Cubosomes, a product of nanobioengineering, are self-structured lipid nanoparticles that act like drug-loaded theranostic probes. Here, we describe a simple method for the preparation of combinatorial drug-loaded cubosomes with, proof-of-principle, therapeutic effect against cancer cells, along with diagnostic capabilities. Anticancer drugs cisplatin and paclitaxel were loaded in the cubosomes in combination. The cubosomes were coated with a layer of poly-Ɛ-lysine, which helped avoid the initial burst release of drug and allowed for a slow and sustained release for better efficacy. Cubosomes were imaged by transmission electron microscope, and their dispersion analyzed in vitro by differential scanning calorimetric and X-ray diffractogram studies. The microscopic images depicted spherical polyangular structures, which are easily distinguishable. The analyses revealed that the drug is uniformly dispersed all through the cubosomes. Further characterization was carried out by zeta-potential measurement, in vitro release, and entrapment efficiency studies. The in vitro studies established that the coating of cubosomes successfully reduced the burst release of drugs initially and confirmed a slow, sustained release over increased time. Comparative cytotoxicity of coated, uncoated, and blank cubosomes was evaluated, using human hepatoma HepG2 cell line, and the formulations were found to be entirely nontoxic, similar to the blank ones. The therapeutic efficiency of the cubosomes against HeLa cells was confirmed by the impedance measurement and fluorescent imaging. Furthermore, the reduction in impedance in cells treated with coated combinatorial cubosomes proved the impairment of HeLa cells, as confirmed by fluorescence microscopy.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently recognized neurodegenerative disorder in fragile X premutation carriers with FMR1 alleles containing 55-200 CGG repeats. Previously, we developed a Drosophila model of FXTAS and demonstrated that transcribed premutation repeats alone are sufficient to cause neurodegeneration, suggesting that rCGG-repeat-binding proteins (RBPs) may be sequestered from their normal function by rCGG binding. Here, we identify Pur alpha and hnRNP A2/B1 as RBPs. We show that Pur alpha and rCGG repeats interact in a sequence-specific fashion that is conserved between mammals and Drosophila. Overexpression of Pur alpha in Drosophila could suppress rCGG-mediated neurodegeneration in a dose-dependent manner. Furthermore, Pur alpha is also present in the inclusions of FXTAS patient brains. These findings support the disease mechanism of FXTAS of rCGG repeat sequestration of specific RBPs, leading to neuronal cell death, and implicate that Pur alpha plays an important role in the pathogenesis of FXTAS.

Expression of the brain-derived neurotrophic factor (BDNF) is under tight regulation to accommodate its intricate roles in controlling brain function. Transcription of BDNF initiates from multiple promoters in response to distinct stimulation cues. However, regardless which promoter is used, all BDNF transcripts are processed at two alternative polyadenylation sites, generating two pools of mRNAs that carry either a long or a short 3′UTR, both encoding the same BDNF protein. Whether and how the two distinct 3′UTRs may differentially regulate BDNF translation in response to neuronal activity changes is an intriguing and challenging question. We report here that the long BDNF 3′UTR is a bona fide cis-acting translation suppressor at rest whereas the short 3′UTR mediates active translation to maintain basal levels of BDNF protein production. Upon neuronal activation, the long BDNF 3′UTR, but not the short 3′UTR, imparts rapid and robust activation of translation from a reporter. Importantly, the endogenous long 3′UTR BDNF mRNA specifically undergoes markedly enhanced polyribosome association in the hippocampus in response to pilocarpine induced-seizure before transcriptional up-regulation of BDNF. Furthermore, BDNF protein level is quickly increased in the hippocampus upon seizure-induced neuronal activation, accompanied by a robust activation of the tropomyosin-related receptor tyrosine kinase B. These observations reveal a mechanism for activity-dependent control of BDNF translation and tropomyosin-related receptor tyrosine kinase B signaling in brain neurons.alternative 3′UTR | tropomyosin-related kinase receptor B | hippocampal mossy fiber | epilepsy B rain-derived neurotrophic factor (BDNF) is known to elicit a plethora of functions in the brain via activation of the tropomyosin-related receptor tyrosine kinase B (TrkB), ranging from neuronal survival and differentiation to circuit development and synaptic plasticity (1-3). Abnormalities in BDNF function have been implicated in both neurological and psychiatric disorders (4-6). To accommodate such diverse functions, a variety of mechanisms have evolved that tightly control BDNF expression. Transcription of the BDNF gene can be initiated from nine distinct promoters in mammals, allowing for sophisticated regulation by divergent extracellular and developmental cues (7-9). Moreover, the primary BDNF transcript can be processed at two alternative polyadenylation sites in all tissues examined, giving rise to two pools of BDNF mRNAs that harbor either a short or a long 3′UTR of 0.35 kb and 2.85 kb in length, respectively (8, 9). Each BDNF mRNA isoform encodes for the same BDNF protein. However, the relative abundance of the short and long 3′UTR BDNF mRNAs differ in various brain regions (10). The different 3′UTRs in BDNF mRNAs presumably interact with distinct trans-acting factors, thus offering a mechanism to increase the capacity and complexity for regulation of BDNF expression at posttranscriptional levels, such as translation and subcellular localization, which ...

We analyzed mutations and gene copy number changes in nontumor, IEN, and ESCC samples, collected from 70 patients. IEN and ESCCs each had similar mutations and markers of genomic instability, including apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like. Genomic changes observed in precancerous lesions might be used to identify patients at risk for ESCC.

BackgroundExisting studies in developed countries show that social participation has beneficial effects on the functional ability of older adults, but research on Chinese older people is limited. This study examined the effects of participating in different types of social activities on the onset of functional disability and the underlying behavioral and psychosocial mechanisms among older adults aged 65 and older in China.MethodsThe 2005, 2008, and 2011 waves of the Chinese Longitudinal Health Longevity Study were used. Life table analysis and discrete time hazard models were adopted to examine the relationship between social participation and functional disability. Social participation was defined as the frequencies of engaging in group leisure-time activities (i.e., playing cards/mahjong) and organized social activities, involving in informal social interactions (i.e., number of siblings frequently visited), and participating in paid jobs. Extensive social participation was measured by a composite index by adding up the four types of social activities that an older person was engaged in.ResultsAfter controlling for the effect of socio-demographic characteristics, health status, and health behavioral factors, extensive social participation is associated with a significant reduced risk for the onset of functional disability (hazard ratio [HR] = 0.92, p < 0.001). Different types of social participation affect the risk of functional decline through different mechanisms. Frequent playing of cards/mahjong is a protective factor for functional decline (HR = 0.78, p < 0.001), and the relationship is partially mediated by cognitive ability and positive emotions (accounting for 18.9% and 7.0% of the association, respectively). Frequent participation in organized social activities is significantly related to a reduced risk of functional decline (HR = 0.78, p < 0.001), and the association is mediated by physical exercises and cognitive ability (accounting for 25.7% and 17.7% of the association, respectively). Frequent visits from siblings has a strong inverse relationship with functional decline (HR = 0.75, p < 0.001). However, no significant association between paid job and functional decline is observed.ConclusionExtensive social participation, regular engagement in group leisure-time activities, organized social activities, and informal social interactions in particular may have beneficial effects on the functional health of older adults through behavioral and psychosocial pathways. The findings shed light for the importance of promoting social participation among older adults.