Interaction of the C9orf72-Amyotrophic Lateral Sclerosis-Related Proline-Arginine Dipeptide Repeat Protein with the RNA-Binding Protein NOVA1 Causes Decreased Expression of UNC13A Due to Enhanced Inclusion of Cryptic Exons, Which Is Reversed by Betulin Treatment.

C9orf72 mutations are the most common form of familial amyotrophic lateral sclerosis (C9-ALS). It causes the production of proline-arginine dipeptide repeat proteins (PR-DPRs) in motor neurons (MNs), leading to the molecular pathology characteristic of ALS. UNC13A is critical for maintaining the synaptic function of MNs. Most ALS patients have nuclear deletion of the splicing repressor TDP-43 in MNs, which causes inclusion of the cryptic exon (CE) of UNC13A mRNA, resulting in nonsense-mediated mRNA decay and reduced protein expression. Therefore, in this study, we explored the role of PR-DPR in CE inclusion of UNC13A mRNA. Our results showed that PR-DPR (PR50) induced CE inclusion and decreased the protein expression of UNC13A in human neuronal cell lines. We also identified an interaction between the RNA-binding protein NOVA1 and PR50 by yeast two-hybrid screening. NOVA1 expression is known to be reduced in patients with ALS. We found that knockdown of NOVA1 enhanced CE inclusion of UNC13A mRNA. Furthermore, the naturally occurring triterpene betulin can inhibit the interaction between NOVA1 and PR50, thus preventing CE inclusion of UNC13A mRNA and protein reduction in human neuronal cell lines. This study linked PR-DPR with CE inclusion of UNC13A mRNA and developed candidate therapeutic strategies for C9-ALS using betulin.

Syringin Prevents 6-Hydroxydopamine Neurotoxicity by Mediating the MiR-34a/SIRT1/Beclin-1 Pathway and Activating Autophagy in SH-SY5Y Cells and the Caenorhabditis elegans Model.

Defective autophagy is one of the cellular hallmarks of Parkinson's disease (PD). Therefore, a therapeutic strategy could be a modest enhancement of autophagic activity in dopamine (DA) neurons to deal with the clearance of damaged mitochondria and abnormal protein aggregates. Syringin (SRG) is a phenolic glycoside derived from the root of Acanthopanax senticosus. It has antioxidant, anti-apoptotic, and anti-inflammatory properties. However, whether it has a preventive effect on PD remains unclear. The present study found that SRG reversed the increase in intracellular ROS-caused apoptosis in SH-SY5Y cells induced by neurotoxin 6-OHDA exposure. Likewise, in C. elegans, degeneration of DA neurons, DA-related food-sensitive behaviors, longevity, and accumulation of α-synuclein were also improved. Studies of neuroprotective mechanisms have shown that SRG can reverse the suppressed expression of SIRT1, Beclin-1, and other autophagy markers in 6-OHDA-exposed cells. Thus, these enhanced the formation of autophagic vacuoles and autophagy activity. This protective effect can be blocked by pretreatment with wortmannin (an autophagosome formation blocker) and bafilomycin A1 (an autophagosome-lysosome fusion blocker). In addition, 6-OHDA increases the acetylation of Beclin-1, leading to its inactivation. SRG can induce the expression of SIRT1 and promote the deacetylation of Beclin-1. Finally, we found that SRG reduced the 6-OHDA-induced expression of miR-34a targeting SIRT1. The overexpression of miR-34a mimic abolishes the neuroprotective ability of SRG. In conclusion, SRG induces autophagy via partially regulating the miR-34a/SIRT1/Beclin-1 axis to prevent 6-OHDA-induced apoptosis and α-synuclein accumulation. SRG has the opportunity to be established as a candidate agent for the prevention and cure of PD.

A Single Center Observational Study of Spirometry Assessments in Children with Congenital Heart Disease after Surgery.

Background: Children with congenital heart disease (CHD) have impaired pulmonary function both before and after surgery; therefore, pulmonary function assessments are important and should be performed both before and after open-heart surgery. This study aimed to compare pulmonary function between variant pediatric CHD types after open-heart surgery via spirometry. Methods: In this retrospective study, the data for forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and the ratio between FEV1 and FVC (FEV1/FVC) were collected from patients with CHD who underwent conventional spirometry between 2015 and 2017. Results: A total of 86 patients (55 males and 31 females, with a mean age of 13.24 ± 3.32 years) were enrolled in our study. The diagnosis of CHD included 27.9% with atrial septal defects, 19.8% with ventricular septal defects, 26.7% with tetralogy of Fallot, 7.0% with transposition of the great arteries, and 46.5% with other diagnoses. Abnormal lung function was identified by spirometry assessments after surgery. Spirometry was abnormal in 54.70% of patients: obstructive type in 29.06% of patients, restrictive type in 19.76% of patients, and mixed type in 5.81% of patients. More abnormal findings were found in patients who received the Fontan procedure (80.00% vs. 35.80%, p = 0.048). Conclusions: Developing novel therapies to optimize pulmonary function will be critical for improving clinical outcomes.

Interaction of a Novel Alternatively Spliced Variant of HSD11B1L with Parkin Enhances the Carcinogenesis Potential of Glioblastoma: Peiminine Interferes with This Interaction.

Glioblastoma (GBM) is a primary brain tumor of unknown etiology. It is extremely aggressive, incurable and has a short average survival time for patients. Therefore, understanding the precise molecular mechanisms of this diseases is essential to establish effective treatments. In this study, we cloned and sequenced a splice variant of the hydroxysteroid 11-ß dehydrogenase 1 like gene (HSD11B1L) and named it HSD11B1L-181. HSD11 B1L-181 was specifically expressed only in GBM cells. Overexpression of this variant can significantly promote the proliferation, migration and invasion of GBM cells. Knockdown of HSD11B1L-181 expression inhibited the oncogenic potential of GBM cells. Furthermore, we identified the direct interaction of parkin with HSD11B1L-181 by screening the GBM cDNA expression library via yeast two-hybrid. Parkin is an RBR E3 ubiquitin ligase whose mutations are associated with tumorigenesis. Small interfering RNA treatment of parkin enhanced the proliferative, migratory and invasive abilities of GBM. Finally, we found that the alkaloid peiminine from the bulbs of Fritillaria thunbergii Miq blocks the interaction between HSD11B1L-181 and parkin, thereby lessening carcinogenesis of GBM. We further confirmed the potential of peiminine to prevent GBM in cellular, ectopic and orthotopic xenograft mouse models. Taken together, these findings not only provide insight into GBM, but also present an opportunity for future GBM treatment.

Polysomnography Is an Important Method for Diagnosing Pediatric Sleep Problems: Experience of One Children's Hospital.

In this study, we collected and analyzed polysomnography (PSG) data to investigate the value of PSG in diagnosing sleep problems in children. The results of PSG studies of children (<18 years old) with sleep problems conducted from April 2015 to May 2017 at a children's hospital in Taiwan were collected and analyzed retrospectively. Data for 310 patients (209 males and 101 females) who underwent PSG were collected. The final diagnoses were as follows: obstructive sleep apnea in 159 (51.3%), snoring in 81 (26.4%), limb movement sleep disorder in 25 (8.1%), hypersomnias in 12 (3.9%), central apnea in 8 (2.9%), enuresis in 7 (2.3%), bruxism in 5 (1.6%), sleep terrors in 5 (1.6%), narcolepsy in 3 (1.0%), sleep seizures in 3 (1.0%), sleep walking in 1 (0.3%), and insomnia in 1 (0.3%). PSG may help detect significant sleep-related problems in children and is useful for making therapeutic decisions regarding children. Obstructive sleep apnea syndrome (OSAS) was the primary sleep problem for most of the children (51.3%); however, only 7.4% of them underwent surgery for OSAS. We therefore suggest that children with sleep problems should undergo PSG.