RESUMEN
This work highlights boosting the tumor targeting efficiency of epirubicin through loading on a new radionanosystem, based on the effective role of silver nanoparticles (AgNPs). Accordingly, PEGylated silver nanoparticles (PEG/AgNPs) were prepared in a size of 20.2 ± 0.1 nm. Additionally, epirubicin was loaded on PEG/AgNPs with a loading efficiency of 63 ± 3 %. Furthermore, both of PEG/AgNPs and EPI/PEG/AgNPs were radiolabeled with 131I isotope with radiolabeling yields of 85 ± 0.2 % and 90.3 ± 1 %, respectively. The in-vivo distribution of 131I-PEG/AgNPs and 131I-EPI/PEG/AgNPs were examined in healthy and tumor bearing mice models. Excitingly, 131I-EPI/PEG/AgNPs revealed a reticuloendothelial system (RES) avoidance and prolonged circulating time. In addition, 131I-EPI/PEG/AgNPs showed fast targeting of tumor site by 25.1 ± 0.1 %ID/g within 0.5 h after intravenous injection. Subsequently, the outcomes provided 131I-EPI/PEG/AgNPs as a new potential system for enhancement of tumor targeting and theranosis (therapy and/or imaging).
Asunto(s)
Nanopartículas del Metal , Nanopartículas , Neoplasias , Ratones , Animales , Epirrubicina , Plata , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , PolietilenglicolesRESUMEN
Employment of mesoporous silica nanostructures (MSNs) in the drug delivery field has shown a significant potential for improving the oral delivery of active pharmaceutical products with low solubility in water. Mirtazapine (MRT) is a tetracyclic antidepressant with poor water solubility (BCS Class II), which was recently approved as a potent drug used to treat severe depression. The principle of this research is to optimize the incorporation of Mirtazapine into MSNs to improve its aqueous solubility, loading efficiency, release performance, and subsequent bioavailability. The formulation was optimized by using of Box-Behnken Design, which allows simultaneous estimation of the impact of different types of silica (SBA-15, MCM-41, and Aluminate-MCM-41), a different drug to silica ratios (33.33%, 49.99%, and 66.66%), and different drug loading procedures (Incipient wetness, solvent evaporation, and solvent impregnation) on the MRT loading efficiency, aqueous solubility and dissolution rate. The optimized formula was achieved by loading MRT into SBA-15 at 33.33% drug ratio prepared by the incipient wetness method, which displayed a loading efficiency of 104.05%, water solubility of 0.2 mg/ml, and 100% dissolution rate after 30 min. The pharmacokinetic profile of the optimized formula was obtained by conducting the in-vivo study in rabbits which showed a marked improvement (2.14-fold) in oral bioavailability greater than plain MRT. The physicochemical parameters and morphology of the optimized formula were characterized by; gas adsorption manometry, scanning electron microscopy (SEM), polarized light microscopy (PLM), Fourier-transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD).
Asunto(s)
Portadores de Fármacos , Nanoestructuras , Animales , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Portadores de Fármacos/química , Mirtazapina , Porosidad , Conejos , Dióxido de Silicio/química , Solubilidad , Solventes/química , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Agua/química , Difracción de Rayos XRESUMEN
BACKGROUND: Development of pharyngo-esophageal protective reflexes among infants with hypoxic ischemic encephalopathy (HIE) is unclear. Our aim was to distinguish these reflexes from controls and examine the maturational changes in HIE infants. METHODS: We evaluated 14 HIE infants (seven males) at 41.4±0.6 (HIE Time-1) and 46.5±0.6 (HIE Time-2) weeks postmenstrual age (PMA). Seven controls (three males) were evaluated at 43.5±1.3 weeks PMA. Graded pharyngeal stimulation with liquids (0.1, 0.3, 0.5 mL in triplicate) concurrent with high-resolution manometry was used to analyze sensory-motor components of pharyngeal reflexive swallowing (PRS), upper esophageal sphincter (UES), contractile reflex (PUCR), and esophageal body characteristics. Linear mixed and generalized estimating equation models were used for comparison among groups. KEY RESULTS: Compared to controls, HIE infants (Time-1 and Time-2) exhibited decreased number of pharyngeal peaks and latency to terminal swallow. HIE Time-1 infants showed increased UES resting tone and distal latency, compared to controls and HIE Time-2. Contractile vigor was increasingly abnormal during maturation, compared to healthy controls. Threshold volumes and frequency distribution of primary responses (PRS: PUCR: None) were not significant among all groups. CONCLUSIONS & INFERENCES: Compared to controls, HIE infants display significant hypertonicity of skeletal muscle components, impairment of pharyngeal provocation-induced reflexes and smooth muscle contractile vigor, reflecting poor propagation with maturation. These mechanisms may be responsible for inadequate clearance of secretions, ascending refluxate, and oropharyngeal bolus in HIE infants.
Asunto(s)
Asfixia Neonatal/fisiopatología , Desarrollo Infantil/fisiología , Atragantamiento/fisiología , Contracción Muscular/fisiología , Asfixia Neonatal/diagnóstico , Femenino , Humanos , Recién Nacido , Masculino , Manometría/métodosRESUMEN
Cryptosporidium is a protozoan parasite of humans and animals and has a worldwide distribution. The parasite has a unique epidemiology in Middle Eastern countries where the IId subtype family of Cryptosporidium parvum dominates. However, there has been no information on Cryptosporidium species in Yemen. Thus, this study was conducted in Yemen to examine the distribution of Cryptosporidium species and subtype families. Fecal samples were collected from 335 patients who attended hospitals in Sana'a city. Cryptosporidium species were determined by PCR and sequence analysis of the 18 s rRNA gene. Cryptosporidium parvum and C. hominis subtypes were identified based on sequence analysis of the 60 kDa glycoprotein (gp60) gene. Out of 335 samples, 33 (9.9%) were positive for Cryptosporidium. Of them, 97% were identified as C. parvum whilst 1 case (3%) was caused by C. hominis. All 7 C. parvum isolates subtyped belonged to the IIaA15G2R1 subtype. The common occurrence of the zoonotic IIa subtype family of C. parvum highlights the potential occurrence of zoonotic transmission of cryptosporidiosis in Yemen. However, this postulation needs confirmation with future molecular epidemiological studies of cryptosporidiosis in both humans and animals in Yemen.
Asunto(s)
Criptosporidiosis/parasitología , Cryptosporidium/aislamiento & purificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Secuencia de Bases , Niño , Preescolar , Criptosporidiosis/epidemiología , Cryptosporidium/clasificación , Cryptosporidium/genética , Cryptosporidium parvum/clasificación , Cryptosporidium parvum/genética , Cryptosporidium parvum/aislamiento & purificación , ADN Protozoario/química , ADN Protozoario/genética , Heces/parasitología , Femenino , Genotipo , Humanos , Lactante , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Prevalencia , ARN Protozoario/genética , ARN Ribosómico 18S/genética , Análisis de Secuencia de ADN , Yemen/epidemiología , Adulto Joven , ZoonosisRESUMEN
Asunto(s)
Malaria/epidemiología , Adolescente , Adulto , Altitud , Niño , Estudios Transversales , Femenino , Humanos , Malaria/etiología , Malaria/transmisión , Masculino , Factores de Riesgo , Factores Socioeconómicos , Yemen/epidemiología , Adulto JovenRESUMEN
Cryptosporidium is a coccidian parasite that is prevalent worldwide, some species of which cause morbidity in both immunocompromised and immunocompetent individuals. The prevalence and predictors of Cryptosporidium infection, and its effect on nutritional status, have recently been explored among 276 children (141 boys and 135 girls, aged 2-15 years) in aboriginal (Orang Asli) villages in the Malaysian state of Selangor. Faecal smears were examined by the modified Ziehl-Neelsen staining technique while socio-economic data were collected using a standardized questionnaire. Nutritional status was assessed by anthropometric measurements. Cryptosporidium infection, which was detected in 7.2% of the aboriginal children, was found to be significantly associated with low birthweight (≤2.5 kg), being part of a large household (with more than seven members) and prolonged breast feeding (>2 years). The output of a binary logistic regression confirmed that large household size was a significant predictor of Cryptosporidium infection (giving an odds ratio of 2.15, with a 95% confidence interval of 1.25-5.02). Cryptosporidium infection is clearly a public-health problem among the aboriginal children of Selangor, with person-to-person the most likely mode of transmission.
Asunto(s)
Criptosporidiosis/etnología , Nativos de Hawái y Otras Islas del Pacífico/estadística & datos numéricos , Adolescente , Antropometría/métodos , Peso al Nacer , Niño , Fenómenos Fisiológicos Nutricionales Infantiles/fisiología , Preescolar , Estudios Transversales , Criptosporidiosis/etiología , Criptosporidiosis/fisiopatología , Composición Familiar , Femenino , Humanos , Malasia/epidemiología , Masculino , Estado Nutricional , Factores de Riesgo , Salud Rural/estadística & datos numéricos , Clase SocialRESUMEN
Cryptosporidium species are protozoan parasites that infect humans and a wide variety of animals. This study was aimed at identifying Cryptosporidium species and genotypes isolated from avian hosts. A total of 90 samples from 37 different species of birds were collected throughout a 3-month period from April 2008 to June 2008 in the National Zoo of Kuala Lumpur, Malaysia. Prior to molecular characterization, all samples were screened for Cryptosporidium using a modified Ziehl-Neelsen staining technique. Subsequently samples were analysed with nested-PCR targeting the partial SSU rRNA gene. Amplicons were sequenced in both directions and used for phylogenetic analysis using Neighbour-Joining and Maximum Parsimony methods. Although 9 (10%) samples were positive for Cryptosporidium via microscopy, 8 (8.9%) produced amplicons using nested PCR. Phylogenetic trees identified all the isolates as Cryptosporidium parvum. Although C. parvum has not been reported to cause infection in birds, and the role of birds in this study was postulated mainly as mechanical transporters, these present findings highlight the significant public health risk posed by birds that harbour the zoonotic species of Cryptosporidium.
Asunto(s)
Enfermedades de las Aves/parasitología , Criptosporidiosis/veterinaria , Cryptosporidium parvum/genética , Animales , Animales de Zoológico/parasitología , Secuencia de Bases , Enfermedades de las Aves/epidemiología , Aves , Criptosporidiosis/epidemiología , Criptosporidiosis/parasitología , Cryptosporidium/clasificación , Cryptosporidium/genética , Cryptosporidium/aislamiento & purificación , Cryptosporidium parvum/clasificación , Cryptosporidium parvum/aislamiento & purificación , ADN Protozoario/genética , ADN Ribosómico/química , ADN Ribosómico/genética , Vectores de Enfermedades , Heces/parasitología , Genotipo , Humanos , Malasia/epidemiología , Datos de Secuencia Molecular , Filogenia , Reacción en Cadena de la Polimerasa , Prevalencia , ARN Ribosómico 18S/genética , Factores de Riesgo , Análisis de Secuencia de ADNRESUMEN
The ubiquitin (Ub)-proteasome system (UPS) promotes the proteasomal degradation of target proteins by decorating them with Ub labels. Emerging evidence indicates a role of UPS in regulating gene transcription. In this study, we provided evidence for the involvement of UPS in the transcriptional activation function of tumor suppressor p53. We showed that both ubiquitylation and proteasomal functions are required for efficient transcription mediated by p53. Disruption of transcription by actinomycin D, 5,6-dichloro-1-beta-D-ribofuranosyl-benzimadazole or alpha-amanitin leads to accumulation of cellular p53 protein. Proteasome inhibition by MG132 increases the occupancy of p53 protein at p53-responsive p21(waf1) promoter. In addition, the Sug-1 component of 19S proteasome physically interacts with p53 in vitro and in vivo. Moreover, in response to ultraviolet-induced DNA damage, both the 19S proteasomal components, Sug1 and S1, are recruited to p21(waf1) promoter region in a kinetic pattern similar to that of p53. These results suggested that UPS positively regulates p53-mediated transcription at p21(waf1) promoter.
Asunto(s)
Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Regiones Promotoras Genéticas , Complejo de la Endopetidasa Proteasomal/fisiología , Activación Transcripcional/genética , Proteína p53 Supresora de Tumor/fisiología , Enzimas Activadoras de Ubiquitina/fisiología , Animales , Línea Celular Tumoral , Células Cultivadas , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Células HeLa , Humanos , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/metabolismo , Síndrome de Li-Fraumeni/patología , RatonesRESUMEN
Cyclosporine A (CsA) nephrotoxicity underweighs the therapeutic benefits of such a powerful immunosuppressant. Whether oxidative stress plays a role in such toxicity is not well delineated. We investigated the potential of green tea extract (GTE) to attenuate CsA-induced renal dysfunction in rats. Three main groups of Sprague-Dawley rats were used: CsA, GTE, and GTE plus CsA-receiving animals. Corresponding control groups were also used. CsA was administered in a dose of 20mg kg(-1) day(-1), i.p., for 21 days. In the GTE/CsA groups, the rats received different concentrations of GTE (0.5, 1.0 and 1.5%), as their sole source of drinking water, 4 days before and 21 days concurrently with CsA. The GTE group was treated with 1.5% concentration of GTE only for 25 days. A concomitant administration of GTE, to CsA receiving rats, markedly prevented the generation of thiobarbituric acid-reacting substances (TBARS) and significantly attenuated CsA-induced renal dysfunction as assessed by estimating serum creatinine, blood urea nitrogen, uric acid and urinary excretion of glucose. A considerable improvement in terms of reduced glutathione content and activity of antioxidant enzymes in the kidney homogenate of the GTE/CsA-receiving rats was observed. The activity of lysosomal enzymes, N-acetyl-beta-glucosaminidase, beta-glucuronidase and acid phosphatase was significantly inhibited following GTE co-administration. Our data prove the role of oxidative stress in the pathogenesis of CsA-induced kidney dysfunction. Supplementation of GTE could be useful in reducing CsA nephrotoxicity in rats. However, clinical studies are warranted to investigate such an effect in human subjects.
Asunto(s)
Ciclosporina/farmacología , Estrés Oxidativo/efectos de los fármacos , Té , Animales , Ciclosporina/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Masculino , Estrés Oxidativo/fisiología , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
The therapeutic value of doxorubicin (DOX) as anticancer antibiotic is limited by its cardiotoxicity. The implication of natural phenolic acids in the prevention of many pathologic diseases has been reported. Herein, the ability of p-coumaric (PC) acid, a member of phenolic acids, to protect rat's heart against DOX-induced oxidative stress was investigated. Three main groups of albino rats were used; DOX, PC, and PC plus DOX-receiving animals. Corresponding control animals were also used. DOX was administered i.p. in a single dose of 15mgkg(-1). PC alone, in a dose of 100mgkg(-1), was orally administered for five consecutive days. In PC/DOX group, rats received PC 5 days prior to DOX. DOX-induced high serum levels of lactic dehydrogenase (LDH) and creatine phosphokinase (CPK), were reduced significantly by PC administration, compared to DOX-receiving rats. Pretreatment with PC ameliorated the cardiac content of glutathione (GSH), and superoxide dismutase (SOD) & catalase (CAT) activities, compared to DOX-receiving rats. On the other hand, accumulation of cardiac content of MDA significantly decreased following PC pretreatment, compared to DOX-treated rats. The data presented here indicate that PC protects rats hearts against DOX-induced oxidative stress in the heart. It may be worthy to consider the usefulness of PC as adjuvant therapy in cancer management.
Asunto(s)
Antibacterianos/farmacología , Ácidos Cumáricos/farmacología , Doxorrubicina/farmacología , Corazón/efectos de los fármacos , Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Catalasa/metabolismo , Creatina Quinasa/metabolismo , Glutatión/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Malondialdehído/metabolismo , Oxidación-Reducción , Propionatos , Proteínas/metabolismo , Ratas , Superóxido Dismutasa/metabolismoRESUMEN
Nucleotide excision repair (NER), the most versatile and ubiquitous mechanism for DNA repair, operates to remove many types of DNA base lesions. We have studied the role of p53 function in modulating the repair of DNA damage following UV irradiation in normal and p53-compromised human mammary epithelial cells (HMEC). The effect of UV-induced DNA damage on cellular cytotoxicity and apoptosis was determined in conjunction with global, gene- and strand-specific repair. Cytotoxicity studies, using clonogenic survival and MTT assays, showed that HPV-16 E6-expressing HMEC were more UV sensitive than p53-WT cell lines. High apoptotic index obtained with p53-compromised cells was in conformity to both the low clonogenic survival and the low cellular viability. No discernible differences in the formation of initial UV-induced cyclobutane pyrimidine dimers (CPD) were observed in the cell lines of varying p53 functional status. However, the extent and the rate of damage removal from genome overall were highest for p53-WT cells. Further examination of strand-specific repair in the p53 gene revealed that the removal of CPD in the non-transcribed strand (NTS) was slower in p53-compromised cells compared to the normal p53-WT cell lines. These results suggest that loss of p53 function, in the absence of other genetic alterations, decreased both overall amount of CPD repaired and their removal rate from the genome. Additionally, normal function of p53 is required for the repair of the NTS, but not of the transcribed strand (TS) in genomic DNA in human epithelial cells. Thus, failure of quantitative removal of CPD by global genomic repair (GGR), due to loss of p53 function, causes the enhanced UV sensitivity and increased damage-induced apoptosis via a p53-independent pathway. Nevertheless, recovery of cells from UV damage requires normal p53 function and efficient GGR.