Delivery of Exogenous miR-124 to Glioblastoma Multiform Cells by Wharton’s Jelly Mesenchymal Stem Cells Decreases Cell Proliferation and Migration,and Confers Chemosensitivity

MicroRNAs (miRs) are potential therapeutic targets in glioblastoma multiforme (GBM), but the difficulties associated with their delivery to tumor target cells have hampered their widespread use. Mesenchymal stem cells (MSCs) can migrate to the sites of cancers, including GBM and exert anti-tumor effects. In this study, it is shown that Wharton’s jelly-MSCs (WJ-MSCs) have the ability to deliver exogenous miRs to GBM cells and the functional impact of this delivery is characterized. It is found that the labeled miR-124, as an example for miR of interest, can be successfully delivered with WJ-MSCs to U87 GBM cells via dependent or exosome-independent processes. It is demonstrated that the delivered exogenous miR-124 significantly decreases the luciferase activity of the target gene CDK6. In addition, the delivered miR-124 enhances the chemosensitivity of GBM cells to temozolomide and decreases the migration of GBM cells. These results suggest that the use of exogenous miRNA delivery with the derived exosomes from WJ-MSCs may provide a novel approach for miRNA replacement therapy in GBM cancers.     

Zinc Protoporphyrin Polymeric Nanoparticles: Potent Heme Oxygenase Inhibitor for Cancer Therapy

Purpose

Oxidation therapy is an antitumor strategy in which, apoptosis or necrosis is caused by either excess delivery of reactive oxygen species (ROS) as an oxidant or anti-oxidant inhibition. Heme oxygenase (HO) is an anti-oxidant enzyme that plays an important role in cell growth and proliferation. The purpose of this study was to prepare poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) loaded with zinc protoporphyrin (ZnPP) to deliver the HO inhibitor into tumor.

Methods

PLGA NPs were prepared using nanoprecipitation technique and their characteristics were optimized by Box-Behnken experimental design. Scanning electron microscopy and in vitro studies consisting of drug release, HO inhibitory effect, cytotoxicity and cellular uptake followed by in vivo biodistribution and blood cytotoxicity were carried out. Internalization of coumerin-6 loaded NPs by PC3 cells was visualized by confocal laser scanning microscopy beside quantitatively analysis.

Results

NPs average size, entrapment efficiency and drug loading were 100.12?±?5.345 nm, 55.6%?±?2.49 and 7.98%?±?0.341 respectively. Equal HO inhibitory effect of NPs compared to free ZnPP was observed. The IC₅₀ value of ZnPP-NPs for PC3 human prostate cancer cells was found to be 2.14?±?0.083 μM.

Conclusion

In conclusion, ZnPP loaded PLGA NPs could exhibit enough HO inhibitory effect against cancer cells to be considered as a promising candidate for cancer treatment investigation.     

Grafted human chorionic stem cells restore motor function and preclude cerebellar neurodegeneration in rat model of cerebellar ataxia

Metabolic Brain Disease - Cerebellar ataxia (CA) is a form of ataxia that adversely affects the cerebellum. Cell replacement therapy (CRT) has been considered as a potential treatment for...     

CD44‐Targeted Docetaxel Conjugate for Cancer Cells and Cancer Stem‐Like Cells: A Novel Hyaluronic Acid‐Based Drug Delivery System

A CD44‐targeted macromolecular conjugate of docetaxel was prepared via a pH‐sensitive linkage to hyaluronic acid and was characterized using NMR, gel permeation chromatography, and differential scanning calorimetry. The conjugated species were further evaluated in terms of drug release, cytotoxicity, cellular uptake, cell cycle inhibition, and subacute toxicity in mice. Cellular microscopic studies revealed that CD44‐expressing cells including MCF‐7 cancer stem cells and MDA‐MB‐231 metastatic breast cancer cells had internalized the conjugates via a selective receptor‐mediated mechanism, leading to cell cycle arrest in the G2/M phase. Hyaluronic acid–docetaxel conjugates showed specific toxicity only in CD44‐expressing cells in vitro, along with a decreased risk of neutropenia and dose‐dependent mortality in vivo. Hyaluronic acid–drug conjugates represent a promising and efficient platform for solubilization of sparingly soluble molecules as well as active and selective targeted delivery to cancer cells and cancer stem cells.     

Effect of chronic lithium administration on endothelium-dependent relaxation in rat aorta

1. The effects of chronic lithium administration on the relaxant responses of rat thoracic aortic rings in the presence of indomethacin (a cyclo-oxygenase inhibitor) and/or NG-nitro-L-arginine (L-NOARG; a nitric oxide synthase inhibitor) to acetylcholine (ACh) or sodium nitroprusside were investigated in the present study. 2. Acetylcholine produced a concentration-dependent relaxation in vessels precontracted by phenylephrine (PE), while in lithium-treated rats the maximal relaxation was significantly increased. 3. Indomethacin (20 mumol/L) significantly potentiated the ACh-induced relaxation in lithium-treated and control rats. 4. NG-Nitro-L-arginine (1 mumol/L) decreased the ACh-induced relaxation in both control and lithium-treated rats. In contrast, indomethacin (20 mumol/L) reversed the inhibitory effect of L-NOARG. 5. Sodium nitroprusside produced similar concentration-dependent relaxations of vessels from both control and lithium-treated rats, which was not affected by indomethacin. In endothelium-denuded rings, indomethacin (20 mumol/L) caused a rightward shift in the concentration-contraction curve to PE. 6. These data support evidence for a possible increase in endothelium-dependent relaxation induced by ACh during long-term administration of lithium in rat aortic rings.     

Neural correlates of auditory repetition priming: reduced fMRI activation in the auditory cortex

Repetition priming refers to enhanced or biased performance with repeatedly presented stimuli. Modality-specific perceptual repetition priming has been demonstrated behaviorally for both visually and auditorily presented stimuli. In functional neuroimaging studies, repetition of visual stimuli has resulted in reduced activation in the visual cortex, as well as in multimodal frontal and temporal regions. The reductions in sensory cortices are thought to reflect plasticity in modality-specific neocortex. Unexpectedly, repetition of auditory stimuli has resulted in reduced activation in multimodal and visual regions, but not in the auditory temporal lobe cortex. This finding puts the coupling of perceptual priming and modality-specific cortical plasticity into question. Here, functional magnetic resonance imaging was used with environmental sounds to reexamine whether auditory priming is associated with reduced activation in the auditory cortex. Participants heard environmental sounds (e.g., animals, machines, musical instruments, etc.) in blocks, alternating between initial and repeated presentations, and decided whether or not each sound was produced by an animal. Repeated versus initial presentations of sounds resulted in repetition priming (faster responses) and reduced activation in the right superior temporal gyrus, bilateral superior temporal sulci, and right inferior prefrontal cortex. The magnitude of behavioral priming correlated positively with reduced activation in these regions. This indicates that priming for environmental sounds is associated with modification of neural activation in modality-specific auditory cortex, as well as in multimodal areas.     

Synthesis and antihypertensive activity of 1-(2-thiazolyl)-3, 5-disubstituted -2-pyrazolines

Several substituted 3-aryl-1-(4-aryl-2-thiazolyl)-5-(3-pyridyl)-2-pyrazolines were synthesized by reacting substituted 3-aryl-5-(3-pyridyl)-1-thiocarbamoyl-2-pyrazolines with phenacyl bromide in ethanol. The structures of all compounds were confirmed by IR, (1)H-NMR, mass spectral data and elemental analyses. The antihypertensive activity of compounds was examined by the tail-cuff method and compared with clonidine. Compounds 24-28 showed significant antihypertensive activity.