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We separately identified microRNAs that can be used to make an AD diagnosis and subjected the predicted gene targets of the most predictive microRNAs to an enrichment analysis. The following key themes emerged from our machine learning and bioinformatics analyses cell death, cellular senescence, energy metabolism, genomic integrity, glia, immune system, metal ion homeostasis, oxidative stress, proteostasis, and synaptic function. Many of the results demonstrated unique age-specificity. For example, terms highlighting cellular senescence only emerged in the earliest and intermediate age ranges while the majority of results relevant to cell death appeared in the youngest patients. Existing literature corroborates the importance of these hallmarks in AD.Buprenorphine is used during pregnancy for the treatment of opioid use disorder. Limited data exist on the central nervous system (CNS) permeation and distribution, and on the fetal exposure to buprenorphine. The aim of our study was to determine the extent of buprenorphine distribution to CNS in the pregnant sheep, and their fetus at steady-state, and their newborn lambs postdelivery, using three different dosing regimens. Twenty-eight pregnant ewes in late gestation received buprenorphine via 7-day transdermal patch releasing buprenorphine 20 µg/h (n=9) or 40 µg/h (n=11), or an extended-release 8 mg/week subcutaneous injection (n=8). Plasma, cerebrospinal fluid, and CNS tissue samples were collected at steady-state from ewes and fetuses, and from lambs 0.33 - 45 hours after delivery. High accumulation of buprenorphine was observed in all CNS tissues. The median CNS/plasma concentration -ratios of buprenorphine in different CNS areas ranged between 13 and 50 in the ewes, and between 26 and 198 in the fetusesCNS tissues at much higher concentrations than in plasma in pregnant sheep, fetuses, and their newborn lambs even 45 hours after delivery.The cellulose-based polymers are extensively employed in oral formulations for addressing ADMET issues of API. Herein, we report the synergistic effect of hydroxyethyl cellulose in solubility/dissolution enhancement of BCS class II, anthelmintic drug niclosamide. The low solubility and poor oral bioavailability are the primary reasons for its high daily dose. The amorphous solid dispersions (ASDs) developed herein demonstrated reproducible solubility and dissolution enhancement in smaller-to-pilot batches. The significant boost in niclosamide solubility in HEC-based binary SD was rationalized as a result of intermolecular H-bonding as indicated by in-silico studies and further supported by characterization data. HEC is plausibly inhibiting the precipitation of drug and thereby enabling high dissolution and permeation across the membrane. The comparative oral pharmacokinetics in Wistar rats at 25 mg/kg provided 4.4-fold higher plasma exposure of niclosamide in SD formulation SB-ASD-N2 over the plain drug. The results presented herein warrant validation of this ASD under clinical settings.An international sampling study yielded 69 samples of extended-release prescription pharmaceuticals for legal sale in the U.S. Samples included 29 lots of innovator and 40 lots of generic solid oral extended-release drugs manufactured at 16 different facilities and containing 6 different active ingredients. Dosage unit uniformity and dissolution were tested for each lot. All samples met the relevant testing criteria for dosage unit uniformity and dissolution. There were no indications that manufacturer or region impacted a product's acceptability for use by patients. The variability of attributes was used to calculate a process performance index (Ppk) for each facility. Higher Ppk values suggest less variability relative to specification limits. Only two manufacturers fell below a 4-sigma manufacturing benchmark Ppk of 1.33 for dosage unit uniformity a European manufacturer of a brand drug and an Asian manufacturer of a generic drug. Conversely, all but four manufacturers fell below a 4-sigma benchmark for the minimum Ppk across their product's dissolution timepoints generic drug manufacturers in India (two), the U.S., and Canada. Compared to the immediate-release products of a previous study, Ppks were generally lower for extended-release products. A retrospective analysis found that manufacturers performing below median Ppks submitted more Field Alert Reports after the end of the sampling period.Although deferoxamine (DFO) has been approved for the treatment the iron overloaded diseases, its clinical application is impeded by very short circulation time and its relating toxicity. In this work, the fluorene methoxycarbonyl (FMOC) for "albumin hitchhiking" was used to prolong the plasma circulation time of DFO and reduce toxicity. The designed FMOC-PEG-DFO conjugates were found to reversible bind to albumin and gradually release DFO in vivo. Herein, the FMOC-PEG1000-DFO conjugates could increase 30 times the blood circulation time of DFO with the improvement of the iron elimination efficacy. Meanwhile, the conjugates markedly reduced the cytotoxicity of DFO. Taken together, the result demonstrated the FMOC-PEG1000-DFO conjugates could be a potential therapeutic choice for iron-overload-related diseases.Nanofibers (NFs) provide several delivery advantages like their great flexibility and similarity with extracellular matrix (ECM) which qualify them to be the unique model of a wound dressing. NFs could create mats of polymeric matrix loaded with an active agent enhancing its solubility and stability. In our study, Gentiopicroside (GPS) and Thymoquinone (TQ) loaded in NFs polymeric mats composed of coblended polyvinyl pyrrolidine (PVP) and methyl ether Polyethylene glycol (m-PEG) were fabricated via electrospinning technique. A morphological study using Scanning Electron Microscopy (SEM) was performed for all formulae as well as in vitro release study using High-performance Liquid chromatography (HPLC) for sample analysis. The optimized formula (F3) was chosen for further assays using Fourier-Transform Infrared Spectroscopy (FTIR), and Differential Scanning Calorimetry (DSC). Study of the antibacterial effect, and in vivo healing action for diabetic infected wounds to quantify Tumor necrosis factor-alpha and Cyclooxygenase-2 were also investigated. F3 achieved the highest % cumulative release (99.79 ± 6.47 for GPS and 96.89 ± 6.87 for TQ) at 60 min, and a smaller diameter (200 nm) showing significant anti-bacterial effects with well-organized skin architecture demonstrating great healing signs. Our results revealed that m-PEG/PVP NFs mats loaded with GPS and TQ could be considered an optimal wound care dressing.Validating numerical models against experimental models of nasal spray deposition is challenging since many aspects must be considered. That being said, it is a critical step in the product development process of nasal spray devices. see more This work presents the validation process of a nasal deposition model, which demonstrates a high degree of consistency of the numerical model with experimental data when the nasal cavity is segmented into two regions but not into three. Furthermore, by modelling the flow as stationary, the computational cost is drastically reduced while maintaining quality of particle deposition results. Thanks to this reduction, a sensitivity analysis of the numerical model could be performed, consisting of 96 simulations. The objective was to quantify the impact of four inputs the spray half cone angle, mean spray exit velocity, breakup length from the nozzle exit and the diameter of the nozzle spray device, on the three quantities of interest the percentage of the accumulated number of particles deposited on the anterior, middle and posterior sections of the nasal cavity. The results of the sensitivity analysis demonstrated that the deposition on anterior and middle sections are sensitive to injection angle and breakup length, and the deposition on posterior section is only, but highly, sensitive to the injection velocity.Natural polysaccharides derived from medicinal plants, that are Dendrobium (DPS), Lycium barbarum (LBP), Ginseng (GPS), and Poria Cocos (PCP) were firstly combined with sodium alginate (SA) to construct microcapsules and improved the morphology, encapsulation efficiency, Biocompatibility and protective capability in drug loading. Diverse typical therapeutics, including VO2@ZIF67 nanoparticles, small molecule drugs salvianolic acid B (SaB)/ginsenoside (Rg1), probiotic Bacillus bifidus, and biomacromolecules SDF-1 were wrapped into 1.5 % GPS-0.5 % SA model microcapsules, respectively. Better mobility and formability were significantly observed, and showed 75 % survival rate of probiotics in simulated gastric juice and around 99 % encapsulation efficiency which is higher than single 2 % SA microcapsules. The microcapsules also obtained a delayed release and a higher cell index for SDF-1, which indicated better stability, biocompatibility and protective effect than single 2 % SA microcapsules. This study provides a strategy in developing plant derived polysaccharides as novel materials for the construction and improvement of traditional microcapsules.D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS)-modified carboxymethyl chitosan-rhein (TCR) polymeric micelles (PMs) self-assembled by TCR conjugate were constructed for oral delivery of paclitaxel (PTX). PTX-loaded TCR PMs with a drug loading capacity of 47.52 ± 1.65 % significantly improved the intestinal absorption and oral bioavailability of PTX. TCR PMs loaded with PTX displayed time- and concentration-dependent cytotoxicity in Caco-2, MCF-7 and Taxol-resistant MCF-7 (MCF-7/Taxol) cells. In MCF-7/Taxol cells, PTX-loaded TCR PMs promoted apoptosis and changed cell cycle, and TCR conjugate exhibited a P-gp inhibition ability and caused ATP depletion. Moreover, confocal imaging of intestinal sections, Caco-2 cell uptake assay and in vivo bioimaging using environmental response fluorescence probe suggested that TCR PMs loaded with drugs can be absorbed as a whole through the intestinal epithelium after oral administration, enter systemic circulation, and then get to the tumor site. Remarkably, PTX-loaded TCR PMs displayed a significant antitumor effect in H22 tumor xenograft mice and the MCF-7 or MCF-7/Taxol xenograft zebrafish model, which was related to the inhibitory function of TCR conjugate for P-gp activity and P-gp and MDR1 expression. Functionalized TCR PMs are expected to improve the oral therapeutic efficacy of poorly water-soluble antitumor drugs and treat drug-resistant tumors.Huntington's Disease (HD) is a devastating disorder characterized by a triad of motor, psychiatric and cognitive manifestations. Psychiatric and emotional symptoms appear at early stages of the disease which are consistently described by patients and caregivers among the most disabling. Here, we show for the first time that Foxp2 is strongly associated with some psychiatric-like disturbances in the R6/1 mouse model of HD. First, 4-week-old (juvenile) R6/1 mice behavioral phenotype was characterized by an increased impulsive-like behavior and less aggressive-like behavior. In this line, we identified an early striatal downregulation of Foxp2 protein starting as soon as at postnatal day 15 that could explain such deficiencies. Interestingly, the rescue of striatal Foxp2 levels from postnatal stages completely reverted the impulsivity-phenotype and partially the social impairments concomitant with a rescue of dendritic spine pathology. A mass spectrometry study indicated that the rescue of spine loss was associated with an improvement of several altered proteins related with cytoskeleton dynamics.