algún daño y en el bloqueo de los procesos apoptóticos donde han sido involucradas distintas rutas de señalización celular. El estudio de esta enzima y de su mecanismo de acción ha sido objeto de estudio por parte de muchos científicos y su esclarecimiento será un paso importante para su posterior inclusión en la clínica.Heme oxygenase is the rate-limiting enzyme in the catabolism of heme, followed by production of biliverdin, free iron and carbon monoxide. It was discovered at the beginning of the 60´s decade, but didn't go until half-filled of eighties when an inducible form of heme oxygenase was discovered, named heme oxygenase-1. This protein plays a very important role in the modulation of inflammatory processes and that has been demonstrated in different experimental models so much in
animals as human, in the mechanisms of antioxidant defense that it possesses the organism before the presence of
different damage and in the blockade of the apoptotic process where different routes of cellular signaling have been involved. The study of this enzyme and of their action mechanism has been matter of study by many scientists and their clarification will be an important step for its later inclusion in the clinic.Colegio de Farmacéuticos de la Provincia de Buenos Aire
Potencialidades como antivirales de compuestos de origen marino: una revisión
No full textA pesar del gran número de evidencias experimentales y el desarrollo de algunos productos, a la fecha, la inmensa mayoría de las enfermedades virales carece de tratamiento terapéutico y profiláctico, y continúan siendo un grave problema de salud. Varias han sido las fuentes descritas como reservorios de compuestos con actividad antiviral contra un amplio espectro de virus. La vasta extensión oceánica ha sido clasificada, en la década de 1980, como el mayor depósito de productos naturales a evaluar por su actividad como posibles drogas. Varios estudios han demostrado que los organismos marinos producen una variedad de compuestos, derivados del metabolismo primario o secundario, que pueden poseer actividades antivirales y aplicaciones farmacéuticas. Esta revisión se propone abordar las tendencias de la investigación sobre los efectos antivirales in vitro e in vivo de organismos marinos en los últimos años, contra diferentes clases de patógenos virales en todo el mundo. Se consultaron varias bases de datos electrónicas, incluidas PubMed, Google Scholar, Journal of Virology y Journal of General Virology, en busca de artículos publicados en inglés que evaluaran la actividad antiviral de compuestos de origen marino. Los datos presentados en esta revisión destacan las potencialidades de compuestos deriva- dos de organismos marinos como fuentes de nuevos antivirales y abren nuevas vías para más investigaciones sobre este tema
Polimorfismos en genes de reparación del daño al material genético y cáncer de pulmón
No full textIntroducción: El cáncer de pulmón es uno de los principales problemas de salud en Cuba y el mundo. Las diferencias genéticas a causa de polimorfismos de un solo nucleótido, son factores importantes involucrados en la susceptibilidad genética a esta enfermedad. En Cuba son escasos los datos disponibles sobre los polimorfismos de un solo nucleótido y su posible influencia sobre la aparición y pronóstico del cáncer.
Objetivo: Exponer la importancia del estudio de los polimorfismos de un solo nucleótido en genes de la reparación del daño al ADN en el cáncer de pulmón.
Desarrollo: El tabaquismo es el principal factor de riesgo para desarrollar cáncer de pulmón, sin embargo, aproximadamente el 15 % de los fumadores desarrollará la enfermedad. Los polimorfismos de un solo nucleótido son factores involucrados en la predisposición genética a las enfermedades. La presencia de variantes polimórficas puede modificar la eficacia de los sistemas de reparación, favoreciendo la aparición de genotoxicidad y/o mutagénesis. También pueden modificar la respuesta a los tratamientos oncológicos y la supervivencia de los pacientes. Por consiguiente, además de ser marcadores de susceptibilidad, los polimorfismos se consideran marcadores de pronóstico individual de respuesta a la terapia. Este trabajo enfatiza la utilidad de su evaluación como biomarcadores clínicos y de susceptibilidad genética a enfermedades en la población cubana.
Conclusiones: El estudio de polimorfismos de un solo nucleótido permitirá el abordaje personalizado de enfermedades oncológicas, lo cual podría contribuir a su detección temprana y a definir grupos de individuos con alto riesgo de padecer cáncer de pulmón
Oral subchronic toxicity of D-003 in NMRI mice
No full textEl D-003 es una mezcla de ácidos alifáticos primarios de muy alto peso molecular purificada de la cera de caña, con efectos hipolipemiante y antiagregante plaquetario demostrados experimental y clí- nicamente. Los estudios toxicológicos han investigado la toxicidad del D-003, administrado como dosis orales únicas y repetidas en ratas y perros. Este estudio investigó la toxicidad oral del D-003 administrado como dosis repetidas a ratones NMRI. Los animales se distribuyeron aleatoriamente en 4 grupos: 1 con- trol y 3 tratados con D-003 (5, 50 y 500 mg/kg/d). Los tratamientos se administraron durante 90 días, a cu- yo término los animales fueron sacrificados. El tratamiento subcrónico oral con D-003 no produjo eviden- cias de toxicidad asociada al tratamiento, según el análisis de su ganancia de peso, consumo de alimentos, observaciones clínicas, indicadores de bioquímica sanguínea, hematología, peso relativo de los órganos y análisis histopatológico, que no mostraron diferencias o tendencias entre tratados y controles. Los resulta- dos en esta segunda especie roedora confirman que el D-003 administrado por vía oral a dosis repetidas no resulta tóxico aún a la máxima dosis investigada.D-003 is a mixture of very high molecular weight aliphatic acids purified from sugarcane wax withlipid-lowering and antiplatelet effects experimentally and clinically proven. Toxicological studies have assessed the oral toxicity of D-003, administered as single or repeated doses, in rats and dogs. This study investigated the oral toxicity of D-003 repeatedly administered to NMRI mice. Animals were randomly distributed into 4 groups: 1 control and 3 treated with D-003 (5, 50 and 500 mg/kg/d, respectively). Treatments were given for 90 days, and at treatment completion animals were sacrificed. Oral subcronic treatment with D-003 did not show evidences of drug-related toxicity, as per the analysis of body- weight gain, food consumption, clinical daily observations, blood biochemistry and haematological safety indica- tors, relative organ weight and histopathological study, which did not show any significant difference or trends between control and treated animals. The results of this study in a second rodent species confirm that D-003 ad- ministered orally at repeated doses was not toxic, even at the highest dose investigated.Colegio de Farmacéuticos de la Provincia de Buenos Aire
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