Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice.

Cognitive impairment, the most common and severe comorbidity of epilepsy, greatly diminishes the quality of life. However, current therapeutic interventions for epilepsy can also cause untoward cognitive effects. Thus, there is an urgent need for new kinds of agents targeting both seizures and cognition deficits. Oxidative stress is considered to play an important role in epileptogenesis and cognitive deficits, and antioxidants have a putative antiepileptic potential. Metformin, the most commonly prescribed antidiabetic oral drug, has antioxidant properties. This study was designed to evaluate the ameliorative effects of metformin on seizures, cognitive impairment and brain oxidative stress markers observed in pentylenetetrazole-induced kindling animals. Male C57BL/6 mice were administered with subconvulsive dose of pentylenetetrazole (37 mg/kg, i.p.) every other day for 14 injections. Metformin was injected intraperitoneally in dose of 200mg/kg along with alternate-day PTZ. We found that metformin suppressed the progression of kindling, ameliorated the cognitive impairment and decreased brain oxidative stress. Thus the present study concluded that metformin may be a potential agent for the treatment of epilepsy as well as a protective medicine against cognitive impairment induced by seizures.

Highly effective permeability and antifouling performances of polypropylene non-woven fabric membranes modified with graphene oxide by inkjet printing and immersion coating methods.

In the current study, graphene oxide (GO)-modified polypropylene non-woven fabric (PP-NWF) membranes were prepared via inkjet printing and immersion coating methods. Scanning electron microscopy, Fourier transform infrared spectroscopy, contact angle measurements, pure water permeation (JPWP) and protein adsorption were tested to evaluate the impact of the GO nanosheet on the characteristics and performance of modified PP-NWF membranes. The results showed that the exfoliated GO nanosheets uniformly deposited on the membrane surface and firmly embedded into the interlaced fibers, resulting in the improvement of membrane hydrophilicity, permeability and antifouling properties comparing with original PP-NWF membranes. The GO-printed and GO-coated membranes had 113 and 188% higher fluxes, and 70.95 and 75.74% lower protein adsorptions than the original PP-NWF membranes, respectively. After cross-linked treatment, ultrasound processing was conducted to evaluate the stability of the modified PP-NWF membranes. The results demonstrated that there was almost no decrease in permeation after ultrasonic treatment indicating that the cross-linking treatment could enhance the immobilization of the GO nanosheets on and into the modified membranes.

SRSF3/AMOTL1 splicing axis promotes the tumorigenesis of nasopharyngeal carcinoma through regulating the nucleus translocation of YAP1.

Dysregulation of serine/arginine splicing factors (SRSFs) and abnormal alternative splicing (AS) have been widely implicated in various cancers but scarcely investigated in nasopharyngeal carcinoma (NPC). Here we examine the expression of 12 classical SRSFs between 87 NPC and 10 control samples, revealing a significant upregulation of SRSF3 and its association with worse prognosis in NPC. Functional assays demonstrate that SRSF3 exerts an oncogenic function in NPC progression. Transcriptome analysis reveals 1,934 SRSF3-regulated AS events in genes related to cell cycle and mRNA metabolism. Among these events, we verify the generation of a long isoform of AMOTL1 (AMOTL1-L) through a direct bond of the SRSF3 RRM domain with the exon 12 of AMOTL1 to promote exon inclusion. Functional studies also reveal that AMOTL1-L promotes the proliferation and migration of NPC cells, while AMOTL1-S does not. Furthermore, overexpression of AMOTL1-L, but not -S, significantly rescues the inhibitory effects of SRSF3 knockdown. Additionally, compared with AMOTL1-S, AMOTL1-L has a localization preference in the intracellular than the cell membrane, leading to a more robust interaction with YAP1 to promote nucleus translocation. Our findings identify SRSF3/AMOTL1 as a novel alternative splicing axis with pivotal roles in NPC development, which could serve as promising prognostic biomarkers and therapeutic targets for NPC.

Wnt3a-Loaded Hydroxyapatite Nanowire@Mesoporous Silica Core-Shell Nanocomposite Promotes the Regeneration of Dentin-Pulp Complex via Angiogenesis, Oxidative Stress Resistance, and Odontogenic Induction of Stem Cells.

Pulp exposure often leads to pulp necrosis, root fractures, and ultimate tooth loss. The repair of the exposure site with pulp capping treatment is of great significance to preserving pulp vitality, but its efficacy is impaired by the low bioactivity of capping materials and cell injuries from the local accumulation of oxidative stress. This study develops a Wnt3a-loaded hydroxyapatite nanowire@mesoporous silica (Wnt3a-HANW@MpSi) core-shell nanocomposite for pulp capping treatments. The ultralong and highly flexible hydroxyapatite nanowires provide the framework for the composites, and the mesoporous silica shell endows the composite with the capacity of efficiently loading/releasing Wnt3a and Si ions. Under in vitro investigation, Wnt3a-HANW@MpSi not only promotes the oxidative stress resistance of dental pulp stem cells (DPSCs), enhances their migration and odontogenic differentiation, but also exhibits superior properties of angiogenesis in vitro. Revealed by the transcriptome analysis, the underlying mechanisms of odontogenic enhancement by Wnt3a-HANW@MpSi are closely related to multiple biological processes and signaling pathways toward pulp/dentin regeneration. Furthermore, an animal model of subcutaneous transplantation demonstrates the significant reinforcement of the formation of dentin-pulp complex-like tissues and blood vessels by Wnt3a-HANW@MpSi in vivo. These results indicate the promising potential of Wnt3a-HANW@MpSi in treatments of dental pulp exposure.

RNA-binding motif protein RBM47 promotes tumorigenesis in nasopharyngeal carcinoma through multiple pathways.

RNA binding motif proteins (RBMs) have been widely implicated in the tumorigenesis of multiple human cancers but scarcely studied in nasopharyngeal carcinoma (NPC). Here, we compare the mRNA levels of 29 RBMs between 87 NPC and 10 control samples. We find that RBM47 is frequently upregulated in NPC specimens, and its high expression is associated with the poor prognosis of patients with NPC. Biological experiments show that RBM47 plays an oncogenic role in NPC cells. Mechanically, RBM47 binds to the promoter and regulates the transcription of BCAT1, and its overexpression partially rescues the inhibitory effects of RBM47-knockdown on NPC cells. Moreover, transcriptome analysis reveals that RBM47 regulates alternative splicing of pre-mRNA, including those cancer-related, to a large extent in NPC cells. Furthermore, RBM47 binds to hnRNPM and cooperatively regulates multiple splicing events in NPC cells. In addition, we find that knockdown of hnRNPM inhibits proliferation and migration of NPC cells. Our study, taken together, shows that RBM47 promotes the progression of NPC through multiple pathways, acting as a transcriptional factor and a modulator of alternative splicing in cooperation with hnRNPM. Our study also highlights that RBM47 and hnRNPM could be prognostic factors and potential therapeutic targets for NPC.

RBFOX2/GOLIM4 Splicing Axis Activates Vesicular Transport Pathway to Promote Nasopharyngeal Carcinogenesis.

20-30% of patients with nasopharyngeal carcinoma (NPC) develop distant metastasis or recurrence leading to poor survival, of which the underlying key molecular events have yet to be addressed. Here alternative splicing events in 85 NPC samples are profiled using transcriptome analysis and it is revealed that the long isoform of GOLIM4 (-L) with exon-7 is highly expressed in NPC and associated with poor prognosis. Lines of evidence demonstrate the pro-tumorigenic function of GOLIM4-L in NPC cells. It is further revealed that RBFOX2 binds to a GGAA motif in exon-7 and promotes its inclusion forming GOLIM4-L. RBFOX2 knockdown suppresses the tumorigenesis of NPC cells, phenocopying GOLIM4-L knockdown, which is significantly rescued by GOLIM4-L overexpression. High expression of RBFOX2 is correlated with the exon-7 inclusion of GOLIM4 in NPC biopsies and associated with worse prognosis. It is observed that RBFOX2 and GOLIM4 can influence vesicle-mediated transport through maintaining the organization of Golgi apparatus. Finally, it is revealed that RAB26 interacts with GOLIM4 and mediates its tumorigenic potentials in NPC cells. Taken together, the findings provide insights into how alternative splicing contributes to NPC development, by highlighting a functional link between GOLIM4-L and its splicing regulator RBFOX2 activating vesicle-mediated transport involving RAB26.

Development of a real-time, high-frequency ultrasound digital beamformer for high-frequency linear array transducers.

A real-time digital beamformer for high-frequency (>20 MHz) linear ultrasonic arrays has been developed. The system can handle up to 64-element linear array transducers and excite 16 channels and receive simultaneously at 100 MHz sampling frequency with 8-bit precision. Radio frequency (RF) signals are digitized, delayed, and summed through a real-time digital beamformer, which is implemented using a field programmable gate array (FPGA). Using fractional delay filters, fine delays as small as 2 ns can be implemented. A frame rate of 30 frames per second is achieved. Wire phantom (20 microm tungsten) images were obtained and -6 dB axial and lateral widths were measured. The results showed that, using a 30 MHz, 48-element array with a pitch of 100 microm produced a -6 dB width of 68 microm in the axial and 370 microm in the lateral direction at 6.4 mm range. Images from an excised rabbit eye sample also were acquired, and fine anatomical structures, such as the cornea and lens, were resolved.

Effects of alpha-lipoic acid on spatial learning and memory, oxidative stress, and central cholinergic system in a rat model of vascular dementia.

Brain oxidative stress due to chronic cerebral hypoperfusion was considered to be the major risk factor in the pathogenesis of vascular dementia. In this study, we investigated the protective efficacy of alpha-lipoic acid, an antioxidant, against vascular dementia in rats, as well as the potential mechanism. Bilateral common carotid arteries occlusion (BCCAO) induced severe cognitive deficits tested by Morris water maze (MWM), along with oxidative stress and disturbance of central cholinergic system. However, administration of alpha-lipoic acid (50mg/kg, i.p.) for 28 days significantly restored cognitive deficits induced by BCCAO. Biochemical determination revealed that alpha-lipoic acid markedly decreased the production of malondialdehyde (MDA) and the generation of reactive oxidative species (ROS), and increased the level of reduced glutathione (GSH) in the hippocampal tissue. Additionally, alpha-lipoic acid raised the level of acetylcholine (ACh) and choline acetyltransferase (ChAT) and decreased the activity of acetycholinesterase (AChE) in the hippocampus. These results indicated that treatment with alpha-lipoic acid significantly improved behavioral alterations, protected against oxidative stress, and restored central cholinergic system in the rat model of vascular dementia induced by BCCAO.

Theoretical calculation and experimental study on the third-order nonlinearity parameter C/A for organic liquids and biological fluids.

In the present paper we deal with calculating and measuring the third-order nonlinearity parameter C/A for organic liquids and biological fluids. For the organic liquids, the second-order derivative of sound speed with respect to pressure at constant entropy is discussed in terms of thermodynamic parameters, and a formula for calculating C/A is established. Calculated results of C/A for various organic liquids demonstrate that omitting the second-order derivative of sound speed with respect to sound pressure in an isentropic process, could overestimate the value of C/A about 20%-30%. For measuring C/A, the finite-amplitude insert substitution technique is employed. A theoretical description of the sound pressure amplitude for the third-order harmonics is obtained using the perturbation method, in which the sound pressure amplitude of the third-order harmonics is shown approximately as a parabolic function of the propagation distance in the medium. By measuring and comparing the sound pressure amplitudes of the third-order harmonics when inserting a test sample, the reference liquid, and a comparative liquid, respectively, the value of C/A for the sample liquid is determined with reference to known C/A values of reference and comparative liquids. An experimental setup is developed, and the measured values of C/A for the organic liquids agree with the predicted ones calculated by the thermodynamic methods. Furthermore, the finite-amplitude method is extended to measure the C/A parameter for biological fluids, and the measured values of C/A for several biological fluids are also presented.