Dioscin Protects against Aß1-42 Oligomers-Induced Neurotoxicity via the Function of SIRT3 and Autophagy.

Alzheimer's disease (AD) is a common neurodegenerative disease with high incidence among old people. Dioscin is a product extracted from natural herbs, which has multiple pharmacological activities. In this study, we investigated the potential effects of disocin on amyloid-ß peptide (Aß1-42) oligomers-treated HT22 cells. Aß1-42 oligomers induced great neurotoxicity to HT22 cells as examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results of terminal deoxynucleoitidyl transferase-mediated deoxyuridine triphosphate biotin nich end labeling (TUNEL) staining and flow cytometry indicated that Aß1-42 oligomers led to increased apoptosis and generation of reactive oxygen species (ROS) in HT22 cells. However, dioscin could remarkably inhibit the neurotoxicity induced by Aß1-42 oligomers, as well as decrease the apoptosis and ROS generation. Sirtuin-3 (SIRT3) staining and quantification indicated that dioscin upregulated the expression of neuroprotective SIRT3. Moreover, dioscin induced the formation of autophagosomes and autolysosomes in HT22 cells. Dioscin also enhanced the levels of Beclin-1 and LC3-II while decreased the level of p62. These results suggested that dioscin could activate autophagy in HT22 cells. It was also found that knocking down SIRT3 resulted in the downregulation of Beclin-1, LC3-II and the aggregation of p62, suggesting that SIRT3 was an important regulator in autophagy. Furthermore, we found that knocking down SIRT3 or inhibiting autophagy suppressed the protective effects of dioscin on Aß1-42 oligomers-induced neurotoxicity, apoptosis and ROS generation. These results revealed that SIRT3 and autophagy functioned together in the neuroprotective mechanisms of dioscin. Therefore, dioscin might be a promising drug to protect against Aß1-42 oligomers-induced neurotoxicity and reduce neuron damage or death in AD.

Functional Connectivity Alterations in Children with Spastic and Dyskinetic Cerebral Palsy.

Cerebral palsy (CP) has long been investigated to be associated with a range of motor and cognitive dysfunction. As the two most common CP subtypes, spastic cerebral palsy (SCP) and dyskinetic cerebral palsy (DCP) may share common and distinct elements in their pathophysiology. However, the common and distinct dysfunctional characteristics between SCP and DCP on the brain network level are less known. This study aims to detect the alteration of brain functional connectivity in children with SCP and DCP based on resting-state functional MRI (fMRI). Resting-state networks (RSNs) were established based on the independent component analysis (ICA), and the functional network connectivity (FNC) was performed on the fMRI data from 16 DCP, 18 bilateral SCP, and 18 healthy children. Compared with healthy controls, altered functional connectivity within the cerebellum network, sensorimotor network (SMN), left frontoparietal network (LFPN), and salience network (SN) were found in DCP and SCP groups. Furthermore, the disconnections of the FNC consistently focused on the visual pathway; covariance of the default mode network (DMN) with other networks was observed both in DCP and SCP groups, while the DCP group had a distinct connectivity abnormality in motor pathway and self-referential processing-related connections. Correlations between the functional disconnection and the motor-related clinical measurement in children with CP were also found. These findings indicate functional connectivity impairment and altered integration widely exist in children with CP, suggesting that the abnormal functional connectivity is a pathophysiological mechanism of motor and cognitive dysfunction of CP.

PKS5 Confers Cold Tolerance by Controlling Stomatal Movement and Regulating Cold-Responsive Genes in Arabidopsis.

Cold stress limits plant growth and development; however, the precise mechanisms underpinning plant acclimation to cold stress remain largely unknown. In this study, the Ser/Thr protein kinase SOS2-LIKE PROTEIN KINASE5 (PKS5) was shown to play a positive role in plant responses to cold stress. A PKS5 loss-of-function mutant (pks5-1) exhibited elevated sensitivity to cold stress, as well as a lower survival rate and increased ion leakage. Conversely, PKS5 gain-of-function mutants (pks5-3, pks5-4) were more tolerant to cold stress and exhibited higher survival rates and decreased ion leakage. Stomatal aperture analysis revealed that stomatal closure was slower during the first 25 min after cold exposure in pks5-1 compared to wild-type, whereas pks5-3 and pks5-4 displayed accelerated stomatal closure over the same time period. Further stomatal aperture analysis under an abscisic acid (ABA) treatment showed slower closure in pks5-1 and more rapid closure in pks5-3 and pks5-4. Finally, expression levels of cold-responsive genes were regulated by PKS5 under cold stress conditions, while cold stress and ABA treatment can regulate PKS5 expression. Taken together, these results suggest that PKS5 plays a positive role in short-term plant acclimation to cold stress by regulating stomatal aperture, possibly via ABA pathways, and in long-term acclimation by regulating cold-responsive genes.

Evaluation of Multilevel Surgeries in Children With Spastic Cerebral Palsy Based on Surface Electromyography.

The root mean square (RMS) of the surface electromyography (sEMG) signal can respond to neuromuscular function, which displays a positive correlation with muscle force and muscle tension under positive and passive conditions, respectively. The purpose of this study was to investigate the changes in muscle force and tension after multilevel surgical treatments, functional selective posterior rhizotomy (FSPR) and tibial anterior muscle transfer surgery, and evaluate their clinical effect in children with spastic cerebral palsy (SCP) during walking. Children with diplegia (n = 13) and hemiplegia (n = 3) with ages from 4 to 18 years participated in this study. They were requested to walk barefoot at a self-selected speed on a 15-m-long lane. The patient's joints' range of motion (ROM) and sEMG signal of six major muscles were assessed before and after the multilevel surgeries. The gait cycle was divided into seven phases, and muscle activation state can be divided into positive and passive conditions during gait cycle. For each phase, the RMS of the sEMG signal amplitude was calculated and also normalized by a linear envelope (10-ms running RMS window). The muscle tension of the gastrocnemius decreased significantly during the loading response, initial swing, and terminal swing (p < 0.05), which helped the knee joint to get the maximum extension when the heel is on the ground and made the heel land smoothly. The muscle force of the gastrocnemius increased significantly (p < 0.05) during the mid-stance, terminal stance, and pre-swing, which could generate the driving force for the human body to move forward. The muscle tension of the biceps femoris and semitendinosus decreased significantly (p < 0.05) during the terminal stance, pre-swing, and initial swing. The decreased muscle tension could relieve the burden of the knee flexion when the knee joint was passively flexed. At the terminal swing, the muscle force of the tibial anterior increased significantly (p < 0.05), which could improve the ankle dorsiflexion ability and prevent foot drop and push forward. Thus, the neuromuscular function of cerebral palsy during walking can be evaluated by the muscle activation state and the RMS of the sEMG signal, which showed that multilevel surgical treatments are feasible and effective to treat SCP.

miR-143-3p inhibition promotes neuronal survival in an Alzheimer's disease cell model by targeting neuregulin-1.

INTRODUCTION: Alzheimer's disease (AD) is still the fifth leading cause of death and most common dementia worldwide. To date, there is no efficient strategy that can slow down the progression of AD owing to delayed diagnosis and limited therapies. MiR-143-3p is up-regulated in serum of AD patients, yet the exact role it plays in AD pathology is still poorly understood. The aim of this study was to investigate the effect of miR-143-3p on neuronal survival. MATERIAL AND METHODS: We induced neuronal differentiation in SH-SY5Y cells using all-trans-retinoic acid (RA), and Aß1-42 was used to establish the in vitro AD cell model. The expression of tubulin ß III and neuregulin-1 (NRG1) was evaluated by immunofluorescence. TUNEL assay was performed to assess cell apoptosis. Cell viability was evaluated using the Cell Counting Kit-8 assay. The binding interaction between miR-143-3p and NRG1 was verified using the luciferase reporter assay. RESULTS: Typical neuronal-like axons were observed in RA-induced SH-SY5Y cells, followed by increased tubulin ß III. A dramatically increased apoptotic rate and reduced cell viability were observed in the AD cell model. Then we silenced the miR-143-3p expression, and Aß1-42 induced cell apoptosis was alleviated after miR-143-3p inhibition, accompanied by decreased cleaved caspase-3 and cleaved caspase-9 levels. Additionally, NRG1 was confirmed to be a downstream target of miR-143-3p, increased cell viability and suppressed cell apoptosis after miR-143-3p inhibition was abolished by NRG1 knockdown. CONCLUSIONS: Our findings reveal that miR-143-3p inhibition promotes neuronal survival in an in vitro cell model via targeting NRG1, and the miR-143-3p/NRG1 axis is a potential therapeutic target and promising biomarker for AD treatment.

Orientin Improves Cognition by Enhancing Autophagosome Clearance in an Alzheimer's Mouse Model.

Alzheimer's disease (AD) is the most common cause of dementia and is characterized by the presence of ß-amyloid (Aß) plaques and defective autophagy in the brain, which is believed to cause neuronal dysfunction. By using APP/PS1 transgenic AD mice, we investigated the influence of orientin (Ori) on cognitive function and its underlying mechanisms in AD models. Our data indicated that Ori improved spatial learning and memory in APP/PS1 mice, possibly through decreasing brain Aß deposition and attenuating autophagy impairment. Ori decreased the LC3-II/I ratio, p62 and cathepsin D (Ctsd) protein levels and the number of autolysosomes, whereas the protein levels of Ulk1 and Beclin-1 were no different between the control and treatment groups, indicating increased autolysosome clearance and thus a decreased Aß burden in the brain. Our results showed that Ori could enhance autolysosome clearance, decrease brain Aß deposition and improve learning and memory in AD mice.

Aberrant Interhemispheric Functional Organization in Children with Dyskinetic Cerebral Palsy.

BACKGROUND: Hemispheric asymmetry is one fundamental principle of neuronal organization. Interhemispheric connectivity and lateralization of intrinsic networks in the resting-state brain demonstrate the interhemispheric functional organization and can be affected by disease processes. This study aims to investigate the interhemispheric organization in children with dyskinetic cerebral palsy (DCP) based on resting-state functional MRI (fMRI). METHODS: 24 children with DCP and 20 healthy children were included. Voxel-mirrored homotopic connectivity (VMHC) was calculated to detect the interhemispheric connectivity, and the lateralization of the resting-state networks was performed to examine the asymmetry of the intrinsic networks of brain. RESULTS: Decreased interhemispheric connectivity was found at visual, motor, and motor-control related regions in children with DCP, while high cognitive related networks including the central executive network, the frontoparietal network, and the salience network represented decreased asymmetry in children with DCP. Abnormal VMHC in visual areas, as well as the altered lateralization in inferior parietal lobule and supplementary motor area, showed correlation with the gross motor function and activities of daily living in children with DCP. CONCLUSION: These findings indicate that the interhemispheric functional organization alteration exists in children with DCP, suggesting that abnormal interhemispheric interaction may be a pathophysiological mechanism of motor and cognitive dysfunction of CP.

Characterization of Engineered Scaffolds with Spatial Prevascularized Networks for Bulk Tissue Regeneration.

Despite significant progress in the fabrication of prevascularized networks over the past decade, a number of challenges remain. One of the most relevant issues is the lack of three-dimensional (3D) structures, which limits the clinical applications of the engineered scaffolds. Another problem is the complexity of prevascularized networks in engineered scaffolds, which is still less than that of human tissues, especially in the case of mature and bulk tissues. Thus, there is still the need to develop more flexible methods to better simulate the structure of natural tissues. In this work, we used a versatile sacrificial template method to fabricate bulk scaffolds with spatial prevascularized networks. Soft poly(vinyl alcohol) (PVA) filaments were used to print the sacrificial template, and the receiving platform was a stepped shaft, allowing the sacrificial template to have a complex 3D structure. The obtained template was embedded into gelatin and microbial transglutaminase (mTG). The inner PVA template could be extracted from the enzymatic cross-linking system, and an engineered scaffold with spatial prevascularized networks was obtained. In vitro experiments demonstrated that the fabrication process is biocompatible with cells.

Evaluation of the efficacy of cervical perivascular sympathectomy on drooling in children with athetoid cerebral palsy.

OBJECTIVE: To evaluate the efficacy of cervical perivascular sympathectomy (CPVS) for drooling in children with athetoid cerebral palsy (ACP). METHODS: The severity and frequency of drooling and the amount of salivation of 32 ACP children with drooling were evaluated before CPVS and at 4th, 12th and 24 weeks postoperatively by the teacher drooling scale (TDS) and salivary flow rate (SFR). RESULTS: Fifteen children exhibited improvements on drooling according to the TDS score at 4th week after surgery (P < 0.05). Later, the number of children decreased to 10 at 12th week (P < 0.05) and to 8 at 24 week after surgery (P < 0.05). SFR was 0.67 mg/min at baseline, which decreased to 0.58 mg/min (P < 0.05) at 4th week after surgery. However, SFR showed a gradual increase at 12th week and 24 week with no significant difference. CONCLUSIONS: Although CPVS was effective in improving drooling in some children with ACP, the results were not satisfactory. Thus, CPVS still needs to be cautiously used. Furthermore, more rigorous clinical studies should be performed to detect the effectiveness and safety of this procedure.