osmotic-pump-based-drug-delivery-for-vivo-remyelination-research-on

Osmotic Pump-based Drug-delivery for <em>In Vivo</em> Remyelination Research on the Central Nervous System

Demyelination has been identified in not only multiple sclerosis (MS), but also other central nervous system diseases such as Alzheimer's disease and ...

Third Military Medical University

Chongqing University

The purpose of this study was to prepare and evaluate a taste-masked berberine hydrochloride orally disintegrating tablet for enhanced patient compliance. Taste masking was performed by coating berberine hydrochloride with Eudragit E100 using a fluidized bed. It was found that microcapsules with a drug-polymer ratio of 1:0.8 masked the bitter taste obviously. The microcapsules were formulated to orally disintegrating tablets and the optimized tablets containing 6% (w/w) crospovidone XL and 15% (w/w) microcrystalline cellulose showed the fastest disintegration, within 25.5 s, and had a pleasant taste. The dissolution profiles revealed that the taste-masked orally disintegrating tablets released the drug faster than commercial tablets in the first 10 min. However, their dissolution profiles were very similar after 10 min. The prepared taste-masked tablets remained stable after 6 months of storage. The pharmacokinetics of the taste-masked and commercial tablets was evaluated in rabbits. The Cmax, Tmax, and AUC0-24 values were not significantly different from each other, suggesting that the taste-masked orally disintegrating tablets are bioequivalent to commercial tablets in rabbits. These tablets will enhance patient compliance by masking taste and improve patients' quality of life.

Preparation and evaluation of orally disintegrating tablets containing taste-masked microcapsules of berberine hydrochloride.

Aggressive NK-cell leukemia (ANKL) is a rare form of NK cell neoplasm that is more prevalent among people from Asia and Central and South America. Patients usually die within days to months, even after receiving prompt therapeutic management. Here we performed the first comprehensive study of ANKL by integrating whole genome, transcriptome and targeted sequencing, cytokine array as well as functional assays. Mutations in the JAK-STAT pathway were identified in 48% (14/29) of ANKL patients, while the extracellular STAT3 stimulator IL10 was elevated by an average of 56-fold (P < 0.0001) in the plasma of all patients examined. Additional frequently mutated genes included TP53 (34%), TET2 (28%), CREBBP (21%) and MLL2 (21%). Patient NK leukemia cells showed prominent activation of STAT3 phosphorylation, MYC expression and transcriptional activities in multiple metabolic pathways. Functionally, STAT3 activation and MYC expression were critical for the proliferation and survival of ANKL cells. STAT signaling regulated the MYC transcription program, and both STAT signaling and MYC transcription were required to maintain the activation of nucleotide synthesis and glycolysis. Collectively, the JAK-STAT pathway represents a major target for genomic alterations and IL10 stimulation in ANKL. This newly discovered JAK/STAT-MYC-biosynthesis axis may provide opportunities for the development of novel therapeutic strategies in treating this subtype of leukemia.

Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia.

As documented in our previous study, notoginsenoside R1 (NGR1) can inhibit neuron apoptosis and the expression of endoplasmic reticulum (ER) stress-associated pro-apoptotic proteins in hypoxic-ischemic encephalopathy. Recent evidence indicates that the Phospholipase C (PLC)/inositol 1,4,5-trisphosphate receptor (IP3R) is important for the regulation of Ca release in the ER. Ca imbalance can stimulate ER stress, CAMKII, and cell apoptosis. The purpose of this study was to further investigate the neuroprotective effect of NGR1 and elucidate how NGR1 regulates ER stress and cell apoptosis in the oxygen-glucose deprivation/reoxygenation (OGD/R) model. Cells were exposed to NGR1 or the PLC activator m-3M3FBS. Then, IP3R- and IP3-induced Ca release (IICR) and activation of the ER stress and CaMKII signal pathway were measured. The results showed that NGR1 inhibited IICR and strengthened the binding of GRP78 with PERK and IRE1. NGR1 also alleviated the activation of the CaMKII pathway. Pretreatment with m-3M3FBS attenuated the neuroprotective effect of NGR1; IICR was activated, activation of the ER stress and CaMKII pathway was increased, and more cells were injured. These results indicate that NGR1 may suppress activation of the PLC/IP3R pathway, subsequently inhibiting ER Ca release, ER stress, and CaMKII and resulting in suppressed cell apoptosis.

Xuelian Hu

Third Military Medical University

Osmotic Pump-based Drug-delivery for In Vivo Remyelination Research on the Central Nervous System