RESUMEN

The circadian clock system coordinates metabolic, physiological, and behavioral functions across a 24-h cycle, crucial for adapting to environmental changes. Disruptions in circadian rhythms contribute to major metabolic pathologies like obesity and Type 2 diabetes. Understanding the regulatory mechanisms governing circadian control is vital for identifying therapeutic targets. It is well characterized that chromatin remodeling and 3D structure at genome regulatory elements contributes to circadian transcriptional cycles; yet the impact of rhythmic chromatin topology in metabolic disease is largely unexplored. In this study, we explore how the spatial configuration of the genome adapts to diet, rewiring circadian transcription and contributing to dysfunctional metabolism. We describe daily fluctuations in chromatin contacts between distal regulatory elements of metabolic control genes in livers from lean and obese mice and identify specific lipid-responsive regions recruiting the clock molecular machinery. Interestingly, under high-fat feeding, a distinct interactome for the clock-controlled gene Dbp strategically promotes the expression of distal metabolic genes including Fgf21. Alongside, new chromatin loops between regulatory elements from genes involved in lipid metabolism control contribute to their transcriptional activation. These enhancers are responsive to lipids through CEBPß, counteracting the circadian repressor REVERBa. Our findings highlight the intricate coupling of circadian gene expression to a dynamic nuclear environment under high-fat feeding, supporting a temporally regulated program of gene expression and transcriptional adaptation to diet.

Asunto(s)

Cromatina , Relojes Circadianos , Ácidos Grasos , Hígado , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad , Animales , Cromatina/metabolismo , Cromatina/genética , Hígado/metabolismo , Ratones , Relojes Circadianos/genética , Obesidad/metabolismo , Obesidad/genética , Ácidos Grasos/metabolismo , Masculino , Dieta Alta en Grasa/efectos adversos , Ensamble y Desensamble de Cromatina , Ritmo Circadiano/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Metabolismo de los Lípidos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/genética , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo

RESUMEN

Evolutionary analyses have estimated that ∼60% of nucleotides in intergenic regions of the Drosophila melanogaster genome are functionally relevant, suggesting that regulatory information may be encoded more densely in intergenic regions than has been revealed by most functional dissections of regulatory DNA. Here, we approached this issue through a functional dissection of the regulatory region of the gene shavenbaby (svb). Most of the ∼90 kb of this large regulatory region is highly conserved in the genus Drosophila, though characterized enhancers occupy a small fraction of this region. By analyzing the regulation of svb in different contexts of Drosophila development, we found that the regulatory information that drives svb expression in the abdominal pupal epidermis is organized in a different way than the elements that drive svb expression in the embryonic epidermis. While in the embryonic epidermis svb is activated by compact enhancers separated by large inactive DNA regions, svb expression in the pupal epidermis is driven by regulatory information distributed over broader regions of svb cis-regulatory DNA. In the same vein, we observed that other developmental genes also display a dense distribution of putative regulatory elements in their regulatory regions. Furthermore, we found that a large percentage of conserved noncoding DNA of the Drosophila genome is contained within regions of open chromatin. These results suggest that part of the evolutionary constraint on noncoding DNA of Drosophila is explained by the density of regulatory information, which may be greater than previously appreciated.

Asunto(s)

Proteínas de Drosophila , Drosophila , Animales , Drosophila/metabolismo , Factores de Transcripción/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Regulación del Desarrollo de la Expresión Génica , ADN , ADN Intergénico/genética , ADN Intergénico/metabolismo , Elementos de Facilitación Genéticos

RESUMEN

The study aimed to determine the enhanced effects of essential oils (EOs) and plant-derived molecules (PDMs) as penetration enhancers (PEs) for transdermal drug delivery (TDD) of caffeine. A 1% w/w solution of eight EOs and seven PDMs was included in the 1% caffeine carbopol hydrogel. Franz diffusion cell experiments were performed using mice with full-thickness skin. At various times over 24 h, 300 µL of the receptor were withdrawn and replaced with fresh medium. Caffeine was analyzed spectrophotometrically at 272 nm. The skin irritation effects of the hydrogels applied once a day for 21 days were investigated in mice. The steady-state flux (JSS) of the caffeine hydrogel was 30 ± 19.6 µg cm-2 h-1. An increase in caffeine JSS was induced by Lippia origanoides > Turnera diffusa > eugenol > carvacrol > limonene, with values of 150 ± 14.1, 130 ± 47.6, 101 ± 21.7, 90 ± 18.4, and 86 ± 21.0 µg cm-2 h-1, respectively. The Kp of caffeine was 2.8 ± 0.26 cm h-1, almost 2-4 times lower than that induced by Lippia origanoides > Turnera diffusa > limonene > eugenol > carvacrol, with Kp values of 11 ± 1.7, 8.8 ± 4.2, 6.8 ± 1.7, 6.3 ± 1.2, and 5.15 ± 1.0 cm h-1, respectively. No irritating effects were observed. Lippia origanoides, Turnera diffusa, eugenol, carvacrol, and limonene improved caffeine's skin permeation. These compounds may be as effective as the PE in TDD systems.

Asunto(s)

Aceites Volátiles , Ratones , Animales , Aceites Volátiles/farmacología , Limoneno , Eugenol , Colombia , Cafeína , Administración Cutánea , Hidrogeles

RESUMEN

Neural induction, both in vivo and in vitro, includes cellular and molecular changes that result in phenotypic specialization related to specific transcriptional patterns. These changes are achieved through the implementation of complex gene regulatory networks. Furthermore, these regulatory networks are influenced by epigenetic mechanisms that drive cell heterogeneity and cell-type specificity, in a controlled and complex manner. Epigenetic marks, such as DNA methylation and histone residue modifications, are highly dynamic and stage-specific during neurogenesis. Genome-wide assessment of these modifications has allowed the identification of distinct non-coding regulatory regions involved in neural cell differentiation, maturation, and plasticity. Enhancers are short DNA regulatory regions that bind transcription factors (TFs) and interact with gene promoters to increase transcriptional activity. They are of special interest in neuroscience because they are enriched in neurons and underlie the cell-type-specificity and dynamic gene expression profiles. Classification of the full epigenomic landscape of neural subtypes is important to better understand gene regulation in brain health and during diseases. Advances in novel next-generation high-throughput sequencing technologies, genome editing, Genome-wide association studies (GWAS), stem cell differentiation, and brain organoids are allowing researchers to study brain development and neurodegenerative diseases with an unprecedented resolution. Herein, we describe important epigenetic mechanisms related to neurogenesis in mammals. We focus on the potential roles of neural enhancers in neurogenesis, cell-fate commitment, and neuronal plasticity. We review recent findings on epigenetic regulatory mechanisms involved in neurogenesis and discuss how sequence variations within enhancers may be associated with genetic risk for neurological and psychiatric disorders.

RESUMEN

Squamous cell carcinoma (SCC) represents 20% of cases of non-melanoma skin cancer, and the most common treatment is the removal of the tumor, which can leave large scars. 5-Fluorouracil (5FU) is a drug used in the treatment of SCC, but it is highly hydrophilic, resulting in poor skin penetration in topical treatment. Some strategies can be used to increase the cutaneous penetration of the drug, such as the combination of liposomes containing penetration enhancers, for instance, surfactants, associated with the use of microneedling. Thus, the present work addresses the development of liposomes with penetration enhancers, such as sorbtitan monolaurate, span 20, for topical application of 5-FU and associated or not with the use of microneedling for skin delivery. Liposomes were developed using the lipid film hydration, resulting in particle size, polydispersity index, zeta potential, and 5-FU encapsulation efficiency of 88.08 nm, 0.169, -12.3 mV, and 50.20%, respectively. The presence of span 20 in liposomes potentiated the in vitro release of 5-FU. MTT assay was employed for cytotoxicity evaluation and the IC50 values were 0.62, 30.52, and 24.65 µM for liposomes with and without span 20 and 5-FU solution, respectively after 72-h treatment. Flow cytometry and confocal microscopy analysis evidenced high cell uptake for the formulations. In skin penetration studies, a higher concentration of 5-FU was observed in the epidermis + dermis, corresponding to 1997.71, 1842.20, and 2585.49 ng/cm2 in the passive penetration and 3214.07, 2342.84, and 5018.05 ng/cm2 after pretreatment with microneedles, for solution, liposome without and with span 20, respectively. Therefore, herein, we developed a nanoformulation for 5-FU delivery, with suitable physicochemical characteristics, potent skin cancer cytotoxicity, and cellular uptake. Span 20-based liposomes increased the skin penetration of 5-FU in association of microneedling. Altogether, the results shown herein evidenced the potential of the liposome containing span 20 for topical delivery of 5-FU.

Asunto(s)

Fluorouracilo , Neoplasias Cutáneas , Hexosas , Humanos , Liposomas/metabolismo , Tamaño de la Partícula , Piel/metabolismo , Absorción Cutánea , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo

RESUMEN

Cutaneous leishmaniasis (CL) is a neglected tropical disease endemic in ~ 90 countries, with an increasing incidence. Presently available pharmacotherapy implies the systemic administration of moderately/very toxic drugs. Miltefosine (Milt) is the only FDA-approved drug to treat CL via the oral route (Impavido®). It produces side effects; in particular, teratogenic effects are of concern. A topical treatment would have the great advantage of minimising the systemic circulation of the drug, preventing side effects. We prepared dispersions containing Milt and liposomes of different compositions to enhance/modulate trans-epidermal penetration and evaluated in vitro and in vivo efficacy and toxicity, in vitro release rate of the drug and particles size stability with time. Treatments were topically administered to BALB/c mice infected with Leishmania (Leishmania) amazonensis. The dispersions containing 0.5% Milt eliminated 99% of the parasites and cured the lesions with a complete re-epithelisation, no visible scar and re-growth of hair. Fluid liposomes decreased the time to heal the lesion and the time needed to eliminate viable amastigotes from the lesion site. Relapse of the infection was not found 1 month after treatment in any case. Ultraflexible liposomes on the other hand had no significant in vitro effect but decreased in vivo efficacy. A topical Milt formulation including fluid liposomes seems a promising treatment against CL.

Asunto(s)

Leishmania , Leishmaniasis Cutánea , Animales , Leishmaniasis Cutánea/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Modelos Teóricos , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacología , Fosforilcolina/uso terapéutico

RESUMEN

Extracts of copoazu (Theobroma gramdiflorum), canangucha (Maurita Flexuosa), and coffee (Coffea arabica) were explored as enhancers of the solar photo-Fenton process to eliminate acetaminophen, sulfamethoxazole, carbamazepine, and diclofenac in raw municipal wastewater. The process, at pH 6.2 and 5 mg L-1 of iron without the presence of extracts, had a very limited action (~35% of the pollutants degradation at 90 min of treatment) due to the iron precipitation. Interestingly, the extract addition increased the soluble iron forms, but only copoazu extract improved the pollutant degradation (~95% of elimination at 20 min of the process action). The copoazu extract components acted as natural complexing agents, maintaining the soluble iron up to 2 mg L-1 even after 90 min and, consequently, enhancing the pollutant degradation. The effect of copoazu extract dose on the process performance was also assessed, finding that an iron:polyphenols (from the copoazu extract) at a molar ratio equal to 1:0.16 was the most favorable condition. Then, the process improved by copoazu extract was applied to raw municipal wastewater. Remarkably, the process led to ~90% of total pharmaceuticals degradation at 20 min of treatment. This work evidenced the feasibility of amazonian fruit extracts to improve the solar photo-Fenton process to degrade pharmaceuticals in aqueous matrices at near-neutral pH.

Asunto(s)

Aguas Residuales , Contaminantes Químicos del Agua , Frutas/química , Peróxido de Hidrógeno , Hierro , Oxidación-Reducción , Preparaciones Farmacéuticas , Extractos Vegetales , Contaminantes Químicos del Agua/análisis

RESUMEN

To overcome the problems associated with bioavailability and systemic side effects of the drug by oral administration, monolithic matrix type transdermal patches containing cinnarizine (CNZ) were developed. For this purpose, films based on hydroxypropyl methylcellulose and polyvinylpyrrolidone as matrix-forming polymers were designed. Physical characteristics of transdermal films and drug-excipient compatibility were investigated. Factors affecting in vitro drug release and ex vivo skin penetration and permeation of the drug were studied. It was confirmed that films displayed sufficient flexibility and mechanical strength for application onto the skin for a long time period. Ex vivo penetration experiments gave satisfactory results for transdermal drug delivery through rat skin. The parameters determining good skin penetration were also evaluated. The highest drug permeation rate was obtained with incorporation of Transcutol® (0.102 mg/cm2/h) into the base CNZ formulation, followed by propylene glycol (0.063 mg/cm2/h), menthol (0.045 mg/cm2/h), and glycerin (0.021 mg/cm2/h) as penetration enhancers (p < 0.05). As a result, the developed transdermal patches of CNZ may introduce an alternative treatment for various conditions and diseases such as idiopathic urticarial vasculitis, Ménière's disease, motion sickness, nausea, and vertigo. Thus, the risk of systemic side effects caused by the drug can be reduced or eliminated

Asunto(s)

Administración Oral , Cinarizina , Agonistas de los Receptores Histamínicos/efectos adversos , Antagonistas Colinérgicos , Anestésicos/clasificación , Piel , Técnicas In Vitro/métodos , Preparaciones Farmacéuticas/análisis , Derivados de la Hipromelosa/efectos adversos , Liberación de Fármacos

RESUMEN

BACKGROUND: Circadian gene expression is essential for organisms to adjust their physiology and anticipate daily changes in the environment. The molecular mechanisms controlling circadian gene transcription are still under investigation. In particular, how chromatin conformation at different genomic scales and regulatory elements impact rhythmic gene expression has been poorly characterized. RESULTS: Here we measure changes in the spatial chromatin conformation in mouse liver using genome-wide and promoter-capture Hi-C alongside daily oscillations in gene transcription. We find topologically associating domains harboring circadian genes that switch assignments between the transcriptionally active and inactive compartment at different hours of the day, while their boundaries stably maintain their structure over time. To study chromatin contacts of promoters at high resolution over time, we apply promoter capture Hi-C. We find circadian gene promoters displayed a maximal number of chromatin contacts at the time of their peak transcriptional output. Furthermore, circadian genes, as well as contacted and transcribed regulatory elements, reach maximal expression at the same timepoints. Anchor sites of circadian gene promoter loops are enriched in DNA binding sites for liver nuclear receptors and other transcription factors, some exclusively present in either rhythmic or stable contacts. Finally, by comparing the interaction profiles between core clock and output circadian genes, we show that core clock interactomes are more dynamic compared to output circadian genes. CONCLUSION: Our results identify chromatin conformation dynamics at different scales that parallel oscillatory gene expression and characterize the repertoire of regulatory elements that control circadian gene transcription through rhythmic or stable chromatin configurations.

Asunto(s)

Ritmo Circadiano/genética , Genoma , Regiones Promotoras Genéticas , Animales , Secuencia de Bases , Relojes Biológicos/genética , Cromatina/metabolismo , Elementos de Facilitación Genéticos , Regulación de la Expresión Génica , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Modelos Genéticos , Factores de Tiempo , Transcripción Genética

RESUMEN

Alzheimer's disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-ß (Aß) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-ß protein precursor (AßPP) producing the membrane-bound fragment CTFα and the soluble fragment sAßPPα with neuroprotective activity; ß-secretase produces membrane-bound fragment CTFß and a soluble fragment sAßPPß. After α-secretase cleavage of AßPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFß is cleaved by γ-secretase producing AICD as well as Aß in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, ß-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aß42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979 Verubecestat, LY2886721, Lanabecestat, LY2811376 and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aß production did not recover cognitive functions or reverse disease progress. Novel strategies are being developed, aiming at a partial reduction of Aß production, such as the development of γ-secretase modulators or α-secretase activity enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Animales , Humanos

RESUMEN

The oral administration of isoniazid (INH) may lead to discontinuation of tuberculosis treatment due to drug-related hepatotoxicity events, and thus, the transbuccal delivery of this drug was investigated, for the first time, as an alternative administration route. Ex vivo permeability assays were performed in Franz-type diffusion chambers, applying INH alone and in combination with sodium dodecyl sulfate (SDS) and sodium taurocholate (ST). After confirming the formation of micelle structures by dynamic light scattering analysis, UV-visible spectroscopy and zeta potential analyses were used to investigate drug-micelle interactions. In zeta potential analyses, no electrostatical interactions were identified for both surfactants in saliva buffer pH 6.8. Spectrophotometric analyses, in turn, indicated chemical interactions between INH and SDS in both pH values (2.0 and 6.8) whereas no interaction between the drug and ST was observed. Despite the interaction between SDS and drug, this surfactant increased the buccal transport rate of INH by approximately 11 times when compared with the control. In contrast, ST did not increase the drug permeability. The INH retention in SDS-treated mucosa was significantly higher when compared with the control and an effect on intercellular lipids was suggested. In vivo studies are needed to confirm the high INH absorption found here. Grapical abstract.

Asunto(s)

Antituberculosos/administración & dosificación , Isoniazida/administración & dosificación , Mucosa Bucal/efectos de los fármacos , Dodecil Sulfato de Sodio/química , Tensoactivos/química , Difusión , Interacciones Farmacológicas , Micelas , Mucosa Bucal/metabolismo , Permeabilidad/efectos de los fármacos , Ácido Taurocólico/farmacología

RESUMEN

AIMS: Biodegradable polymeric microneedles containing atorvastatin calcium were developed in order to improve the percutaneous absorption of the drug, useful for the treatment of hypercholesterolemia. BACKGROUND: The use of physical enhancers like microneedles have shown good results to increase the delivery of drugs through the skin, the use of microneedles has very important advantages for transdermal drug delivery, for example, they are painless, easy to use and safe, they increase time interval of drug activity, dose, and reductions in adverse reactions, they also offer, the facility to remove the system instantly of the skin. OBJECTIVE: Develop polymer microneedles loaded with a calcium atorvastatin and evaluate them by Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), bioadhesion, postwetting- bioadhesion, breaking strength, drug release test and in vitro percutaneous absorption studies to demonstrate the use of microneedles atorvastatin is able to cross the skin. METHODS: The microneedles were made with poly (methyl vinyl ether-alt-maleic acid) as biodegradable polymer using the technique of casting in solution in a mold. After solidification these microneedles were characterized by Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), bioadhesion, post-wetting-bioadhesion, breaking strength, drug release test and in vitro percutaneous absorption studies. RESULTS: In general, the performances were satisfactory for optimal formulation in terms of DSC with no interactions between drug and excipients, SEM shows microneedles with a conical shape, bioadhesion of 1570 g.f, post wetting-bioadhesion of 1503.4 g.f, breaking strength of 1566.7g.f that is sufficient to disrupt Stratum corneum, good drug release and a flux of 33.4 µg/cm2*h with a tLag of 15.14 h for the in vitro percutaneous absorption. CONCLUSION: The results indicate that it is possible to generate microneedles to increase the percutaneous absorption of calcium atorvastatin transdermally, with the potential to be used as an alternative to the oral route for the treatment of dyslipidemias.

Asunto(s)

Anticolesterolemiantes/administración & dosificación , Atorvastatina/administración & dosificación , Plásticos Biodegradables/química , Portadores de Fármacos/química , Maleatos/química , Polietilenos/química , Administración Cutánea , Animales , Anticolesterolemiantes/farmacocinética , Atorvastatina/farmacocinética , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos , Humanos , Técnicas In Vitro , Agujas , Piel/metabolismo , Absorción Cutánea

RESUMEN

Benznidazole (BZN) represents the only drug currently available for the treatment of Chagas disease in most endemic countries. When administered orally, high doses are required due to its extensive hepatic metabolism and its toxicity represents the main reason for treatment withdrawals. Because of these complications, transbuccal administration of BZN was investigated. This route avoids the first-pass hepatic metabolism and presents high permeability, with direct access to the systemic circulation. BZN was applied on porcine buccal mucosa after pretreatment with pure eugenol, carvacrol or limonene. Thermal (DSC) and spectroscopic (FT-IR) analyzes were performed to investigate the mechanisms of drug absorption enhancement. The permeability coefficient values of BZN increased 2.6, 2.9 and 4.9-fold after pretreatment with eugenol, carvacrol and limonene, respectively. The lag time, in turn, was shortened in the pretreated samples. The DSC and FT-IR analyzes suggested that transport of BZN through the buccal mucosa is associated with log P and size of monoterpenes. Limonene, the most effective absorption enhancer, contributed to greater interaction with non-polar domains of the buccal epithelium. Overall, BZN showed to be efficiently transported through the buccal route, but in vivo pharmacokinetic studies should be performed to confirm these findings.

Asunto(s)

Monoterpenos/administración & dosificación , Mucosa Bucal/metabolismo , Nitroimidazoles/administración & dosificación , Tripanocidas/administración & dosificación , Administración Bucal , Animales , Permeabilidad , Porcinos

RESUMEN

The conceptual representation and sensory profiling of low sodium salted meat containing different flavor enhancers (n = 9) were investigated using the Q methodology. Seventy consumers performed a Q-sorting task having in mind the health concept, using a hedonic test and sensory description of the samples. Regular sodium salted meats were associated to the health concept and were characterized by as too much salt, fatty, salty taste, strange taste, and high blood pressure, while the low-sodium samples were associated with good appearance, metallic taste, and healthy. The Health questionnaire showed it is a valorization of food with improved sensory characteristics in addition and the importance of physical and emotional health. Our findings suggested the Q methodology can be an interesting tool for meat processors, together with the traditional sensory test with consumers, to obtain more consistent and complementary information about meat products.

Asunto(s)

Aromatizantes/administración & dosificación , Manipulación de Alimentos/métodos , Preferencias Alimentarias , Productos de la Carne/análisis , Cloruro de Potasio/administración & dosificación , Carne Roja/análisis , Adolescente , Adulto , Animales , Brasil , Bovinos , Comportamiento del Consumidor , Dieta Hiposódica , Femenino , Calidad de los Alimentos , Humanos , Masculino , Persona de Mediana Edad , Cloruro de Sodio Dietético/administración & dosificación , Gusto , Adulto Joven

RESUMEN

The objective was to evaluate the associative effect of monensin sodium to virginiamycin on the performance, dry matter intake, apparent digestibility and ingestive behavior of steers in the initial feedlot phase. The experiment lasted for 30 days, divided into two experimental periods. Thirty-six Angus Nellore steers, non-castrated, with a mean age of 10 months and an average weight of 300 kg, were divided into 18 pens. Animals were assigned to three treatments with six replications each, with the inclusion of the following additives: T1-monensin sodium, dose of 200 mg day-¹; T2-monensin sodium, dose of 125 mg day-¹ + virginiamycin, dose of 125 mg day-¹; and T3-monensin sodium, dose of 200 mgday-¹ + virginiamycin, dose of 125 mg day-¹. All experimental procedures were previously submitted to the UNICENTRO Committee for Ethics in Animal Experimentation (CEUA), and were approved for execution (Official Letter 021/2019). The combination of monensin sodium with virginiamycin at adose of 200 mg + 125 mg animal day-¹ showed greater (P 0.05) difference in DM intake, with a mean value of 7.88 kg animal day-¹. Regardless of the isolated or combined supplementation of the additives, no significant differences were detected in the analysis of the feeder and feces scores, ingestive behavior, and rectal temperature or infrared thermography during the evaluation period. The combination of monensin sodium with virginiamycin at 200 mg + 125 mg animal day-¹ proved to be efficient in the initial feedlot period, determined by the greater weight gain and better feed conversion observed in this study.

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O objetivo foi avaliar o efeito associativo da monensina sódica à virginiamicina sobre o desempenho, consumo de matéria seca, digestibilidade aparente e comportamento ingestivo de novilhos na fase de inicial de confinamento. A duração do experimento foi de 30 dias, divididos em dois períodos experimentais de 15 dias cada. Utilizou-se de 36 novilhos inteiros ½ sangue Angus Nelore, com idade média 10 meses e peso médio de 300 kg, divididos em 18 baias. Os animais foram divididos em três tratamentos com seis repetições cada, com a associação dos seguintes aditivos inclusos as rações: T1 –monensina sódica, dose de 200 mg dia-¹; T2 – monensina sódica, dose de 125 mg dia-¹ + virginiamicina, dose de 125 mg dia-¹; e T3 – monensina sódica, dose de 200 mg dia-¹ + virginiamicina, dose de 125 mgdia-¹. Todos os procedimentos experimentais foram previamente submetidos à apreciação do Comitê de Conduta Ética no Uso de Animais em Experimentação (CEUA) da UNICENTRO, tendo sido aprovados para execução (Ofício n° 021/2019). A associação de monensina sódica com virginiamicina na dose de 200 mg + 125 mg animal dia-¹ apresentou maior (P 0,05) diferença na ingestão de MS, apresentando valor médio de 7,88 kg animal dia-¹. Independentemente da suplementação isolada ou associada dos aditivos, não encontrou-se estatisticamente diferenças na análise dos escores de comedouro e fezes ,comportamento ingestivo e temperatura retal ou termografia infravermelha durante o período avaliativo. A associação de monensina sódica [...].

Asunto(s)

Animales , Bovinos , Aditivos Alimentarios/administración & dosificación , Bovinos/crecimiento & desarrollo , Bovinos/metabolismo , Fenómenos Fisiológicos Nutricionales de los Animales , Virginiamicina/análisis

RESUMEN

The objective was to evaluate the associative effect of monensin sodium to virginiamycin on the performance, dry matter intake, apparent digestibility and ingestive behavior of steers in the initial feedlot phase. The experiment lasted for 30 days, divided into two experimental periods. Thirty-six Angus Nellore steers, non-castrated, with a mean age of 10 months and an average weight of 300 kg, were divided into 18 pens. Animals were assigned to three treatments with six replications each, with the inclusion of the following additives: T1-monensin sodium, dose of 200 mg day-¹; T2-monensin sodium, dose of 125 mg day-¹ + virginiamycin, dose of 125 mg day-¹; and T3-monensin sodium, dose of 200 mgday-¹ + virginiamycin, dose of 125 mg day-¹. All experimental procedures were previously submitted to the UNICENTRO Committee for Ethics in Animal Experimentation (CEUA), and were approved for execution (Official Letter 021/2019). The combination of monensin sodium with virginiamycin at adose of 200 mg + 125 mg animal day-¹ showed greater (P < 0.05) average daily weight gain (1.919 kg day-¹) and better feed conversion (4.27 kg DM kg of weight gain-¹) compared to diets with monensinalone (200 mg animal day-¹) or monensin combined with virginiamycin (125 mg + 125 mg animal day1), even with no significant (P> 0.05) difference in DM intake, with a mean value of 7.88 kg animal day-¹. Regardless of the isolated or combined supplementation of the additives, no significant differences were detected in the analysis of the feeder and feces scores, ingestive behavior, and rectal temperature or infrared thermography during the evaluation period. The combination of monensin sodium with virginiamycin at 200 mg + 125 mg animal day-¹ proved to be efficient in the initial feedlot period, determined by the greater weight gain and better feed conversion observed in this study.(AU)

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O objetivo foi avaliar o efeito associativo da monensina sódica à virginiamicina sobre o desempenho, consumo de matéria seca, digestibilidade aparente e comportamento ingestivo de novilhos na fase de inicial de confinamento. A duração do experimento foi de 30 dias, divididos em dois períodos experimentais de 15 dias cada. Utilizou-se de 36 novilhos inteiros ½ sangue Angus Nelore, com idade média 10 meses e peso médio de 300 kg, divididos em 18 baias. Os animais foram divididos em três tratamentos com seis repetições cada, com a associação dos seguintes aditivos inclusos as rações: T1 –monensina sódica, dose de 200 mg dia-¹; T2 monensina sódica, dose de 125 mg dia-¹ + virginiamicina, dose de 125 mg dia-¹; e T3 monensina sódica, dose de 200 mg dia-¹ + virginiamicina, dose de 125 mgdia-¹. Todos os procedimentos experimentais foram previamente submetidos à apreciação do Comitê de Conduta Ética no Uso de Animais em Experimentação (CEUA) da UNICENTRO, tendo sido aprovados para execução (Ofício n° 021/2019). A associação de monensina sódica com virginiamicina na dose de 200 mg + 125 mg animal dia-¹ apresentou maior (P < 0,05) ganho de peso médio diário (1,919 kg dia-¹) e melhor conversão alimentar (4,27 kg de MS kg de ganho de peso-¹) comparativamente as dietas commonensina isolada (200 mg animal dia-¹) ou monensina associada a virginiamicina (125 mg + 125 mg animal dia-¹), mesmo não tendo sido observada (P > 0,05) diferença na ingestão de MS, apresentando valor médio de 7,88 kg animal dia-¹. Independentemente da suplementação isolada ou associada dos aditivos, não encontrou-se estatisticamente diferenças na análise dos escores de comedouro e fezes ,comportamento ingestivo e temperatura retal ou termografia infravermelha durante o período avaliativo. A associação de monensina sódica [...].(AU)

Asunto(s)

Animales , Bovinos , Bovinos/crecimiento & desarrollo , Bovinos/metabolismo , Fenómenos Fisiológicos Nutricionales de los Animales , Aditivos Alimentarios/administración & dosificación , Virginiamicina/análisis

RESUMEN

Nanotechnology-based delivery systems have been considered a promising approach for topical application, considering their characteristics of penetration into/across the skin. The present review aimed to evaluate the recent international scenario of patents concerning the use of nanotechnology- based delivery systems as skin penetration enhancers. A survey of recent patent documents was conducted by using the Espacenet patent database including the terms "skin" in the title and "promot* or enhanc* and penetrat* or absorp* or permeat*" and "nano*" with the truncation symbol (*) in the abstract of documents. A total of 110 patents were published from 2008 to 2018, with 94 technologies being considered. The results demonstrated an increase in innovations concerning nanotechnologybased delivery systems as skin penetration enhancers in recent years. Most patent applicants are from China (60.6%) and Korea (21.3%), and companies (68%) were the most prominent owners. The majority of patent applications (76%) were intended for cosmetic purposes; the types of products and nanostructures were also investigated. Overall results demonstrated the increased interest around the world in patenting products involving skin permeation promotion and nanotechnology for pharmaceutical and, mainly, for cosmetics purposes.

Asunto(s)

Sistemas de Liberación de Medicamentos , Nanotecnología , Absorción Cutánea , Administración Cutánea , Cosméticos , Humanos , Nanoestructuras , Patentes como Asunto , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/metabolismo

RESUMEN

Donepezil is one of the main compounds used in the therapy of Alzheimer's disease. Oral administration of this drug presents many drawbacks, resulting in treatment non-adherence among patients. Thus, the development of transdermal formulations for donepezil delivery is important. The aim of this study was to prepare and to evaluate nanostructured lipid carrier-based gels (NLC gel) able to improve the skin delivery of donepezil free base (DPB). The components of nanostructured lipid carriers (NLCs) were selected after evaluating their enhancing effects using in vitro DPB skin delivery assays. DPB-loaded NLC were prepared by a microemulsion technique, by employing stearic acid as a solid lipid, oleic acid as a liquid lipid, lecithin as a surfactant, and sodium taurodeoxycholate as a co-surfactant. The DPB-NLC dispersions were characterized morphologically using atomic force microscopy and physicochemically using dynamic light scattering and surface charge measurements. These data along, with the encapsulation studies, indicated that uniformly nano-sized particles with high drug encapsulation were fabricated. In vitro skin permeation assays were performed, and the results indicated that drug skin permeation from DPB-NLC gel was increased, not only by the enhancing effect of their components, but the lipid nanocarriers also presented an additional enhancing effect to increase drug flux across the skin. Therefore, DPB-NLC gel is an interesting formulation for the enhanced treatment of Alzheimer's disease.

Asunto(s)

Donepezilo/química , Sistemas de Liberación de Medicamentos , Lípidos/química , Nanoestructuras/química , Portadores de Fármacos/química , Liberación de Fármacos , Geles/química , Tamaño de la Partícula , Absorción Cutánea , Propiedades de Superficie

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Selected Peruvian Amazon plants are macerated into sugar cane distillates to prepare alcoholic beverages used to improve male sexual performance. The tree bark from Campsiandra angustifolia Spruce ex Benth (Fabaceae), Swartzia polyphylla DC (Fabaceae), Minquartia guianensis Aubl. (Olacaceae) and Thynantus panurensis (Bureau) Sandwith (Bignoniaceae) usually are used as crude drugs in mixtures of several ingredients. AIM OF STUDY: Describe the chemical composition of the most traded traditional male enhancer beverages, namely "Levántate Lazaro" and "Siete veces sin sacarla", and their single crude drug constituents, as well as their inhibitory activity towards the enzyme phosphodiesterase-5. The presence of pro-sexual drugs such as Sildenafil® and derivatives was assessed in the samples. MATERIALS AND METHODS: Single plant constituents and the preparation mixtures were purchased in the Mercado Belen (Iquitos, Peru). Chemical profiling was carried out by HPLC-DAD-ESI-MS/MS. The extracts were assessed for phosphodiesterase-5 inhibition. The occurrence of pro-sexual drugs was determined by HPLC-DAD-ESI-MS/MS. RESULTS: Chemical profiling allowed the identification of condensed tannins as the main constituents of C. angustifolia and S. polyphylla, hydrolysable tannins for M. guianensis, and C-glycosides for T. panurensis. The traditional preparations showed similar composition compared to the crude drugs. At 200 µg/mL, the traditional preparation "Levántate Lázaro" and "Siete veces sin sacarla" inhibited the phosphodiesterase-5 by 49.88% and 27.90%, respectively. No adulterations with pro-sexual drugs were found in the samples. From the crude drugs, low effect was found for the extracts of S. polyphylla and T. panurensis and high activity for C. angustifolia which inhibited the enzyme by 89.37% and 81.32% at 200 and 100 µg/mL, respectively. CONCLUSION: The traditional preparations used to improve sexual performance in the Peruvian Amazon showed activity as phosphodiesterase-5 inhibitors. The most active ingredient of the traditional preparations was C. angustifolia, with some contribution from T. panurensis. These results encourage additional studies, including animal models to confirm the male enhancer effect of the preparations.

Asunto(s)

Afrodisíacos/farmacología , Magnoliopsida , Inhibidores de Fosfodiesterasa 5/farmacología , Preparaciones de Plantas/farmacología , Afrodisíacos/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Etanol/farmacología , Humanos , Masculino , Perú , Inhibidores de Fosfodiesterasa 5/química , Fitoquímicos/análisis , Fitoquímicos/farmacología , Corteza de la Planta , Preparaciones de Plantas/química

RESUMEN

Enhancer profiling is a powerful approach for discovering cis-regulatory elements that define the core transcriptional regulatory circuits of normal and malignant cells. Gene control through enhancer activity is often dominated by a subset of lineage-specific transcription factors. By integrating measures of chromatin accessibility and enrichment for H3K27 acetylation, we have generated regulatory landscapes of chronic lymphocytic leukemia (CLL) samples and representative cell lines. With super enhancer-based modeling of regulatory circuits and assessments of transcription factor dependencies, we discover that the essential super enhancer factor PAX5 dominates CLL regulatory nodes and is essential for CLL cell survival. Targeting enhancer signaling via BET bromodomain inhibition disrupts super enhancer-dependent gene expression with selective effects on CLL core regulatory circuitry, conferring potent anti-tumor activity.

Asunto(s)

Cromatina/genética , Elementos de Facilitación Genéticos/genética , Regulación Leucémica de la Expresión Génica/genética , Leucemia Linfocítica Crónica de Células B/genética , Acetilación , Animales , Azepinas/farmacología , Línea Celular Tumoral , Cromatina/efectos de los fármacos , Cromatina/metabolismo , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Histonas/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/metabolismo , Ratones Noqueados , Factor de Transcripción PAX5/genética , Factor de Transcripción PAX5/metabolismo , Unión Proteica , Proteínas/antagonistas & inhibidores , Proteínas/genética , Proteínas/metabolismo , Triazoles/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos